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Synthesis, Molecular Docking and DFT Studies on Biologically Active 1,4-Disubstituted-1,2,3-Triazoles-Semicarbazone Hybrid Molecules
Abstract
Some biologically active semicarbazone-triazole hybrid molecules have been designed and synthesized from semicarbazone linked terminal alkyne and aromatic azides via Cu(I)-catalyzed cycloaddition reaction. All newly synthesized compounds were successfully characterized by IR, 1H-NMR, 13C-NMR, and HRMS spectral techniques. The synthesized molecules were screened in vitro for anti-bactericidal property on E. coli (MTCC 16521), B. subtilis (MTCC441), S. Aureus (MTCC 3160), P. aeruginosa (MTCC 424) and S. epidermidis (MTCC 6880). The antibacterial property results revealed that the semicarbazone-triazoles hybrid molecules (9b, 9e, and 9f) are better alternative to the existing antibacterial drug ciprofloxacin. The docking study on most active compound 9b and its alkyne precursor 8 of DNA Gyrase enzyme of E. coli bacteria supported the biological activity results.
... A combination of two or more pharmacophores or synthesis of hybrid compounds constituting two or more bioactive entities could be a viable solution to fight multidrug resistant bacteria [6]. Hybrid drugs can extend the spectrum of biological activity, enhance the potency, overcome drug resistance, reduce side effects, and improve pharmacokinetic, pharmacodynamic as well as physicochemical profiles [7][8][9][10][11]. Hybridization of 1,2,3-triazole with other antibacterial pharmacophores appears to be a judicious strategy to develop novel effective candidates to combat the drug-sensitive and drug-resistant infectious diseases [12,13]. ...
... Eleven primary amines were subjected to reaction with 2-((1-phenyl-1H-1,2,3-triazol-4 yl)methoxy)benzaldehyde (5) in the presence of glacial acetic acid as a catalyst and provided the corresponding hybrids of 1,2,3-triazole and Schiff bases (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) as coloured solids in 70 -82% yield (Scheme 2). They were further dissolved in ethanol/diethyl ether for purification and crystallization. ...
... The 1 H NMR spectra of compounds (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) showed characteristic signals of the protons corresponding to the imine moiety between 9.01 ppm and 8.77 ppm and the 1,2,3-triazole group between 8.91 ppm and 7.89 ppm. The appearance of characteristic high field singlet signal between 5.44 ppm and 5.21 ppm was attributed to the methylene protons attached to the phenolic and 1,2,3-triazole groups. ...
Hybrid drugs help combat antibacterial drug resistance, which is an increasing problem globally. In addition to saving time and money, hybrid drugs offer multiple benefits. Using the triazole precursor compound 5 in conjunction with primary amines, a series of novel 1,2,3-triazole and Schiff base compounds were synthesized (6-16). Their chemical structures were characterized using 1H NMR, 13C NMR, FTIR, CHN-elemental, high-resolution mass spectrometry and SC-XRD analyses. All the compounds showed good antibacterial activities against twelve bacterial strains at different concentrations. From the minimum inhibitory concentration and cytotoxicity studies, compounds 7, 9, 10, 11, 12 and 15 were selected as the most potent potential drug candidates against Mycobacterium smegmatis, Proteus mirabilis, Escherichia coli and Klebsiella pneumonia. Molecular docking studies of the most active compounds …
... Five-membered 1,2,3-triazoles are considered to be an important class of biologically active units. 1 1,2,3-Triazoles possess significant chemical properties such as aromatic stability, resistance to acid−base hydrolysis, high dipole moment, and the ability to form H-bonds. 2,3 Triazoles have been used as precursors in the synthesis of various pharmaceutical drugs of medicinal use, and they also play important roles in organic synthetic chemistry. 1,2,3-Triazoles exhibit peculiar biological properties such as antibacterial, 4−6 antitubercular, 4 anti-inflammatory, 4 antifungal, 7,8 antiallergic, 9 and anticancer properties. 2,4,10−12 The triazole moiety readily associates with biological targets such as DNA via H-bonds and other noncovalent interactions, improving solubility and metabolic stability. ...
... The infrared spectrum showed characteristic absorption peaks at 1448, 1240, and 3142 cm −1 corresponding to NN aromatic, cyclic N−NN, and C−H proton, indicating formation of the 1,2,3-triazole ring. 8,34 In the UV−vis spectrum, compound 6a showed a characteristic broad spectrum with maxima at around 330 nm, which could be attributed to the π−π* transitions of the 2-HBT skeleton. Finally, the structure of 6a was supported and assigned at m/z 480.14 (molecular ion) peak for C 27 H 21 N 5 O 2 S in electrospray ionization mass spectrometry (ESI-MS). ...
... Frontier molecular orbitals (abbreviated as FMOs) have extensively been studied with the help of DFT, an important property to calculate molecular reactivity parameters and design important drugs efficiently from the available database or a newly explored library of various chemical compounds of interest. 8,14,49 Molecular geometry optimization of all of the synthesized compounds containing 8-hydroxyquinoline/naphthalene and o,p-hydroxyphenyl benzothiazoles 6a−l was performed using the Gaussian 09 program at B3LYP/6-311G(d,p). 50 The synthesized compounds 6a−l were successfully optimized and verified at local minima. ...
A new series of 1,2,3-triazole hybrids containing either 2- or 4-hydroxyphenyl benzothiazole (2- or 4-HBT) and naphthalen-1-ol or 8-hydroxyquinoline (8-HQ) was synthesized in high yields and fully characterized. In vitro DNA binding studies with herring fish sperm DNA (hs-DNA) showed that quinoline- and 2-HBT-linked 1,2,3-triazoles of shorter alkyl linkers such as 6a are better with a high binding affinity (3.90 × 10⁵ L mol–1) with hs-DNA as compared to naphthol- and 4-HBT-linked 1,2,3-triazoles bound to longer alkyl linkers. Molecular docking of most active 1,2,3-triazoles 6a–f showed high binding energy of 6a (−8.7 kcal mol–1). Also, compound 6a displayed considerable antibacterial activity and superior antifungal activity with reference to ciprofloxacin and fluconazole, respectively. The docking results of the fungal enzyme lanosterol 14-α-demethylase showed high binding energy for 6a (−9.7 kcal mol–1) involving dominating H-bonds, electrostatic interaction, and hydrophobic interaction. The absorption, distribution, metabolism, and excretion (ADME) parameter, Molinspiration bioactivity score, and the PreADMET properties revealed that most of the synthesized 1,2,3-triazole molecules possess desirable physicochemical properties for drug-likeness and may be considered as orally active potential drugs. The electrophilicity index and chemical hardness properties were also studied by density functional theory (DFT) using the B3LYP/6-311G(d,p) level/basis set.
... To explore the possible therapeutic characteristics of P. lentiscus extract, we employed molecular docking techniques to anticipate the antioxidant, antibacterial, and antifungal features of the seven phytocompounds present in the extract ( Figure 2, Table 1). Our research approach was based on established methods previously described in the literature [34][35][36][37][38][39]. We acquired the three-dimensional (3D) configurations of the molecules from PubChem in March 2023 and converted them into a "pdb" file via the PyMol program. ...
... The interactions of these components have been investigated with specific enzymatic proteins, including lipoxygenase-3 (PDB ID: 1N8Q) [53,54] and cytochrome P450 (PDB ID: 1OG5) [53,55], which are known target receptors for antioxidant chemicals. For proteins known to have bactericidal/bacteriostatic activity, DNA Gyrase Topoisomerase II and Enoyl-Acyl Carrier Protein Reductase were selected as therapeutic targets (PDB IDs: 1KZN and 3GNS, respectively) [36,38,53]. Furthermore, the investigation focused on two proteins associated with antifungal activity, namely Cytochrome P450 14 alpha-sterol Deme-thylase (PDB ID: 1EA1) and N-Myristoyl transferase (PDB ID: 1IYL) [53]. ...
The mastic tree, scientifically known as Pistacia lentiscus, which belongs to the Anacardi-aceae family, was used in this study. The aim of this research was to analyze the chemical composition of this plant and assess its antioxidant and antibacterial properties using both laboratory experiments and computer simulations through molecular docking, a method that predicts the binding strength of a small molecule to a protein. The soxhlet method (SE) was employed to extract substances from the leaves of P. lentiscus found in the eastern region of Morocco. Hexane and meth-anol were the solvents used for the extraction process. The n-hexane extract was subjected to gas chromatography-mass spectrometry (GC/MS) to identify its fatty acid content. The methanolic extract underwent high-performance liquid chromatography with a diode-array detector (HPLC-DAD) to determine the presence of phenolic compounds. Antioxidant activity was assessed using the DPPH spectrophotometric test. The findings revealed that the main components in the n-hexane extract were linoleic acid (40.97 ± 0.33%), oleic acid (23.69 ± 0.12%), and palmitic acid (22.83 ± 0.10%). Catechin (37.05 ± 0.15%) was identified as the predominant compound in the methanolic extract through HPLC analysis. The methanolic extract exhibited significant DPPH radical scavenging, with an IC50 value of 0.26 ± 0.14 mg/mL. The antibacterial activity was tested against Staphylococcus aureus, Listeria innocua, and Escherichia coli, while the antifungal activity was evaluated against Ge-otrichum candidum and Rhodotorula glutinis. The P. lentiscus extract demonstrated notable antimicro-bial effects. Additionally, apart from molecular docking, other important factors, such as drug similarity , drug metabolism and distribution within the body, potential adverse effects, and impact on bodily systems, were considered for the substances derived from P. lentiscus. Scientific algorithms, such as Prediction of Activity Spectra for Substances (PASS), Absorption, Distribution, Metabolism, Excretion (ADME), and Pro-Tox II, were utilized for this assessment. The results obtained from this research support the traditional medicinal usage of P. lentiscus and suggest its potential for drug development. Citation: Ouahabi, S.; Loukili, E.H.; Elbouzidi, A.; Taibi, M.; Bouslamti, M.; Nafidi, H-A.; Salamatullah, A.M.; Saidi, N.; Bellaouchi, R.; Addi, M.; et al.
... The binding affinity values, represented by ∆G, were used to indicate the preference of the compound towards the target in comparison to a known inhibitor. Specifically, this method was utilized to investigate the binding affinities of the 12 compounds present in the essential oil towards four proteins related to bactericidal/bacteriostatic activity, namely DNA Gyrase Topoisomerase II, Enoyl-Acyl Carrier Protein Reductase, Glucosamine-6-Phosphate Synthase, and Penicillin Binding Protein 3 (PDB IDs: 1KZN, 3GNS, 2VF5, and 3VSL, respectively) [34][35][36][37][38][39]. In addition, two proteins related to antifungal activity, Cytochrome P450 14 Alpha-Sterol Demethylase (PDB ID: 1EA1) and N-Myristoyl Transferase (PDB ID: 1IYL), were selected for examination [34,35]. ...
... Furthermore, relevant target proteins were identified from the existing literature to explore the possible mechanisms of action of the compounds discovered in PVEO. The study focused on four antibacterial proteins, namely DNA Gyrase Topoisomerase II (PDB ID: 1KZN), Enoyl-Acyl Carrier Protein Reductase (PDB ID: 3GNS), Glucosamine-6-Phosphate Synthase (PDB ID: 2VF5), and Penicillin Binding Protein 3 (PDB ID: 3VSL) [35][36][37][38][39], as well as two antifungal target proteins, namely Cytochrome P450 14 α-Sterol Demethylase (PDB ID: 1EA1) and N-Myristoyl Transferase (PDB ID: 1IYL) [34,35]. Moreover, the study selected four protein structures as antioxidant proteins, namely lipoxygenase, CYP2C9, NADPH oxidase, and bovine serum albumin (PDB IDs: 1N8Q, 1OG5, 2CDU, and 4JK4, respectively) [65,81]. ...
Ptychotis verticillata Duby, referred to as Nûnkha in the local language, is a medicinal plant that is native to Morocco. This particular plant is a member of the Apiaceae family and has a longstanding history in traditional medicine and has been utilized for therapeutic purposes by practitioners for generations. The goal of this research is to uncover the phytochemical makeup of the essential oil extracted from P. verticillata, which is indigenous to the Touissite region in Eastern Morocco. The extraction of the essential oil of P. verticillata (PVEO) was accomplished through the use of hydro-distillation via a Clevenger apparatus. The chemical profile of the essential oil was then determined through analysis utilizing gas chromatography–mass spectrometry (GC/MS). The study findings indicated that the essential oil of P. verticillata is composed primarily of Carvacrol (37.05%), D-Limonene (22.97%), γ-Terpinene (15.97%), m-Cymene (12.14%) and Thymol (8.49%). The in vitro antioxidant potential of PVEO was evaluated using two methods: the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical trapping assay and the ferric reducing antioxidant power (FRAP) method. The data demonstrated considerable radical scavenging and relative antioxidative power. Escherichia coli, Staphylococcus aureus, Listeria innocua, and Pseudomonas aeruginosa were the most susceptible bacterial strains tested, while Geotrichum candidum, Candida albicans, and Rhodotorula glutinis were the most resilient fungi strains. PVEO had broad-spectrum antifungal and antibacterial properties. To elucidate the antioxidative and antibacterial characteristics of the identified molecules, we applied the methodology of molecular docking, a computational approach that forecasts the binding of a small molecule to a protein. Additionally, we utilized the Prediction of Activity Spectra for Substances (PASS) algorithm; Absorption, Distribution, Metabolism, and Excretion (ADME); and Pro-Tox II (to predict the toxicity in silico) tests to demonstrate PVEO’s identified compounds’ drug-likeness, pharmacokinetic properties, the anticipated safety features after ingestion, and the potential pharmacological activity. Finally, our findings scientifically confirm the ethnomedicinal usage and usefulness of this plant, which may be a promising source for future pharmaceutical development.
... Additionally, the target proteins were sourced from literature to investigate the potential mechanisms of action of the compounds found in PVEO. Four antibacterial proteins, DNA Gyrase Topoisomerase II (PDB ID: 1KZN), Enoyl-Acyl Carrier Protein Reductase (PDB ID: 3GNS), Glucosamine-6-Phosphate Synthase (PDB ID: 2VF5), and Penicillin Binding Protein 3 (PDB ID: 3VSL) [15][16][17][18][19], and two antifungal target proteins, namely, Cytochrome P450 14 α-sterol Demethylase (PDB ID: 1EA1), and N-Myristoyl transferase (PDB ID: 1IYL) [19,20]. Lipoxygenase, CYP2C9, NADPH Oxidase, and Bovine serum albumin (PDB IDs: 1N8Q, 1OG5, 2CDU, and 4JK4, respectively), are the four protein structures that were chosen as antioxidant proteins [21,22]. ...
... The binding affinity values (ΔG) were used to indicate the compound's preference towards a target in comparison to a known inhibitor. By using this method, binding affinities of the 12 compounds present in the essential oil towards 4 proteins were examined which are related to bactericidal/bacteriostatic activity, these proteins are DNA Gyrase Topoisomerase II, Enoyl-Acyl Carrier Protein Reductase, Glucosamine-6-phosphate Synthase, and Penicillin Binding Protein 3 (PDB IDs: 1KZN, 3GNS, 2VF5, and 3VSL respectively) [15][16][17][18][19][20]. Additionally, two proteins related to antifungal activity were also selected for the examination, the Cytochrome P450 14 alpha-sterol Demethylase (PDB ID: 1EA1) and the N-Myristoyl transferase (PDB ID: 1IYL) [19,20]. ...
... [8,[10][11][12][13][14]16,17] For example, itraconazole, fluconazole, and voriconazole are commonly used in clinical antifungals. [8,[16][17][18] Ribavirin is a broadspectrum antiviral drug used to treat hepatitis. Rizatriptan has been selected among candidate antimigraine drugs, and anastrozole and vorozole have shown remarkable efficacy as anticancer agents. ...
The new, unexpected bioactive bis‐hydrazone derivative (4) was obtained, in 74 % yield, by reacting two molar equivalents of pyrazole‐4‐carbaldehyde (1) with one molar equivalent of 2,5‐dihydrazineyl‐1,3,4‐thiadiazole (2). The compound was comprehensively characterized, including X‐ray single crystal, DFT calculations, and bioactivity assessments. Hirschfeld surface analysis confirmed the presence of hydrogen bonding interactions, particularly N−H⋅⋅⋅N and C−H⋅⋅⋅π interactions, which influence the overall crystal packing. The target bis‐hydrazone exhibited significant antimicrobial activity against multi‐drug‐resistant bacterial strains, with the largest activity against S.typhimurium with an inhibition zone of 17.1±0.6 mm and MIC 31.25 μg/mL. The compound also demonstrated significant cytotoxic effects on cancer cells, with a higher IC50 ratio of 134.43 μg/mL against the normal cell line Wi38 and the lowest IC50 value of 45.88 μg/mL against the cancer cell line Caco2. Molecular docking was carried out with estrogen receptor alpha (ERα) and sodium‐glucose transporter SGLT1, which are relevant to Mcf7 and Caco2 cancer cell lines, respectively. Docking suggests the presence of specific amino acids that may influence the binding affinity between the ligand and receptor active sites through residue overlaps in chains A for SGLT1 and B for Erα, offering the ligand as a promising anticancer consistent with the IC50 outcomes.
... The unique structural features of 1,2,3-triazoles, arising from the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction [22][23][24][25][26], offer opportunities to fine-tune the physicochemical properties of the resulting sensing scaffolds. The ability to easily modify the 1,2,3-triazole core allows for a rational design strategy, where crucial parameters such as binding specificity, response kinetics, and signal output can easily be tailored to match the unique requirements of sensing. ...
Herein, two new molecular probes of quinizarin-linked bis-1,2,3-triazoles have been synthesized via CuAAC reaction to detect transition metal(s), such as iron (Fe). FTIR, 1H & 13C-NMR, and HRMS spectroscopy fully characterized the synthesized probes. Absorption spectroscopy showed selective binding of probes with Fe(II) and Fe(III) ions. Job's plot suggested a 1:1 stoichiometric ratio of ligand and metal ion. Both probes 3a and 3b showed association constant of 4.42 × 103 M−1 and 4.35 × 103M−1 for Fe(II) and 4.35 × 103 M−1 and 4.59 × 103 M−1 for Fe(III), through Benesi-Hildebrand (B-H) plots. The DFT was performed for geometrical optimization of probes and their complexes, supported by Mulliken charges and Molecular electrostatic potential. Above and beyond, probes and their complexes were also docked with human histamine H1 receptor (PDB ID: 3RZE) protein, providing foretastes of its anti-allergic activity.
... The 1,2,3-triazole and its derivatives play a critical role as essential heterocyclic compounds extensively employed as pharmacophores in pharmaceutical drugs and diverse fields. Their biological activities have been extensively explored and validated through various studies [28][29][30][31][32][33][34][35][36][37][38][39][40]. By incorporating donepezil-triazole with a sugar moiety, these compounds demonstrate the ability to effectively target and deliver drugs across the blood-brain barrier, allowing for potential therapeutic benefits in combating neurological conditions such as AD. ...
... The approach used in this investigation adhered to a pre-established protocol specified in earlier research [50,58,70]. The automated docking experiments were performed using Auto Dock Vina v1.5.6 software [71]. The study focused on two antibacterial proteins, DNA gyrase topoisomerase II (PDB ID: 1KZN) [72,73] and enoyl-acyl carrier protein reductase (PDB ID: 3GNS) [41,42], as well as two antifungal target proteins, cytochrome P450 14 α-sterol demethylase (PDB ID: 1EA1) and N-myristoyl transferase (PDB ID: 1IYL) [4,5,74,75]. ...
Throughout history, essential oils have been employed for their pleasing scents and poten-
tial therapeutic benefits. These oils have shown promise in various areas, including aromatherapy,
personal care products, natural remedies, and even as alternatives to traditional cleaning agents or
pest control solutions. The study aimed to explore the chemical makeup, antioxidant, and antibacte-
rial properties of Origanum compactum Benth., Salvia officinalis L., and Syzygium aromaticum (L.) Merr.
et Perry. Initially, the composition of the three essential oils, O. compactum (HO), S. officinalis (HS),
and S. aromaticum (HC) was analyzed using GC-MS technology, revealing significant differences in
the identified compounds. α-thujone emerged as the predominant volatile component in the oils,
making up 78.04% of the composition, followed by eugenol, which constituted 72.66% and 11.22% of
the HC and HO oils, respectively. To gauge antioxidant capabilities, tests involving DPPH scavenging
capacity and total antioxidant capacity were conducted. Antioxidant activity was determined through
the phosphomolybdate test and the DPPH• radical scavenging activity, with the HO essential oil
displaying significant scavenging capacity (IC50 of 0.12 ± 0.02 mg/mL), similar to ascorbic acid (IC50
of 0.26 ± 0.24 mg/mL). Similarly, the TAC assay for HO oil revealed an IC50 of 1086.81 ± 0.32 µM
AAE/mg. Additionally, the oils’ effectiveness against four bacterial strains, namely Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, and Listeria monocytogenes, and five fungi, Geotrichum
candidum, Aspergillus niger, Saccharomyces cerevisiae, Candida glabrata, and Candida albicans, was tested
in vitro. The examined essential oils generally exhibited limited antimicrobial effects, with the excep-
tion of HC oil, which demonstrated an exceptionally impressive level of antifungal activity. In order
to clarify the antioxidant, antibacterial, and antifungal effects of the identified plant compounds,
we employed computational methods, specifically molecular docking. This technique involved
studying the interactions between these compounds and established protein targets associated with
antioxidant, antibacterial, and antifungal activities.
... Generally, triazoles are stable to hydrolysis under acidic or alkaline conditions, metabolic degradation and redox process. 1,2,3-Triazole derivatives exhibit a broad spectrum of pharmacological activities such as antibacterial [6][7][8], antitubercular [6], anti-inflammatory [6], antifungal [9,10], antiallergic [11] and anticancer properties [4,6,[12][13][14]. In addition, several bioactive compounds containing chromene nuclei display a wide range of medicinal properties such as anti-HIV [15][16][17][18][19][20], the involved chemical reactions in this work were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254), visualizing with ultraviolet light/iodine vapours, column chromatography was performed on silica gel (60-120 mesh) using distilled hexane and ethyl acetate solvents. ...
An easy and convenient approach has been adopted to synthesize a new series of chromene/[1,2,3]triazole hybrid derivatives involving Cu(I) catalyzed alkyne-azide 1,3-dipolar cycloaddition and a single step multicomponent reaction. The novel synthesized compounds (8a-l) were screened for cytotoxicity against three tumour cell lines i.e. MCF-7, PC-3 and HeLa using reference drug doxorubicin. Compound 8j (m-acetyl) showed an outstanding activity against all the three cell lines with IC50 values of 2.67 ± 0.03, 3.13 ± 0.03 and 3.05 ± 0.05 μM respectively. Compound 8k (p-acetyl) also exhibited good activity with IC50 values of 3.16 ± 0.05, 4.68 ± 0.03 and 3.81 ± 0.02 μM and the values are closer to doxorubicin IC50 values. The rest of the synthesized compounds have displayed good to moderate activity compared to reference drug. Molecular docking simulations of compounds 8b, 8f and 8j exhibited an excellent binding interactions against the crystal structure of epidermal growth factor receptor (EGFR).
... These significant biological and medicinal properties of triazoles have encouraged investigations into the synthesis and detailed structural characterization of new 1,2,3triazole derivatives. 6,7 The Cu(I)-catalyzed azide−alkyne cycloaddition, also known as the CuAAC "click reaction," significantly improved the preparation of 1,4-disubstituted 1,2,3-triazole-based compounds under mild conditions. 8,9 Especially, 1,2,3-triazole derivatives have been thoroughly studied as potent tools in anticancer research. ...
We report herein a new 1,2,3-triazole derivative, namely, 4-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-hydroxybenzaldehyde, which was synthesized by copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC). The structure of the compound was analyzed using Fourier transform infrared spectroscopy (FTIR), 1H NMR, 13C NMR, UV–vis, and elemental analyses. Moreover, X-ray crystallography studies demonstrated that the compound adapted a monoclinic crystal system with the P21/c space group. The dominant interactions formed in the crystal packing were found to be hydrogen bonding and van der Waals interactions according to Hirshfeld surface (HS) analysis. The volume of the crystal voids and the percentage of free spaces in the unit cell were calculated as 152.10 Å3 and 9.80%, respectively. The evaluation of energy frameworks showed that stabilization of the compound was dominated by dispersion energy contributions. Both in vitro and in silico investigations on the DNA/bovine serum albumin (BSA) binding activity of the compound showed that the CT-DNA binding activity of the compound was mediated via intercalation and BSA binding activity was mediated via both polar and hydrophobic interactions. The anticancer activity of the compound was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using human cell lines including MDA-MB-231, LNCaP, Caco-2, and HEK-293. The compound exhibited more cytotoxic activity than cisplatin and etoposide on Caco-2 cancer cell lines with an IC50 value of 16.63 ± 0.27 μM after 48 h. Annexin V suggests the induction of cell death by apoptosis. Compound 3 significantly increased the loss of mitochondrial membrane potential (MMP) levels in Caco-2 cells, and the reactive oxygen species (ROS) assay proved that compound 3 could induce apoptosis by ROS generation.
... Medicinal chemists continuously explore novel chemical entities to combat various diseases and improve patient outcomes. Our lab works keenly to develop new chemicals with improved properties by employing a molecular hybridization approach with the help of coppercatalyzed azide-alkyne cycloaddition (CuAAC) reaction, commonly known as click reaction [1,2]. This versatile synthetic approach offers several advantages, including mild reaction conditions, high regioselectivity, and compatibility with various functional groups. ...
... The 1,2,3-triazole and its derivatives play a critical role as essential heterocyclic compounds extensively employed as pharmacophores in pharmaceutical drugs and diverse fields. Their biological activities have been extensively explored and validated through various studies [28][29][30][31][32][33][34][35][36][37][38][39][40]. By incorporating donepezil-triazole with a sugar moiety, these compounds demonstrate the ability to effectively target and deliver drugs across the blood-brain barrier, allowing for potential therapeutic benefits in combating neurological conditions such as AD. ...
... 1,2,3-Triazoles are of synthetic origin and are extensively explored in various drugs like antifungal [7][8][9][10][11][12], antibacterial [13][14][15][16][17][18], anti-HIV [19,20], anti-allergic [21],anticancer [22][23][24][25], antitubercular [26][27][28], pesticides [29], insecticides [30,31], weedicides [32], etc. Considering the stability of 1,2,3-triazoles under oxidation, reduction, acid, base, humidity, light, and biological environment, they are synthetic reagents in organic and medicinal chemistry [33,34]. The stability of the triazoles with other chemiclas fascinated its application in the targeted drug delivery using nanogels [35]. ...
The demand for environmental friendly methodologies had shifted the the approach of scientific community for using easy and green reaction conditions instead of using hazardous and harsh reaction conditions. One of the suggested approaches, use of catalyst remained prime choice for harsh free green reaction. The difficulty in the separation of homogeneous catalyst from reaction product increased the attention of chemists for heterogeneous catalysts. The present review summarizes some recent important developments in heterogeneous catalysis using “click reaction” for obtaining 1,2,3-triazoles via Cu-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC). A vast collection of papers is efficiently grouped into two significant classes to increase readability in easy language. Firstly, the CuAAC reactions, and secondly, other metal-catalyzed azide-alkyne cycloaddition (MAAC) reactions are discussed. The CuAAC reactions are further grouped into two sub-classes of Cu(I)-nanoparticle catalyzed azide-alkyne cycloaddition (Cu-NPs-AAC) and simple Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. In most cases, the formation of 1,4-disubstituted 1,2,3-triazoles, as reported, was conveniently presented with the help of colored schemes.
... The observed results, in the form of binding affinity values, may indicate an increased/decreased affinity of the studied molecule toward the given target in comparison to a native ligand (a known inhibitor), assuming that binding energy reduces as compound affinity increases. This method was used to assess the binding affinity of the 15 essential oil compounds to target proteins known to have bactericidal/bacteriostatic actions, including DNA Gyrase Topoisomerase II, Enoyl-Acyl Carrier Protein Reductase, and Glucosamine-6-phosphate synthase (PDB IDs: 1KZN, 3GNS, and 2VF5, respectively) [40][41][42][43]. The reduction of ROS production in vitro by DAEOs compounds was mechanistically evaluated by assessing their molecular docking contacts with certain enzymatic proteins, namely Lipoxygenase-3 (PDB ID: 1N8Q) [44], Cytochrome P450 (PDB ID: 1OG5) [45], NADPH oxidase (PDB ID: 2CDU) [46], and Bovine Serum Albumin (PDB ID: 4JK4) [47]; all of these proteins have long been described as target receptors for antioxidant chemicals and are recognized to have a part in the process of oxidative homeostasis in the body. ...
Dysphania ambrosioides (L.) Mosyakin and Clemants, also known as Mexican tea, and locally known as Mkhinza, is a polymorphic annual and perennial herb, and it is widely used in folk medicine to treat a broad range of illnesses in Morocco. The aim of this study was to determine the phytochemical content and the antioxidant and the antibacterial properties of essential oils isolated from D. ambrosioides aerial components, growing in Eastern Morocco (Figuig). Hydrodistillation was used to separate D. ambrosioides essential oils, and the abundance of each phytocompound was determined by using Gas Chromatography coupled with Mass Spectrometry (GC–MS). In vitro
2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and inhibition of β-carotene/linoleic acid bleaching assays were used to determine D. ambrosioides essential oils’ antioxidant activity. The
findings revealed relative antioxidative power and modest radical scavenging. The antibacterial activity of the essential oils was broad-spectrum, with Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis as the most susceptible strains tested. To elucidate the physicochemical nature, drug-likeness, and the antioxidant and antibacterial action of the identified phytocomponents, computational techniques, such as ADMET analysis, and molecular docking were used.
... Due to high dipole moment, hydrogen boding efficiency of this highly inert and rigid scaffold, it became an important pharmacophore in drug findings. 1,2,3-Triazoles possess a vast array of pharmaceutical applications including antimicrobial [6][7][8], antioxidant [9,10], antidiabetic [11][12][13], anticancer [14][15][16], anticonvulsant activity [17,18], etc. The synthesis of 1,4-disubstituted 1,2,3-triazoles was a complex task initially, but presently Cu(I)-catalysed click chemistry under moderate temperatures not only gives relief from obtaining a mixture of regioisomers, but also provides easy and high yielding pathways for 1,4-disubstituted 1,2,3-triazoles. ...
Some urea-thiazole/benzothiazole hybrids with a triazole linker were synthesized via Cu(I)-catalysed click reaction. After successfully analysed by various spectral techniques including FTIR, NMR and HRMS, antimicrobial screening of the synthesized hybrids along with their precursors was carried out against two Gram (+) bacteria (Staphylococcus aureus and Bacillus endophyticus), two Gram (−) bacteria (Escherichia coli and Pseudomonas fluorescens) and two fungi (Candida albicans and Rhizopus oryzae). All the synthesized compounds (4a–4l) displayed better biological response than the standard fluconazole against both of the tested fungi. Compounds 4h and 4j were found to be the most active compounds against R. oryzae and C. albicans, respectively. Molecular docking of hybrid 4j and its alkyne precursor 1b in the active site of C. albicans target sterol 14-α demethylase was also performed and was also supported by molecular dynamics studies. In silico ADME prediction of synthesized urea-thiazole/benzothiazole hybrids with a triazole linker and their alkyne precursors was also predicted.
Graphic abstract
... The pharmacological potential of triazole is supported by its broad spectrum activities like anti-tubercular (Keri et al., 2015;Zhang et al., 2017), anti-fungal (Emami et al., 2019), anti-cancer Xu et al., 2018, anti-bacterial (Tittal et al., 2019Zhang, 2019), anti-oxidant (Kumar, Kalluraya, et al., 2018;Rajavelu et al., 2018;Santosh et al., 2018), anti-infective (Batra et al., 2018;Tarawneh et al., 2018), and anti-viral (Kaoukabi et al., 2018;Tian et al., 2018) activities. Some of the well-known drugs with triazole moiety are presented in Figure 2, including tazobactum (Giacobbe et al., 2018) and cefatrizine as βlactum anti-biotic carboxyamidotriazole (Ju et al., 2016) as anti-cancer, mubritinib (Calderon et al., 2020) as a protein kinase inhibitor, rufinamide (White et al., 2008) as anti-convulsant, and clozapine (1-A09; Walss-Bass et al., 2008) as anti-psychotic drug among various others. ...
Over the past few decades, the dynamic progress in the synthesis and screening of heterocyclic compounds against various targets has made a significant contribution in the field of medicinal chemistry. Among the wide array of heterocyclic compounds, triazole moiety has attracted the attention of researchers owing to its vast therapeutic potential and easy preparation via copper and ruthenium-catalyzed azide-alkyne cycloaddition reactions. Triazole skeletons are found as major structural components in a different class of drugs possessing diverse pharmacological profiles including Anti-Cancer, Anti-Bacterial, Anti-Fungal, Anti-Viral, Anti-Oxidant, Anti-Inflammatory, Anti-Diabetic, Anti-Tubercular, and Anti-Depressant among various others. Furthermore, in the past few years, a significantly large number of triazole hybrids were synthesized with various heterocyclic moieties in order to gain the added advantage of the improved pharmacological profile, overcoming the multiple drug resistance and reduced toxicity from molecular hybridization. Among these synthesized triazole hybrids, many compounds are available commercially and used for treating different infections/disorders like Tazobactam and Cefatrizine as potent Anti-Bacterial agents while Isavuconazole and Ravuconazole as Anti-Fungal activities to name a few. In this review, we will summarize the biological activities of various 1,2,3-triazole hybrids with copious oxygen-containing heterocycles as lead compounds in medicinal chemistry. This review will be very helpful for researchers working in the field of molecular modeling, drug design and development, and medicinal chemistry.
... Thus, the theoretical methods are extremely used for the analyses of the proposed structure of the compound. Naveen et.al reported Synthesis, molecular docking, and DFT studies on biologically active 1,4-disubstituted-1,2,3triazole-semicarbazone hybrid molecules [28]. V. Narayan et.al published Electronic structure, electric moments and vibrational analysis of 5-nitro-2-furaldehyde semicarbazone: A D.F.T. study [29]. ...
In this work, the FT-IR spectra of synthesized molecule Salicilaldehyde Semicarbazone (SASC) was characterized by using density functional theory (DFT) with B3LYP/6-311++ G (d, p) basis set. Natural Bond Orbital (NBO) analysis, Non-Linear Optical (NLO) properties, Mulliken atomic charges of the title compound were calculated. The ¹H NMR chemical shifts of the molecule were calculated by the GIAO method. Molecular electrostatic potential (MEP), HOMO–LUMO energy gap analysis supports the possibility of charge transfer in the SASC compound. Topological parameters obtained from Quantum Theory of Atoms in Molecules (QTAIM) framework and Reduced Density Gradient (RDG) – Non-Covalent Interactions (NCI) are used to describe the nature of different intermolecular interactions. Estimated ADME profiles and bioactivity results of the compound were calculated. Drug likeness criteria based on the rules of Lipinski and Veber appraise that the SASC has the classic physicochemical and pharmacokinetic properties to be a good candidate for drug orally. Docking studies of the header compound were investigated to predict the binding energy.
Herein, we report design, synthesis and characterization of a new library of 7‐azaindole N‐ethyl linked 1,2,3‐triazoles containing ethylene as a spacer unit, and evaluation of all the synthesized compounds for their antimicrobial properties. Antibacterial potential was checked against two Gram positive (B. subtilis and S. aureus) and two Gram negative (E. coli and P. aeruginosa) bacterial strains while antifungal potential was assayed against two fungal strains (C. albicans and A. niger). All the tested compounds showed satisfactory antibacterial potency in comparison to reference drug ciprofloxacin with MIC values ranging from 0.0108 to 0.0432 μmol/mL. Interestingly, except two, all the target compounds showed better antifungal property as compared to the reference drug fluconazole with MIC values less than 0.0408 μmol/mL. One of the compounds exhibited two‐fold better antifungal potential in comparison to fluconazole. Furthermore, in‐silico ADMET and DFT studies reported drug likeness behavior and chemical reactivity parameters, respectively. The cytotoxicity results on substrate azide 3 and most potent 1,2,3‐triazoles (5 d and 5 l) were found to be non‐toxic.
The synthesis of triazoles has attracted a lot of interest in the field of organic chemistry because of its versatile chemical characteristics and possible biological uses. This review offers an extensive overview of the different pathways used in the production of triazoles. A detailed analysis of recent research indicates that triazole compounds have a potential range of pharmacological activities, including the ability to inhibit enzymes, and have antibacterial, anticancer, and antifungal activities. The integration of computational and experimental methods provides a thorough understanding of the structure–activity connection, promoting sensible drug design and optimization. By including triazoles as essential components in drug discovery, researchers can further explore and innovate in the synthesis, biological assessment, and computational studies of triazoles as drugs, exploring the potential therapeutic significance of triazoles.
Graphical abstract
A new, easy-to-prepare, and highly selective fluorescent chemosensor, i.e., 5-aminoisophthalate-based kojic acid-appended bis-1,2,3-triazole, was synthesized from an alkyne of 5-aminoisophthalic acid and azido-kojic acid using Cu(i)-catalyzed click chemistry and then successfully characterized. The alkyne structure of 5-aminoisophthalic acid, 1, was supported by the single-crystal X-ray crystallographic data. The fluorescent probe 3 was found to be highly selective for Cu²⁺ ions supported by the Job's plot with a stoichiometric ligand : metal ratio of 2 : 1, exhibiting almost a two-fold enhancement in the emission intensity upon the addition of Cu²⁺ ions (0–25 μM) with a detection limit of 8.82 μM. A comparison with LODs from previously developed chemosensors for Cu²⁺ ions was also conducted. Reversibility analysis indicated that probe 3 could be used as both a reusable sensor and as a scavenger of copper ions. DFT calculations with the basis sets B3LYP/6-311G(d,p) and LanL2DZ were employed for geometrical optimizations of structures of the alkyne 1, azide 2, probe 3, and complex 3.Cu²⁺. Hirshfeld surface analysis revealed significant intermolecular interactions in compound 1. Additionally, molecular docking for the antimicrobial activity showed the better antibacterial efficacy of probe 3.
A new series of hybrids of α-tocopherol and aryl/heterocyclic moieties through 1,2,3-triazole linker were made by rationally combining a biologically active α-tocopherol and substituted aromatic or heterocyclic moieties in single molecular frame using the click chemistry method. In a nutshell, the novel compounds (3a-h) were made by O-alkylating α-tocopherol, proceeded by copper (I)-catalyzed click reaction and the Huisgen [3 + 2] cycloaddition using various aromatic and heterocyclic azides (2a-h). By using 1H, 13C NMR, and mass spectroscopy techniques, all of the recently synthesized compounds were characterized and their antibacterial and antioxidant capabilities were assessed. Among the synthesized compounds, the most effective synthetic molecule against all bacterial strains was 3e with a naphthyl moiety, whereas 3d with a phenolic moiety showed potent antioxidant activity. To better understand the binding interactions, exploratory molecular docking investigation was conducted against the faBH enzyme of E. coli.
A series of novel 1,2,3-triazole and chiral Schif base hybrids 2–6 were synthesized by Schif base condensation reaction from pre-prepared parent component of the hybrids (1,2,3-triazole 1) and series of primary chiral amines and their chemical structure were confrmed using NMR and FTIR spectroscopies, and CHN elemental analysis. Compounds 1–6 were evaluated for their anticancer activity against two cancer PC3 (prostate) and A375 (skin) and MRC-5 (healthy) cell lines by Almar
Blue assay method. The compounds exhibited signifcant cytotoxicity against the tested cancer cell lines. Among the tested compounds 3 and 6 showed very good activity for the inhibition of the cancer cell lines and low toxicity for the healthy cell lines. All the compounds exhibited high binding afnity for Androgen receptor modulators (PDB ID: 5t8e) and Human MIA (PDB ID: 1i1j) inhibitors compared
to the reference anticancer drug (cisplatin). Structure activity relationships (SARs) of the tested compounds is in good agreement with DFT and molecular docking studies. The compounds exhibited desirable physicochemical properties for drug likeness.
To achieve environmentally benign synthesis and develop pharmacologically active compounds, a library of novel thiophene‐clubbed pyrazole‐1,2,3‐triazole hybrids was designed and successfully synthesized using L‐ascorbic acid as a green acid catalyst and ethanol as a green solvent. The reaction was carried out using microwave and ultrasonic irradiation methods to achieve a highly efficient reaction route. All title compounds were characterized and evaluated for their potential in vitro antimicrobial activity using Ciprofloxacin and Nystatin as standard drugs, in which compounds with chloro and naphthyl substitutions exhibited excellent antibacterial activity at concentrations of 25 μg/mL and compounds with methyl and methoxy substitutions exhibited excellent antifungal activity at concentrations of 100 μg/mL. Additionally, the molecular docking study showed that all compounds examined had excellent binding energies ranging from −9.3 to −10.3 kcal/mol, and naphthyl substitution displayed the highest binding energy (−10.3 kcal/mol) on the target protein of E. coli DNA gyrase subunit B. Furthermore, the final moieties were evaluated for in silico ADMET prediction to examine their drug‐likeness profile and toxic effects. The present study revealed that this structural information will be helpful in future antimicrobial drug design and development.
A new class of 3‐hydroxypyridine‐4‐one derivatives was synthesized and screened against several Gram‐positive and Gram‐negative bacteria, as well as two species of fungi. Among these synthesized compounds, the substituted derivatives with ortho‐ and para‐nitro and para‐methoxy groups showed the highest antibacterial activities against S. aureus and E. coli species with MIC value of 32 μg/mL, which were more potent compared to ampicillin as a reference drug. Furthermore, the substituted derivatives with ortho‐methoxy, ortho‐, para‐chloride, ortho‐, and para‐hydroxy groups exhibited MIC values of 64 μg/mL against S. aureus and E. coli species. In addition, the synthesized compounds were evaluated for their antifungal activities against C. albicans and A. niger strains. The best antifungal activity was observed for compounds with ortho‐methoxy, ortho‐hydroxy, and para‐methyl substitutions against A. niger species with MIC values of 64 μg/mL. The analysis of the antimicrobial results revealed that the type and position of the phenyl ring substituents greatly influence the antimicrobial activities of the synthesized compounds. Subsequently, molecular docking studies on E. coli species were performed to predict the interaction mode of these compounds in the active site of the receptor. Also, in silico ADME profile outputs showed that the compounds comply with the rule of five.
Aim: To obtain new hybrids derived from isatin and triazole. Materials & methods: A series of oxindole-1-H-1,2,3-triazole hybrids (4a-l) were synthesized from 3-sulfenylated N-propargylated oxindoles and organic azides employing Cu(I)-catalyzed azide-alkyne cycloaddition. These compounds were evaluated in vitro for antimicrobial activity by the standard serial dilution method and DNA photocleavage activity. Results: Antimicrobial assay revealed that compounds 4l and 4f exhibited promising efficacy against Candida albicans and Rhizopus oryzae, respectively, with a minimum inhibitory concentration (MIC) value of 0.0008 μmol/mL. Compounds 4h and 4k completely degraded plasmid DNA. Further molecular docking of compounds with 1KZN (4j and 4k) and 5TZ1 (4h and 4l) revealed good binding interactions. Conclusion: Results of the current research can help in the development of new antimicrobial agents with high efficacy.
Herein, a novel 5-nitro isophthalate linked bis-triazole as a fluorescent molecular probe, i.e., 5-nitro isophthalic
acid bis-(1-phenylcarbamoylmethyl-1H- [1,2,3]triazol-4-ylmethyl) ester was efficiently synthesized by employing CuAAC catalyzed ‘Click’ reaction. The molecular probe exhibited a fastidious response towards selective and
efficient sensing of Fe3+ ions with a binding constant of 3.41×103 M-1 and LOD of 9.18 µM. The molecular probe
and its Fe3+ complex were fully characterized by FTIR, 1
H & 13C NMR, ESI-MS, and SEM-EDX data. A real-life
application of the molecular probe was presented as a paper strip test to detect and differentiate Fe3+ from
Fe2+ ions to mitigate their impact on the environment and human health. Molecular docking and DFT results
supported the probe’s efficacy.
Two libraries of biologically essential and fluorescent 7-azaindole N-linked benzyl 1,2,3-triazole (4a-4i) and 7-azaindole N-linked phenyl 1,2,3-triazole (4j-4q) hybrids have been designed and synthesized from N-propargyl 7-azaindole, i.e., 1-prop-2-ynyl-1H-pyrrolo[2,3-b]pyridine (2)...
In present era, heterocyclic compounds containing two or three nitrogen atoms play a vital role in drug discovery. In this context, a new class of isatin-semicarbazone tethered 1,2,3-triazole hybrids was synthesized via Cu(I)-mediated azide alkyne cycloaddition reaction. Structural characteristics of the newly derived compounds were identified by various spectral techniques like FTIR, 1H NMR, 13C NMR, HRMS and single crystal X-ray crystallography. Synthesized derivatives were also screened for in vitro antimicrobial and antibiofilm activity against different microbial species. Triazole hybrid 7e showed significant efficacy towards E. coli having MIC of 0.0063 µmol/mL, whereas 6a, 6b, 7a, 7c, 7e, and 7f showed highest percentage of biofilm inhibition against P. aeruginosa. Bioassay results suggested that these triazole hybrids could act as biomaterial for antimicrobial and antibiofilm applications and may constitute a new promising class of antimicrobial and antibiofilm agents. These results were further supported by in silico docking, DFT calculations and ADME studies.
ESKAPE pathogens, as priority 1 and 2 pathogens, are prevalent infectious agents associated with high morbidity and mortality. ESKAPE can cause broad-spectrum diseases with increasing tendency of resistance acquisition to antibiotics and have enhanced the urge for the development of alternate therapeutics. 1,2,3-Triazole, a highly privileged moiety for the discovery of novel drugs, not only can act as a linker to tether different pharmacophores, but also can serve as a pharmacophore. Notably, several 1,2,3-triazole-containing hybrids which are exemplified by cefatrizine, radezolid and tazobactam have already approved as antibiotics to treat infections caused by various organisms including ESKAPE pathogens and their drug-resistant forms, revealing that 1,2,3-triazole-containing hybrids are useful prototypes for clinical deployment in the control of bacterial infections. The purpose of the present review article is to provide an emphasis on the current scenario (2018–2022) of 1,2,3-triazole-containing hybrids with potential antibacterial activity against ESKAPE pathogens to facilitate further rational design of more effective candidates.
In an effort to develop new antimicrobial agents, a novel series of new phenylhydrazone linked triazole hybrids was synthesized via Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) using the concept of molecular hybridization. In the present era, molecular hybridization is one of the most significant tool to develop novel drug molecules by combining two or more bioactive scaffolds. All synthesized compounds were characterized by using various spectral methods like FTIR, ¹H NMR, ¹³C NMR including HRMS data. The antimicrobial evaluation results indicated that all the synthesized phenylhydrazone linked triazole hybrids were more efficacious than phenylhydrazone linked terminal alkynes towards the tested bacterial strains and also showed comparable antifungal potency to standard drug fluconazole. Compound 6e exhibited very good potency against E. coli (MIC = 0.0113 µmol/mL), P. fluorescens (MIC = 0.0113 µmol/mL), S. enterica (MIC = 0.0057 µmol/mL), and C. albicans (MIC = 0.0057 µmol/mL). The docking simulations of all three alkynes (3a–3c) and their corresponding 1,2,3-triazole hybrids (5b, 6e, 7e and 7b) were also carried out onto E. coli DNA gyrase and C. albicans lanosterol 14-α demethylase The docking score of most promising compound 6e with lanosterol 14-α demethylase is − 11.6 kcal/mol.
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Antimicrobial resistance (AMR) and multidrug resistance (MDR) have become global therapeutic barriers and due to this, there is increasing global mortality. To overcome antimicrobial resistance, we developed a novel set of fifteen pyrazole-imidazolidinone hybrids. The synthesized compounds were characterized, and structures confirmed by spectral techniques like IR, NMR spectra and Mass data. Compounds (4a-o) were evaluated for their in vitro antimicrobial activity against Gram-positive, Gram-negative bacterial strains, as well as fungal strains by using the serial dilution method. The results demonstrated that the compounds 4f with MIC (Minimum Inhibitory Concentration) 12.5 μg/mL against A. clavatus and 4l with MIC 12.5 μg/mL against P. aeruginosa were the most active compared to the standard drugs. The biological activity revealed that the electron-withdrawing group (4l) is responsible for the antibacterial activity whereas the electron-donating group (4b, 4d, 4e, 4f, and 4g) is accountable for the antifungal activity. The in-silico results prove the affinity of 4f, and 4l for bacterial and fungal targets. Compounds, 4a, 4b, and 4c have residues in their cavities that are comparable and have excellent affinity for such bacterial target. Further, 100 ns molecular dynamics simulations were used to evaluate the promising compound 4f interactions and stability on the fungal target 14α–demethylase enzyme. Optimization parameters, MESP (Molecular Electrostatic Potential) analysis, HUMO (Highest Occupied Molecular Orbital), and LUMO (Lowest Unoccupied Molecular Orbital) quantum parameters of the most active compound 4f were also calculated by using DFT/B3LYP theory and the 6-31 G ** base set, and the results were correlated with the anti-microbial activity.
A diverse series of imine linked 1,2,3-triazole hybrids has been synthesized via Cu(I)-promoted click reaction, with an aim to develop some new antimicrobial molecules. The structural characterization of the synthesized triazole hybrids was accomplished using various spectral techniques like ¹H NMR, ¹³C NMR, FTIR and HRMS. Among the synthesized hybrids, 7d exhibited highest antimicrobial efficacy against R. oryzae and S. aureus with MIC of 0.0123 µmol/mL and 0.0061 µmol/mL, respectively. Docking studies of the terminal alkynes (4a, 4b) and triazole hybrids (6a, 6d, 7c, 7g) showing high potency towards E. coli DNA gyrase and C. albicans sterol 14-α demethylase were also undertaken to understand the binding behaviour.
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The design and synthesis of a new series of indole-chalcone linked 1,2,3-triazole hybrids via Cu(Ι)-catalyzed azide-alkyne cycloaddition is reported. All the compounds (2, 4a-4e and 6a-6j) were well characterized by different analytical and spectral methods and screened in vitro for antimicrobial evaluation against Gram-positive bacteria, Gram-negative bacteria and fungal strains. Most of the synthesized hybrids showed significant potency with MIC values from 10.9 µM to 39.4 µM. Antifungal data revealed that compound 6a with MIC of 6.3 µM was found to be most effective against R. oryzae. Docking simulations of the compounds 2, 4b and 6b were performed with of E. coli DNA gyrase, while molecule 6g along with 4b and 2 was docked into active sites of C. albicans alpha lanosterol demethylase.
A series of symmetrical bis(urea-1,2,3-triazole) hybrids (5a–5f, 6a–6f) were synthesized via Cu(I)-catalyzed click reaction followed by their complete analysis by techniques like FTIR, NMR and HRMS. All the synthesized hybrids were screened against three Gram ( +) bacteria strains (Staphylococcus aureus, Bacillus endophyticus and Streptococcus entericus), one Gram (−) bacterium (Escherichia coli) and two fungal strains (Candida albicans and Rhizopus oryzae), using ciprofloxacin and fluconazole as standard drugs, respectively. Most of the compounds (5a–5f, 6a–6f) showed higher antimicrobial potency against the tested microbes than the reference drugs. Compounds 5d and 6d were found to be the most potent compounds of the series with MIC values of 0.0045 µmol/mL (E. coli, C. albicans, R. oryzae), 0.0090 µmol/mL (S. entericus, S. aureus, B. endophyticus), and 0.0040 µmol/mL (E. coli, C. albicans, R. oryzae), 0.0080 µmol/mL (S. entericus, B. endophyticus) and 0.0160 µmol/mL (S. aureus), Docked poses of compounds 5d and 6d in the binding pockets of enzyme sterol 14-α demethylase displayed various binding interactions, thereby correlating the experimental and computational results.
Some 3-benzylideneamino-1,2,3-triphenylpropan-1-ones thio/ semicarbazide (1–5) were synthesised. 1H NMR, 13C NMR, FT-IR, UV–Vis, and Fluorescence spectroscopy were used to analyze the manufactured compounds (1–5). The yields of the described compounds 1–5 were satisfactory. DFT calculations with Gaussian-03 W at the B3LYP/6-31G(d,p) level discovered the stable conformer.. The atomic calculation of the designated compounds, optical and NLO properties were upheld by DFT, which uncovered upgrade polarizability, hyperpolarizability, and dipole movement. Electrochemical amounts, for example, synthetic hardness and electronegativity were estimated and investigated by the utilization of HOMO-LUMO and Mulliken nuclear charges were likewise determined.
A simpler and selective turn-on fluorescent probe namely 4-(benzothiazol-2-yl) phenyl 2-chloroacetate ester 2 was synthesized by chloro-acylation of 4-hydroxyphenyl benzothiazole (4-HBT). The probe 2 was investigated for the detection of biothiols among amino acids. The addition of Homocysteine (Hcy) selectively induced significant fluorescence enhancement and the detection limit was determined to be 7.7 × 10⁻⁶ M. The probe 2 conserves simple structure, and %atom economy. Paper strip tests were carried out to explore the potential application for naked-eye fluorescence detection of Hcy under UV lamp. We expect the presented probe 2 will offer a valuable approach to acquire selective detection and discrimination of Hcy over other biothiols especially cysteine (Cys).
A new series of pyrazoline-amide linked 1,2,3-triazole hybrids was wisely designed and synthesized using 1,3-dipolar cycloaddition between pyrazoline linked alkynes and 2-bromo-N-arylacetamide. All the newly synthesized compounds were evaluated in vitro against different microbial strains viz. Escherichia coli, Bacillius subtilis, Staphylococcus aureus, Aspergillus niger, and Candida. albicans. Pyrazoline linked terminal alkynes (4a-4c) showed MIC = 0.062-0.078 μmol/mL against different bacterial and fungal strain. However, pyrazoline-amide linked 1,2,3-triazole hybrids showed MIC = 0.0229- 0.050 μmol/mL. Compound 6e exhibited better efficacy against E. coli and both the fungal strains compared to standard drugs used. Docking studies of the most potent compounds were carried out against bacterial DNA Gyr A and fungal 14α-steroldemethylase were also performed. The binding potential of 4a and 6e with both the target using molecular dynamics simulations was also investigated.
A new series of C-14 curcumol derivatives as potent anticancer agents were designed and synthesized by click reaction, whose structures were confirmed by ¹H NMR,¹³C NMR, and HRMS analysis. All the synthesized compounds were evaluated for in vitro antitumor activity against colorectal cancer cell lines SW620 and HCT116. Most of them exhibited higher inhibitory activity than curcumol. Especially, compound 3j shows good inhibitory activity against SW620 with IC50 value of 8.10 ± 0.13 μM. The structure–activity relationships (SARs) of these derivatives were discussed. In addition, flow cytometry revealed that compound 3j induced SW620 cells apoptosis by facilitating apoptosis-related proteins expressions. Our findings suggested that fluorine functional group on phenyl ring tended to increase the anticancer activity.
In search of new bioactive 1,2,3-triazole hybrids, some 4-hydroxyphenyl benzothiazole (4-HBT) linked 1,2,3-triazole with varying lengths of alkyl spacers were synthesized from bromo alkoxy derivatives of 4-HBT. All the synthesized hybrids were satisfactorily characterized, and were evaluated for in-vitro antifungal activity against C. tropicalis and A. terreus fungal strains wherein compound 4h showed better activity for both fungal strains compared to the reference drug Fluconazole. Molecular docking with the active site of 14α-sterol demethylase enzyme (PDBID:1EA1) showed that all compounds exhibited strong H-bonding interactions with Thr260, Ala256, Arg96, Phe78, Leu321, Tyr76 while compound 4h with the lone pair of -Cl have shown better interaction with the active site and were involved in H-bond interaction with THR 260. DNA binding study exhibited very good DNA-interaction (2.03 × 10⁵ Lmol⁻¹) of compound 4b with the hs-DNA. The results of DFT study and ADME investigations were accessed for the pharmacodynamics and pharmacokinetic properties of the synthesized molecules.
Bismuth (III) nitrate pentahydrate (BN) was found to be a mild and efficient catalyst for the electrophilic condensation of 5-nitroindazole with a wide range of aldehydes to obtain Bis (5-nitro indazolyl) methanes 3 (a-h) at ambient temperature. This was structurally confirmed from FTIR, NMR, and HR-MS technique. Molecular docking studies of all compounds was carried out using breast cancer-causing human estrogen receptor (ER) from Molegro Virtual Docker software. Hydroxy Bis (nitro indazolyl) methanes (3b) were shown better binding affinities and the score obtained was -150.146 Kcal/mol compared with Tamoxifen drug. The major H-bond interactions were observed with the compound 3f and the value was -5.679. The antimicrobial activity results revealed that compounds 3b and 3d showed promising activity against bacteria Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Pseudomonas aeruginosa and maximum inhibition against Aspergillus niger and Aspergillus flavus. Methoxy derivatives of Bis (nitro indazolyl methanes) (3e) have shown better antioxidant activity and low MIC (6.25 µg/ml) observed for the compounds 3a and 3b. The synthesized compounds have a very promising starting point for the development and improvement of anti-breast cancer drugs.
A series of three different classes of benzothiazole linked 1,2,3‐triazole hybrid molecules with varying alkyl spacers (ethyl, propyl, and butyl) between 2‐hydroxyphenyl benzothiazoles and 1,2,3‐triazoles are efficiently synthesized under CuAAC condition. All compounds are satisfactorily characterized by FTIR, ¹H‐NMR, ¹³C‐NMR, ESI‐MS data and structures of some compounds were finally supported by single‐crystal X‐ray diffraction data. Most of the synthesized compounds exhibited good to better DNA binding property (0.28×10⁵ M⁻¹ to 2.91×10⁵ M⁻¹) and well drug‐like properties. Some promising compounds showed good agreement to all experimental and theoretical computed properties (fluorescence study, DNA binding, molecular docking, DFT, and ADME Predictions).
The continuous demand of medicinally important scaffolds has prompted the synthetic chemists to identify simple and efficient routes for their synthesis. 1H-1,2,3-triazole, obtained by highly versatile, efficacious and selective “Click Reaction” has become a synthetic/medicinal chemist’s favorite not only because of its ability to mimic different functional groups but also due to enhancement in the targeted biological activities. Triazole ring has also been shown to play a critical role in biomolecular mimetics, fragment-based drug design, and bioorthogonal methodologies. In addition, the availability of triazole containing drugs such as fluconazole, furacyclin, etizolam, voriconazole, triozolam etc. in market has underscored the potential of this biologically enriched core in expediting development of new scaffolds. The present review, therefore, is an attempt to highlight the recent synthetic/biological advancements in triazole derivatives that could facilitate the in-depth understanding of its role in the drug discovery process.
The in vitro antimicrobial properties of some chalcones (1a–1c ) and chalcone tethred 1,4-disubstituted 1,2,3-triazoles (2a–2u) towards different microbial strains viz. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans are reported. Compounds 2g and 2u exhibited better potency than the standard Fluconazole with MIC values of 0.0063 µmol/mL and 0.0068 µmol/mL, respectively. Furthermore, molecular docking was performed to investigate the binding modes of two potent compounds 2q and 2g with E. coli topoisomerase II DNA gyrase B and C. albicans lanosterol 14α-demethylase, respectively. Based on these results, a statistically significant quantitative structure activity relationship (QSAR) model was successfully summarized for antibacterial activity against B. subtilis.
A series of furo[3,2‐c]pyrones and furo[3,2‐c]coumarins agents were efficiently synthesized and structure recognizable proof was performed by FTIR and NMR. The furo[3,2‐c]pyrones and furo[3,2‐c]coumarins were evaluated against three bacterial strains (Bacillus subtilis, Staphylococcus aureus and Escherichia coli) and two parasitic strains (Aspergillus niger and Candida albicans). The antimicrobial results demonstrated that a couple of compounds showed noteworthy outcomes relating to the standard medications. Compounds 6 b and 9 f indicated great action against Escherichia coli and Bacillus subtilis with MIC value 0.0108 μmol/ml and 0.0120 μmol/ml, respectively. Compound 9 f also showed better activity against fungal strains with MIC value 0.0120 μmol/ml. Based on the outcomes of antimicrobial activities, docking study was performed to know the binding interface of furo[3,2‐c]pyrones and furo[3,2‐c]coumarins with DNA gyrase topoisomerase II.
In search of 1,2,3-triazole-based antimicrobials, some symmetrical bis(urea-1,2,3-triazole) hybrids were synthesized via clicked Huisgen cycloaddition. The structural characterization was done by different physical and spectral techniques like NMR, FTIR and HRMS. In vitro antimicrobial evaluation of all the synthesized compounds was performed against three bacterial strains (Staphylococcus epidermidis, Escherichia coli and Bacillus subtilis) and two fungal strains (Aspergillus niger and Candida albicans). All the synthesized urea-linked bis(1,2,3-triazole) hybrids (4a–4o) were found to exhibit higher potency than their alkyne precursors (3a–3c). Also, all the synthesized hybrids elicited better antifungal activity than the reference drug Fluconazole against both the fungal strains. Compound 4e and 4o were found to be more potent toward C. albicans with lowest MIC values 0.0112 µmol/mL and 0.0105 µmol/mL, respectively. The docking studies of compounds 4e and 4o and their respective alkynes 3b and 3c were carried out in the active site of sterol 14-α-demethylase of C. albicans.
Graphic abstract
Cu(NO3)2 supported on natural phosphate, Cu(ii)/NP, was prepared by co-precipitation and applied as a heterogeneous catalyst for synthesizing xanthenes (2-3 h, 85-97%) through Knoevenagel-Michael cascade reaction of aromatic aldehydes with 1,3-cyclic diketones in ethanol under refluxing conditions. It was further used for regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles (1-25 min, 95-99%) via a three-component reaction between organic halides, aromatic alkynes and sodium azide in methanol at room temperature. The proposed catalyst, Cu(ii)/NP, was characterized using X-ray fluorescence, X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, Brunauer-Emmett-Teller, Barrett-Joyner-Halenda and inductively coupled plasma analyses. Compared to other reports in literature, the reactions took place through a simple co-precipitation, having short reaction time (<3 hours), high reaction yield (>85%), and high recyclability of catalyst (>5 times) without significant decrease in the inherent property and selectivity of catalyst. The proposed protocols provided significant economic and environmental advantages.
A new series of semicarbazone-triazole hybrid derivatives have been synthesized by condensation between heterocyclic aldehydes and the commercial semicarbazide hydrochloride. The in vitro antioxidant activity of these species was tested using 1,1-diphenyl-2-picrylhydrazyl radical, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) and Ferric reducing antioxidant power assays and their antimicrobial activity against different microbial strains was carried out. Furthermore, molecular properties prediction and drug likeness were also determinated using Molinspiration. Among such derivatives, compounds (E)-2-(4-((1-(2,6-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)hydrazine carboxamide (4c), and (E)-2-(4-((1-(2-methoxyphenyl)-1-H-1,2,3-triazol-4-yl)methoxy)benzylidene)hydrazine-carboxamide (4e) exhibit excellent scavenging ability, especially with IC50 = 1.57 ± 1.66 mg/mL (4c) and IC50 = 1.82 ± 0.15 mg/mL (4e) with 1,1-diphenyl-2-picrylhydrazyl radical and IC50 = 1.90 ± 1.33 mg/mL (4c) with 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) as compared to the standards butylhydroxytoluene (IC50 = 1.60 ± 1.98 mg/mL) and Trolox (IC50 = 1.45 ± 1.33 mg/mL), respectively. The antimicrobial assay results, show that compounds 4c and 4e highlighted the most interesting profile with the potent activity was obtained against S. enteritidis (1.56-fold) and then M. luteus (1.45-fold) which are significantly higher than the positive control, chloramphenicol. By the other hand, the synthesized semicarbazone derivatives met the Lipinski’s rule criteria by presenting good drug likeness and bioactivity scores. The structure–property–activity relationships have been carried out in order to determine the effect of various substituents on the molecular and the biological properties. All these investigations confirm that our synthetic semicarbazone can be explored for generating new potential drug with good oral bioavailability.
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Macrocyclic compounds play an important role in many research fields including drug discovery and development, bioorganic chemistry, and materials sciences. Carbohydrate‐based macrocycles are important compounds with unique structures and many potential applications. In this study, we have designed and synthesized a series of 1,2,3‐triazole linked and pyranose embedded macrocycles in short steps through the copper (I) catalyzed azide and alkyne cycloaddition reactions (CuAACs). Eight non‐symmetrical glucosamine based and bis‐triazole linked macrocycles have been synthesized starting from the readily available N‐acetyl‐d‐glucosamine. These triazole‐linked glycomacrocycles showed remarkable reaction rate accelerations for CuSO4 mediated azide and alkyne cycloaddition reactions in aqueous mixtures. Several azides including a sugar azide, which react sluggishly with alkynes, have been accelerated with the synthesized macrocycles. The benzoylated macrocycles with three methylene linkage at anomeric positions were the most effective among the eight macrocycles.
The continuing rise of infections caused by multi-drug resistant bacteria has led to a renewed interest in bacteriophage therapy. Here we characterize phage vB_AbaM-KARL-1 with lytic activity against multi-drug resistant clinical isolates of Acinetobacter baumannii (AB). Besides genomic and phenotypic phage analysis, the objective of our study was to investigate the antibacterial outcome when the phage acts in concert with distinct antibiotics. KARL-1 belongs to the family of Myoviridae and is able to lyse 8 of 20 (40%) tested clinical isolates. Its double-stranded DNA genome consists of 166,560 bp encoding for 253 open reading frames. Genome wide comparison suggests that KARL-1 is a novel species within the subfamily Tevenvirinae, sharing 77% nucleotide identity (coverage 58%) with phage ZZ1. The antibacterial efficacy at various multiplicities of infection (MOI) was monitored either alone or in combination with meropenem, ciprofloxacin, and colistin. A complete clearance of liquid cultures was achieved with KARL-1 at an MOI of 10-1 and meropenem (>128 mg/l). KARL-1 was still effective at an MOI of 10-7, but antibacterial activity was significantly augmented with meropenem. While ciprofloxacin did generally not support phage activity, the application of KARL-1 at an MOI of 10-7 and therapeutic doses of colistin significantly elevated bacterial suppression. Hence, KARL-1 represents a novel candidate for use against multi-drug resistant AB and the therapeutic outcome may be positively influenced by the addition of traditional antibiotics.
A simple, rapid and efficient copper-catalyzed 1,3-dipolar cycloaddition reaction is described for the synthesis of a novel family of twelve triazolic dendrimers structurally related. The products were the result of the click reaction of three cores and four different azides in tetrahydrofuran applying a homogeneous copper catalysis. The reaction intermediates and products were obtained in very good to excellent yields using straightforward and simple work-up procedures. This new family of compounds contain electroactive moieties such as carbazole and triphenylamine which may turn them into excellent candidates for the development of optoelectronic organic materials.
A series of 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehydes was prepared by the propargylation of 2-hydroxynaphthaldehyde followed by Copper(I)-catalyzed azide-alkyne cycloaddition with various organic azides. 2-((1-substituted-1H-1,2,3-triazol-4-yl)-1-naphthaldehyde analogues were transformed to corresponding oxime derivatives upon grinding with hydroxylamine hydrochloride under solvent free conditions. All the synthesized compounds were characterized by various analytical and spectral techniques and screened in vitro for antimicrobial activity. The activity data revealed that most of the compounds exhibited good to significant activities. Compounds 4c and 5c exhibited very good and broad spectrum activity towards all the tested bacterial strains. Further, to understand the binding interactions, 4c and 5c were docked into the active sites of E. coli topoisomerase II DNA gyrase.
Background:
Nonsteroidal anti-inflammatory drugs are of vast therapeutic benefit in the treatment of different types of inflammatory conditions. 1,2,3-Triazoles and their derivatives have a wide range of applications as anti-bacterial, anti-fungal, anti-tubercular, cytostatic, anti-HIV, anti-allergic, anti-neoplastic and anti-inflammatory (AI) agents. Considering the individual biological and medicinal importance of ibuprofen and 1,2,3-triazoles, we wanted to explore novel chemical entities based on ibuprofen and triazole moieties towards their biological significance.
Results:
Click chemistry has utilized as an ideal strategy to prepare novel ibuprofen-based 1,4-disubstituted 1,2,3-triazole containing molecules. These compounds were screened for their in vivo AI activity, among all the synthesized analogues 13o was shown potent effect than the reference AI drug ibuprofen at the same concentration (10 mg/kg body weight). Compounds 13l, 13g, 13c, 13k, 13i, 13n, 13m and 13j were shown significant AI activity. These triazole analogues were also screened for their bactericidal profile. Compounds 13c, 13i, 13l and 13o exhibited considerable bactericidal activity against gram positive and gram negative strains. In addition to this, molecular docking studies were also carried out into cyclooxygenase-2 active site to predict the affinity and orientation of these novel compounds (13a-q).
Conclusions:
In summary, we have designed and synthesized 1,2,3-triazole analogues of ibuprofen in good yields using Click chemistry approach. AI and bactericidal activities of these compounds were evaluated and shown remarkable results.
Background:
Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity.
Methods:
The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation.
Results:
The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor.
Conclusion:
The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.
The paper presents the synthesis of new artemisinin triazole derivatives via click chemistry and their in vitro cytotoxic evaluation against four cancer cell lines including MCF-7, LU-1, HL-60 and P388. The bioassay result showed that most of the target compounds were active against four cell lines, in which compounds 11g displayed the most potent inhibitory activity against HL-60 cell line with IC50 value of 2.5 μM.
A series of new coumarin-based 1,2,3-triazole derivatives were designed, synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H37Ra, antioxidant activity by DPPH radical scavenging assay, antimicrobial activity in vitro against three gram-positive bacteria (Staphylococcus aureus, Micrococcus luteus and Bacillus cereus) and three gram-negative bacteria (Escherichia coli, Pseudomonas fluorescens and Flavobacterium devorans as well as three fungi (Aspergillus niger, Penicillium chrysogenum and Curvularia lunata). The bioactive assay showed that some synthesized coumarin triazoles displayed comparable or even better antitubercular, antioxidant, antibacterial and antifungal efficacy in comparison with reference drugs. Furthermore, docking study has been performed against DprE1 enzyme of M. tuberculosis that showed good binding interactions. Moreover, the synthesized compounds were also analyzed for ADME properties and showed potential to build up as good oral drug candidates.
Graphical Abstract
New coumarin-based 1,2,3-triazole derivatives were designed, synthesized and evaluated for their antitubercular, antioxidant, antibacterial and antifungal activity. Some of the coumarin-based triazole derivatives displayed comparable or even better efficacy in comparison with reference drugs. Molecular docking study has been performed against DprE1 enzyme of Mycobacterium tuberculosis showed good binding interactions.
A diverse series of 4-((1-benzyl/phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde analogues has been synthesized in good yield by the click reaction between 4-O-propargylated benzaldehyde and various organic bromides/azides. All the synthesized compounds were tested in vitro for their antimicrobial activity against Gram-positive bacteria (Staphylococcus epidermidis and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans and Aspergillus niger). Most of the compounds exhibited good-to-excellent antimicrobial activity. Compound 7b was found to be more potent than ciprofloxacin against B. subtilis, whereas it showed activity comparable to ciprofloxacin against E. coli. Compounds 4h and 4i showed activity comparable to fluconazole against A. niger. Further, the binding mode of compound 7b into the active site of E. coli topoisomerase II DNA gyrase B has also been investigated.
Density functional theory (DFT) calculations have been used to investigate the structural properties, dipole moments, polarizabilities, Gibbs energies, hardness, electronegativity, HOMO/LUMO energies, and chemical potentials of trans and cis configurations of eight para-substituted azobenzene derivatives. All properties have been obtained using the B3LYP functional and 6-31++G(d,p) basis set. The planar structures have been obtained for all optimized trans configurations. The energy difference between trans and cis configurations for considered deriva-tives was found to be between 64.2–73.1 kJ/mole. It has been obtained that the p-aminodiazo-benzene (ADAB) has the difference in the dipole moments between trans and cis forms higher than for trans and cis azobenzene.
A series of amide-linked 1,4-disubstituted 1,2,3-bistriazoles have been synthesized employing copper(I)-catalyzed azide–alkyne cycloaddition reaction. All the newly synthesized compounds were screened for in vitro cytotoxicity against a panel of five human cancer cell lines; Fibrosarcoma (HT-1080), Colon (colo205, HCT-116), and Lung (A549, NCIH322). Some of the bistriazoles exhibited moderate to good activity. Compounds 3n and 3o were found to be the more active and displayed broad spectrum activity against all the cancer cell lines under investigation. Further, to study the binding modes for the two more potent compounds 3n and 3o against Human topoisomerase II, docking simulations have been carried out.
Researchers explore the potential of click chemistry for drug development and diverse chemical-biology applications. Click chemistry is a newer approach to the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions. Researchers have defined the click reaction as wide in scope and easy to perform, which uses only readily available reagents and is insensitive to oxygen and water. Some of the attributes of click reactions include many of these components being derived from derived from alkenes and alkynes, along with from the cracking of petroleum and many of these reactions involve the formation of carbon-heteroatom bonds. Click chemistry-based drug discovery are mainly of three types, such as high-throughput screening, fragment-based drug discovery, and dynamic template-assisted strategies in fragment-based drug discovery.
A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC(50) values ranging from 0.73 to 11.61 μM and 0.49-12.45 μM, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h.
Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded.
A bioactive ligand, 2,5-diamino-1,3,4-thiadiazole (L), derived from semicarbazide hydrochloride, and its metal complexes were prepared and characterized. The complexes were characterized using elemental, infra-red, ultraviolet/visible, magnetic moment, atomic absorption, thin layer chromatography and molar conductance measurements. The IR data revealed that the ligand (L) behaved as a tridentate neutral ligand. It coordinated to the metal ion via sulphur and nitrogen of the amines. The molar conductance data reveal that the chelates are non-electrolytes. From the Ultraviolet/Visible spectra and magnetic moment data, the complexes were found to have octahedral geometrical structure. In vivo evaluation of the antimicrobial activities of the metal complexes and the ligands showed greater activity against some micro-organisms when compared to the parent compounds. The chelates do not show toxicity against the activities of enzymes from homogenates of liver, kidney and serum in experimental rats.
Polymicrobial wound infections often requires high dosage of antibiotics and fungicides. However, prolonged antimicrobial therapies are associated with potential systemic side effects and increased risk for the development of drug resistant microbes. With this focus, we aimed at developing chitosan bandages loaded with anti-microbial (ciprofloxacin and fluconazole) drug loaded nanoparticles for a sustained slow release of drugs. The particle sizes of the prepared ciprofloxacin and flucanazole loaded fibrin nanoparticles were observed to be 132 ± 16 and 175 ± 17 nm respectively. The chitosan bandages with drug containing nanoparticles were flexible with adequate tensile strength and porosity of 80-85%, which would favour excess exudates absorption in an infectious wound. The in vitro toxicity of the bandages studied against human dermal fibroblast (HDF) cell line proved its cytocompatibility. Ciprofloxacin and fluconazole from bandages released upto 14 days in a sustained manner. The antimicrobial drugs loaded bandages showed significant antimicrobial activity towards polymicrobial cultures of C. albicans, E. coli & S. aureus in vitro and ex vivo. In vivo studies were conducted on polymicrobial infected rat wound model. A significant reduction in microbial load was obtained upon application of antimicrobial drug loaded chitosan bandages in vivo.
Volatile oil composition of leaves and fruits of Terminalia arjuna (Roxb.) was reported for the first time. Oils were extracted by microwave assisted hydrodistillation where yield of both oils were found to be 0.20% and their GC-MS analyses led to the identification of 65 and 48 constituents, respectively. Major constituents of leaves were carvacrol (11.17%), thymol (6.52%), α-terpinyl acetate (5.92%) and anethole (5.13%) while that of fruits were (E)-Isoeugenol (11.48%), furfural (8.25%), p-vinylguaiacol (6.8%) and p-ethylguaiacol (5.72%) that demonstrated a significant difference between composition of its aerial parts, however, 33 constituents were identical that showed similarity characteristics in quality of these oils. Both leaf and fruit oils were found active against pathogenic and drug-resistant microbes: E. coli, Methicillin-resistant S. aureus, P. aeruginosa, Total-drug-resistant P. aeruginosa and K. pneumoniae with MIC values of 0.32, 0.32, 0.64, 0.64, 2.56 mg/mL and 0.16, 0.16, 0.32, 0.64, 1.28 mg/mL, respectively.
Semicarbazide (SEM) was used as a metabolic marker to indicate the use (abuse) of the antibiotic nitrofurazone. It can be generated from azodicarbonamide and also had been observed from other unrelated sources. The purpose of this study is to evaluate the existence of SEM in different foods and conjecture the producing pathway. In this article, a LC–MS/MS method for the detection of SEM in different food products had been validated, and the limit of detection was 0.5 μg/kg. Several different sample pretreatment methods had been developed and 31 samples had been evaluated, 80.03–120.15% recoveries of the spiked samples were obtained. It was shown that SEM was detected in various foods. Different types of food might have different mechanisms for retaining SEM, and blank shrimp flesh had been chosen to further study. Several processing methods were performedand the concentration of SEM in processed shrimps was higher than that in unprocessed shrimps, and temperature, moisture, oil, may influence the formation of SEM. Meanwhile, the simulation experiment proved that SEM was produced by amino acids under high temperature. It was shown that the excessive level of SEM in shrimp was endogenous, presumably, it also can be found in rich‐protein food after processing.
Practical applications
This study reflected the SEM universality in different food. In previous studies where using LC–MS to detect SEM in different foods, the pretreatments of different substrate foods rarely varied, this would easily lead to experimental error and solvent waste, this study carried out sample pretreatment classification for the main components of different foods, which provided a reference for the subsequent SEM detection. In view of the endogenous SEM, the possible formation pathways of endogenous SEM were analyzed from the aspects of processing methods and amino acid compositions, providing a theoretical basis for the future study of endogenous SEM.
Polyphenolic compounds have attracted much interest because of their antioxidant properties and multiple applications, from food or cosmetic preservatives to free radical scavengers as therapeutic agents. Inspired by common OH substitutions in natural products, here we describe a small library of 1,2,3-triazoles disubstituted with polyphenol groups at 1,4-positions, in an attempt to correlate the number and position of hydroxyl groups in the aromatic rings with the antioxidant activity. Some compounds from this library exhibit strong radical scavenging activities in the oxygen radical absorbance capacity assay, similar or even higher than resveratrol and other well-kwon flavonoids. The antioxidant activity for selected compounds was confirmed in vitro through the 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonate) test and in vivo by a Saccharomyces cerevisiae model organism assay. The activity depends on the number and position of the hydroxyl groups, with compounds bearing a 2’’5’’-hydroxyl substituents on the phenyl ring at position 4 showing the best antioxidant values. The presence of two quinone-forming phenolic groups at the same molecule is behind the instability of some of these compounds in aqueous media.
A new series of 1,4-disubstituted-1,2,3-triazole derivatives were synthesized through the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (Click chemistry) and their inhibitory activities were evaluated against different human glioblastoma (GBM) cell lines, including highly drug-resistant human cell lines GBM02, GBM95. The most effective compounds were 9d, containing the methylenoxy moiety linked to triazole and the tosyl-hydrazone group, and the symmetrical bis-triazole 10a, also containing methylenoxy moiety linked to triazole. Single crystal X-ray diffraction analysis was employed for structural elucidation of compound 9d. In silico analyses of physicochemical, pharmacokinetic, and toxicological properties suggest that compounds 8a, 8b, 8c, 9d, and 10a are potential candidates for central nervous system-acting drugs.
Alzheimer’s disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of Cu(II)-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation. Structure-activity relationships revealed that pyridine-derived hydrazones represent a promising pharmacophore for future design strategies due to their ability to bind critical Fe(II) pools. Collectively, the unique multi-functional activity of these agents provides a novel therapeutic strategy for AD treatment.
Epilepsy is one of the dreadful neurodegenerative disorder characterized by recurrent, unprovoked seizures. Currently available antiepileptic drugs are still associated with enormous side effects resulting in search of newer, more effective and safer agents. In view of this, we have investigated anticonvulsant activity of 2-amino-6-nitrobenzothiazole derived semicarbazones (7-32) in various in-vivo animal seizure models viz. maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6Hz psychomotor seizure model. Neurotoxicity was estimated by rotarod test. The compounds were also assessed for their neuroprotective potential from excitotoxic insult using organotypic hippocampal slice culture neuroprotection assay. Several compounds exhibited excellent anticonvulsant activity in MES and scPTZ models compared to reference drugs, phenytoin and levetiracetam. The results of kainic acid (KA) - induced neuroprotection assay indicated that compounds 26 and 24 were found to be most potent with IC50 of 99.54±1.27 and 101.00±1.20μM respectively. Both the compounds attenuated KA-mediated cell death in organotypic hippocampal slice cultures. Some of the compounds were found to be good antidepressants, better than the reference drug citalopram, when analyzed in forced swim test. Since semicarbazones exhibited profile resembling phenytoin, an attempt was made to screen them against human neuronal sodium channel isoform (hNav1.2) by performing computational molecular docking using AutoDock 4.2. Compound 30, 1-(5-Chloro-2-oxoindolin-3-ylidene)-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as lead candidate possessing excellent in-vivo MES activity and high binding affinity computationally, better than the reference drug phenytoin and also exhibited neuroprotection from excitotoxic insult in KA-induced neuroprotection assay (IC50=126.80±1.24μM). However, some of the active compounds were neurotoxic at their anticonvulsant doses. Further optimization studies are needed to reduce toxicity and develop them as novel therapeutic agents for epilepsy.
Tuberculosis (TB) is a lift-threatening chronic deadliest infectious disease caused predominantly by Mycobacterium tuberculosis (MTB) which affects primarily the lungs (pulmonary TB) apart from other vital organs. The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and the recently cases of totally drug resistant (TDR) towards currently accessible standard drugs was increased up to alarming level in the recent decades. In pursuit of searching new anti-TB agents, numerous of derivatives have been synthesized and screened for their anti-TB activity. Coumarins are one of the most important classes of natural products that exhibited various biological activities, and their derivatives regarded as a new class of effective anti-TB candidates owing to their potential anti-TB activity. Thus, coumarin skeleton has attracted great interest in the development of new anti-TB agents. This review outlines the advances in the application of coumarin-containing derivatives as anti-TB agents and the critical aspects of design and structure-activity relationship of these derivatives.
Objective: The resurgence of tuberculosis (TB) caused by Mycobacterium TB (MTB) is associated with the rapid spread of multidrug-resistant,therefore, the development of new antimycobacterial agents is necessary. The aim of this study was to evaluate the antimycobacterial activity ofursolic acid (UA) when it using alone and combination with TB drugs.Methods: MTB H37Rv strain, streptomycin-rifampicin resistant strain, and isoniazid-ethambutol resistant strain were evaluated by susceptibility testusing a serial number of UA (25-150 µg/mL). Minimum inhibitory concentration (MIC) was read as minimum concentration of drugs that completelyinhibit visible growth of organism. Activities of drug combination of UA with TB drug were determined in Lowenstein-Jensen media by calculatingthe fractional inhibitory concentration index.Results: The results showed that MIC of UA was 50 µg/mL against three different strains of MTB. The combination of UA and TB drugs displayedsynergistic interaction, and no antagonism result from the combination was observed for strains of MTB.Conclusion: These results indicate that UA may serve as a promising lead compound for future antimycobacterial drug development.Keywords: Ursolic acid, Tuberculosis, Drug combination, Susceptibility test
Objective: This work is designed at finding new structure leads with potential anticonvulsant activities of 4(3H)-quinazolinone pharmacophore scaffold.Methods: A new series of 4(3H)-quinazolinone pharmacophore was designed with substituted moieties possesses different electronic environment in the hope of developing potent and safe new effective compounds. In such fashion, in this paper, we report the synthesis and anticonvulsant activity (Chemo shock) of N-1(substituted-N-4[(4-oxo-3-phenyl-3, 4-dihydro-quinazoline-2-ylmethyl) semicarbazones 3A-d (1-7), 3B-d (1-7), 3C-d (1-7), their chemical structure were characterized using IR, H-H NMR, and elemental analysis techniques. Their anticonvulsant activity was evaluated using chemicals strychnine, thiosemicarbazide and 4-aminopyridine induced seizure models at a dose of 30, 100, 300 mg/kg unto 2 hrs tests in mice. The rotarod assay was performed in mice to evaluate the neurotoxicity of the compounds. 1Results: Compounds 3C (d-4), 3B (d-4), and 3A (d-4) were observed to be most feasible to act against glutamate receptor for anticonvulsant activity.Conclusions: The results obtained revealed that numbers of novel quinazolinone semicarbazone derivatives are effective in chemical to induce (chemo shock) model and showing good anticonvulsant activity.Keywords: Quinazolinone, Semicarbazones, Strychnine, Thiosemicarbazide, 4-aminopyridine, Anticonvulsant activity, Chemo shock.
1,2,3-Triazoles are important five-membered heterocyclic scaffold due to their extensive biological activities. This framework can be readily obtained in good to excellent yields on the multigram scale through click chemistry via reaction of aryl/alkyl halides, alkynes and NaN3 under ambient conditions. It has been an emerging area of interest for many researchers throughout the globe owing to its immense pharmacological scope. The present work aims to summarize the current approaches adopted for the synthesis of the 1,2,3-triazole and medicinal significance of these architectures as a lead structure for the discovery of drug molecules such as COX-1/COX-2 inhibitors (celecoxib, pyrazofurin), HIV protease inhibitors, CB1 cannabinoid receptor antagonist and much more which are in the pipeline of clinical trials. The emphasis has been given on the major advancements in the medicinal prospectus of this pharmacophore for the period during 2008-2016.