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New Antibacterial 1, 3, 4-Thiadiazole Derivatives With Pyridine Moiety
Abstract
1,3,4‐Thiadiazole compounds were synthesized using pyridine carboxylic acid derivatives and thiosemicarbazide derivatives. The molecular structures of the resulting compounds were characterized by spectroscopic methods such as ATR‐FTIR, 1H‐NMR, and elemental analysis. Its compounds were also examined for their antibacterial properties against some strains of bacteria. Five synthesized compounds showed varying antibacterial effects on Escherichia coli, Salmonella kentucky, Bacillus substilis and Klebsiella pneumoniae. This result revealed that some of the resulting compounds could be antibacterial agents.
... pyridin-2-amine was successfully synthesized by reacting 2-aminonicotinic acid with cyclohexylthiosemicarbazide as depicted in Scheme 1 [15,16]. ...
... A four-bond HMBC correlation indicates a coupling between H 6 and the C 7 , C 8 carbons. The data obtained were consistent with the literature [16]. ...
... 3-[5-(Cycloheximino)-4,5-dihydro-1,3,4-thiadiazol-2-yl]pyridin-2-amine was prepared as previously described [15,16]. IR spectrum, ν, cm The data obtained were found to be compatible with the literature [15,16]. ...
... Structurally, thiadiazole is a five-member heterocyclic ring that contains one sulfur and two nitrogen heteroatom. Thiadiazole ring containing compounds showed diverse range of therapeutics activity such as antidiabetic [4], antioxidant [5], anticancer [6], anti-inflammatory [7], insecticidal [8] , Antiviral [9], antibacterial [10], anticonvulsant [11]. Anticancer agents exert their effect by cell suppression and inhibition of several enzymes, growth factor such as histone deacetylase (HDAC), thymidylate synthase (TS), telomerase enzyme, topoisomerase enzyme, methionine aminopeptidase (MetAP), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), focal adhesion kinase (FAK) and glycogen synthase kinase-3 (GSK-3), etc [12]. ...
Cancer is a deadlier disease now a day. Heterocyclic compounds are playing a crucial role for the treatment of cancer. Numerous anti-cancer agents are available in market which contain heterocyclic ring. Among the heterocyclic ring thiadizole is of great interest in the recent era due to their potential anti-cancer activity. Histone deacetylases (HDAC) is a crucial player in oncogenesis, proliferation, differentiation, DNA repair, up-regulation of silenced tumor suppressors, and tumor progression. Therefore, it is become a promising target for cancer drug design. This review explores the chemical structure of thiadiazole derivatives, anticancer activity and binding analysis of HDAC inhibitors from the year 2019 to 2024. Through comprehensive examination of thiadiazole scaffold containing derivatives. Overall, this review underscores the pivotal role of HDAC inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.
... It is particularly notable for its bacteriostatic, antiviral, antifungal, and insecticidal properties, thereby playing a crucial role in the creation and advancement of novel pesticides [18][19][20]. 1,3,4-Thiadiazole derivatives constitute a class of aromatic five-membered heterocyclic compounds distinguished by the inclusion of two nitrogen atoms and one sulfur atom [21,22]. These compounds demonstrate a wide range of biological activities, such as antifungal, insecticidal, and anticancer properties. ...
In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC50 values of 180.7, 190.3 and 215.8, 218.6 μg/mL, respectively, surpassing the efficacy of NingNanmycin, which exhibited EC50 values of 284.1 and 247.1 μg/mL. The preliminary mechanistic studies indicated that H6 and Y5 had ahigh binding affinity for the tobacco mosaic virus capsid protein (TMV-CP), potentially obstructing the self-assembly and replication processes of TMV particles. Furthermore, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. H6 has the potential to be developed as a novel antiviral.
Graphical abstract
A series of studies on the mechanism of action of H6 have demonstrated its antiviral activity.
... It is particularly notable for its bacteriostatic, antiviral, antifungal, and insecticidal properties, thereby playing a crucial role in the creation and advancement of novel pesticides [18][19][20]. 1,3,4-Thiadiazole derivatives constitute a class of aromatic ve-membered heterocyclic compounds distinguished by the inclusion of two nitrogen atoms and one sulfur atom [21,22]. These compounds demonstrate a wide range of biological activities, such as antifungal, insecticidal, and anticancer properties. ...
In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC 50 values of 180.7, 190.3 and 215.8, 218.6 µg /mL, respectively, surpassing the efficacy of NingNanmycin, which exhibited EC 50 values of 284.1 and 247.1 µg /mL. The preliminary mechanistic studies indicated that H6 and Y5 had ahigh binding affinity for the tobacco mosaic virus capsid protein (TMV-CP), potentially obstructing the self-assembly and replication processes of TMV particles. Furthermore, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. H6 has the potential to be developed as a novel antiviral.
Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N′-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = −8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19.
Pyridine, 1,3,4-thiadiazole, and 1,3-thiazole derivatives have various biological activities, such as antimicrobial, analgesic, anticonvulsant, and antitubercular, as well as other anticipated biological properties, including anticancer activity. The starting 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-phenylthiourea (2) was prepared and reacted with various hydrazonoyl halides 3a–h, α-haloketones 5a–d, 3-chloropentane-2,4-dione 7a and ethyl 2-chloro-3-oxobutanoate 7b, which afforded the 3-aryl-5-substituted 1,3,4-thiadiazoles 4a–h, 3-phenyl-4-arylthiazoles 6a–d and the 4-methyl-3- phenyl-5-substituted thiazoles 8a,b, respectively. The structures of the synthesized products were confirmed by spectral data. All of the compounds also showed remarkable anticancer activity against the cell line of human colon carcinoma (HTC-116) as well as hepatocellular carcinoma (HepG-2) compared with the Harmine as a reference under in vitro condition. 1,3,4-Thiadiazole 4h was found to be most promising and an excellent performer against both cancer cell lines (IC50 = 2.03 ± 0.72 and 2.17 ± 0.83 µM, respectively), better than the reference drug (IC50 = 2.40 ± 0.12 and 2.54 ± 0.82 µM, respectively). In order to check the binding modes of the above thiadiazole derivatives, molecular docking studies were performed that established a binding site with EGFR TK.
Phenanthroimidazole-thiadiazole hybrid derivatives, which are new heterocyclic compounds with fluorescence properties, were synthesized by designing a two-step reaction mechanism and their photophysical properties were investigated. The synthesized derivatives were purified and their structures were elucidated by ATR-IR, ¹H-NMR, elemental analysis and HR-MS methods. In the next stage of the study, the absorption and emission spectra of the synthesized new phenanthroimidazole-thiadiazole hybrid derivatives were determined by UV–Vis and fluorescence spectroscopy. Stokes’ shifts, molar extinction coefficients (ε), singlet energy levels (Es), quantum yield (ϕf), lifetimes (τ), the radiative (kr) and the nonradiative (knr) constant for new hybrid derivatives were measured in DMSO. In addition, aggregation measurements, which is an important parameter that changes the photophysical properties were performed and for these compounds, structure: photophysical properties were discussed.
The novel compounds bearing 1,3,4‐thiadiazole moiety were obtained and their structures were identified using FT‐IR, NMR methods, elemental, and mass analysis. UV‐Vis and fluorescence spectra were obtained in six different polarity solvents. In addition, antimicrobial, antibiofilm, and the efflux pump inhibiting activities of the new compounds on K. pneumoniae, methicillin‐resistant S. aureus (MRSA), E. coli, and C. albicans were investigated. Furthermore, druglikeness and ADMET properties of the compounds were determined. As a result, it was observed that some of the derivatives presented antimicrobial activity against K. pneumoniae, S. aureus, and C. albicans. But the MBC/MFC test showed that all the activities were bacteriostatic. In addition, these derivatives have the potential of using both inhibiting and activating biofilm formation depending on the concentration. 1,3,4‐thiadiazole derivatives also presented good efflux pump inhibition in K. pneumoniae and E. coli. ADMET tests showed that 1,3,4‐thiadiazole derivatives have the potential of being used as therapeutic compounds.
Schiff-base-bearing new bis(thiosemicarbazone) derivatives were prepared from terephthalaldehyde and various thiosemicarbazides. FT-IR, 1H NMR, 13C NMR, and UV-Vis spectroscopic methods and elemental analysis were used to elucidate the identification of the synthesized molecules. The in vitro antioxidant activity of the synthesized compounds was analysed with the 1,1-diphenyl-2-picryl hydrazyl free-radical-trapping process. The synthesized compounds exhibited lower antioxidant activity than the standard ascorbic acid. IC50 values of the synthesized molecules measured from 3.81 ± 0.01 to 29.05 ± 0.11 μM. Among the synthesized compounds, compound 3 had the best antioxidant activity. Moreover, this study explained the structure-activity relationship of the synthesized molecules with different substituents in radical trapping reactions.
The reaction of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarbohydrazide with variety of carbonyl compounds such as substituted benzaldehydes, cycloalkanones and hetero-cyclic ketones under grinding method under catalyst- and solvent-free conditions at room temperature, in the presence of catalytic drops of acetic acid gave a new series of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarbohydrazone derivatives in good to excellent yields. The structures of new products were elucidated on the basis of their spectral data and elemental analysis. Most of the newly prepared compounds were evaluated towards HepG2 cell lines and showed good IC50 for some compounds. Additionally, molecular docking of the novel chemical entities using Autodock Vina demonstrated their binding modes within the active site of DYRK1A.
A novel series of bis(1,3,4-thiadiazole) derivatives were synthesized as a sole product in one step methodology by reaction of bis-hydrazonoylchloride 3 with many of hydrazinecarbodithioate derivatives 2a–e, 6a,b, and 8a–e. We discuss the mechanisms of the reactions studied and use elemental and spectral data to identify the assigned structure for each of the new products. This research aimed at synthesizing a novel series of derivatives of bis-thiadiazoles and investigating their antimicrobial and anticancer activity. The results showed that compound 6b was the most efficient synthesized antimicrobial compound. Moreover Compounds 8c, 10d, 6b, and 8d were the most active (IC50 values of 0.37 ± 0.15, 0.93 ± 0.32, 1.03 ± 0.45, and 3.52 ± 0.43 µg/mL, respectively) against human breast carcinoma cell line (MCF-7) and compounds 8c, 10d, 6b, and 8d were the most active (IC50 value of 0.38 ± 0.12, 0.88 ± 0.46, 2.15 ± 0.16, and 2.47 ± 0.44 µg/mL, respectively) against the human hepatocellular carcinoma cell line (HepG-2).
Twelve bis-thiadiazole derivatives were synthesized in high yield via the reaction of 2,2′-terephthaloyl bis(N-phenylhydrazine carbothioamide) with a variety of hydrazonoyl chlorides in ethanol containing catalytic amounts of TEA. All the newly synthesized compounds were characterized by physical and chemical tools (FT-IR, ¹H NMR, ¹³C NMR, and Mass spectrometry). Moreover, all the novel synthesized derivatives were screened for their antihypertensive α-blocking efficacy against to assess their pharmaceutical significance. The encouraging promising results obtained from antihypertensive α-blocking activity studies on the newly synthesized derivatives make the synthesis of a new series of these compounds and studying of their pharmaceutical importance an active area for more and more investigations. The molecular docking of the most active derivative 15 b against the human dopamine D3 receptor was performed by the Molecular Operating Environment (MOE 2014. 0901) program.
Abstract The resinous exudates from Escallonia illinita by products was characterized by FT-IR, NMR and HRMS. Six compounds were isolated and identified as follows: 1,5-diphenylpent-1-en-3-one (1), 4-(5-hydroxy-3,7-dimethoxy-4-oxo-4H-chromen-2-yl)phenyl acetate (2), pinocembrin (3), kaempferol 3-O-methylether (4), (3S,5S)-(E)-1,7-diphenylhept-1-ene-3,5-diol (5) and the new diarylheptanoid (3S,5S)-(E)-5-hydroxy-1,7-diphenylhept-1-en-3-yl acetate (6). The anti-oomycete potential of the resinous exudate, as well as the main compounds, was tested in vitro against Saprolegnia parasitica and Saprolegnia australis. The resinous exudate showed a strong anti-oomycete activity. In addition, the compounds 6, 1 and 3 demonstrated significant inhibition of Saprolegnia strains development. These findings strongly suggest that E. illinita is a potential biomass that could be used as a natural anti-oomycete product.
Pathogenic microorganisms are causative agents for different types of serious and even lethal infectious diseases. Despite advancements in medication, bacterial and fungal infections continue to be a growing problem in health care. As more and more bacteria become resistant to antibiotics used in therapy and an increasing number of invasive fungal species become resistant to current antifungal medications, there is considerable interest in the development of new compounds with antimicrobial activity. The compounds containing a heterocyclic ring play an important role among organic compounds with biological activity used as drugs in human and veterinary medicine or as insecticides and pesticides in agriculture. Thiadiazoles belong to the classes of nitrogen–sulfur heterocycles with extensive application as structural units of biologically active molecules and as useful intermediates in medicinal chemistry. The potency of the thiadiazole nucleus is demonstrated by the drugs currently used. 1,3,4-Thiadiazoles and some of their derivatives are extensively studied because of their broad spectrum of pharmacological activities. The aim of this review was to highlight the main antimicrobial properties exhibited by derivatives possessing 2-amino-1,3,4-thiadiazole moiety. Many of the reported 2-amino-1,3,4-thiadiazole derivatives can be considered as lead compounds for drug synthesis, and several of them have demonstrated higher antimicrobial activity in comparison to standard drugs. Furthermore, taking into account the reactivity of the amine group in the derivatization process, 2-amino-1,3,4-thiadiazole moiety may be a good scaffold for future pharmacologically active 1,3,4-thiadiazole derivatives.
In this study, 1-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethan-1-one, was reacted with Thiosemicarbazide, alkyl carbodithioate and benzaldehyde to give thiosemicarbazone, alkylidenehydrazinecarbodithioate and 3-phenylprop-2-en-1-one-1,2,3-triazole derivatives. The 1,3,4-thiadiazole derivatives containing the 1,2,3-triazole moiety were obtained via reaction of alkylidenecarbodithioate with hydrazonoyl halides. Also, hydrazonoyl halides were reacted with thiosemicarbazone and pyrazolylthioamide to give 1,3-thiazoles derivatives. Subsequently, 3-phenyl-2-en-1-one was used to synthesize substituted pyridines and substituted nicotinic acid ester. The latter was converted to its azide compound which was reacted with aromatic amines and phenol to give substituted urea and phenylcarbamate containing 1,2,3-triazole moiety. The newly synthesized compounds were established by elemental analysis, spectral data and alternative synthesis whenever possible.
A series of dipicolinic acid derivatives was synthesized and investigated for antimicrobial and antioxidant activity. Mono and bis derivatives of ethyl dipicolinate were utilized as starting materials for synthesis of mono- and bis-hydrazides. Thiosemicarbazides were obtained by reaction of hydrazides with isothiocyanates and cyclized into triazoles, thiadiazoles, oxadiazoles and thiazolidinones. Some of these products, especially those incorporating a thiazolidinone moiety in their structure, are excellent antioxidants, DPPH scavengers and antifungal agents.
In this paper, the synthesis of bis-thiazoles and bis-1,3,4-thiadiazoles linked to a thienothiophene nucleus is described. The synthesis was achieved through interaction between 2,5-diacetylthieno[2,3-b]thiophene bis-thiosemicarbazones with a variety of hydrazonyl halides in a basic medium. All the synthesised compounds were characterised by IR, 1H NMR, 13C NMR and mass spectroscopic analyses. The newly synthesised compounds represent a variety of novel polyheteroatomic moieties containing nitrogen and sulfur. Most of the synthesised compounds were evaluated for their antitumour activity against the breast cancer MCF-7 cell line. The results revealed that four compounds are equipotent to tamoxifen (IC50 = 8.04 μg mL-1) with IC50 = 8.23, 8.26, 8.68 and 9.12 μg mL-1 respectively.
A copper(II) complex with picolinic acid as ligand has been synthesised and characterised by elemental analysis, magnetic susceptibility, Fourier transform infrared spectroscopy (FTIR) and ultraviolet-visible spectroscopic techniques. The crystal structure of the complex has been determined by single crystal X-ray diffraction technique and the ligand was found to coordinate through N- and O-atoms. The ligand and the complex were screened for their activity against resistant strains of fungi (Candida albicans ATCC P37039, Candida albicans 194 B, Candida glabrata 44B, Cryptococcus neoformans) and bacteria (Staphylococcus aureus CIP 7625, Pseudomonas aeruginosa CIP 76110, Salmonella typhi and Escherichia coli ATCC 25922) isolated from humans in Cameroon.
The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.
Reactions of hydrazonoyl halides and each of methyl 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-carbodithioate and 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-carbothioamide afforded 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-3-phenyl-5-substituted-2,3-dihydro-1,3,4-thiadiazoles and 5-(4-substituted)diazenyl)-2-(2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazinyl)-4-arylthiazoles, respectively. Analogously, the reactions of hydrazonoyl halides with 7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-5-phenyl-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one gave 3-(4-substituted)-8-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-6-phenyl-1-arylpyrido[2,3-d]-[1,2,4]-triazolo-[4,3-a]pyrimidin-5(1H)-ones in a good yield. The structures of the newly synthesized were elucidated via elemental analysis, spectral data and alternative synthesis routes whenever possible. Twelve of the newly synthesized compounds have been evaluated for their antitumor activity against human breast carcinoma (MCF-7) and human hepatocellular carcinoma (HepG2) cell lines. Their structure activity relationships (SAR) were also studied. The 1,3,4-thiadiazole derivative 9b (IC50 = 2.94 µM) has promising antitumor activity against the human hepatocellular carcinoma cell line and the thiazole derivative 12a has promising inhibitory activity against both the human hepatocellular carcinoma cell line and the breast carcinoma cell line (IC50 = 1.19, and 3.4 µM, respectively).
SnO nanoparticles as an efficient catalyst have been used for the preparation of chromeno [2,3-b] pyridines and 2-amino-3,5-dicyano-6-sulfanyl pyridines under reflux conditions in ethanol in good to excellent yields. This flexible and nano-catalytic procedure showed good recyclability and provides cleaner condensation reaction in a short reaction time.
A series of novel bis-1,2,4-triazoles and bis-1,3,4-thiadiazoles bearing pyridine rings was synthesised, by multistep reaction sequences, in good to high yields. Reaction of pyridine-2,5-bis- and pyridine-2,6-bis-carbohydrazides with alkyl- or aryl-isothiocyanates gave the corresponding
bis(thiosemicarbazide) derivatives, which could be cyclised under strongly basic conditions to give novel pyridine bis(1,2,4-triazole-3-thiols). However, under strongly acidic conditions the corresponding bis(2-amino-1,3,4- thiadiazoles) were obtained. The synthetic routes and spectroscopic
characterisation of the new compounds are reported.
In this paper we have investigated the in vitro antioxidant property of two triazolo-thiadiazoles, 6-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (FPNT) and 6-[3-(4-chlororophenyl)-1H-pyrazol-4-yl]-3-[(phenyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (CPPT) by spectrophotometric DPPH and ABTS radical scavenging methods as well as by lipid peroxide assay. The anticancer activity along with possible mechanism of action of triazolo-thiadiazoles in Hep G2 cells was explored using MTT assay, [3H] thymidine assay, flow cytometry and chromatin condensation studies. Both FPNT and CPPT exhibited a dose dependent cytotoxic effect on hepatocellular carcinoma cell line, HepG2. The IC50 value was very low for both the compounds when compared to standard drug, doxorubicin. Incorporation of [3H] thymidine in conjunction with cell cycle analysis suggested that FPNT inhibited the growth of HepG2 cells. Flow cytometric studies revealed more percentage of cells in sub-G1 phase, indicating apoptosis, which was further confirmed through chromatin condensation studies by Hoechst staining. FPNT was found to be a potent antioxidant when compared to the standard in DPPH, ABTS radical scavenging assays and lipid peroxidation studies.
Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to humanity due to easy transmission and difficult-to-treat skin and flimsy diseases. The most threatening aspect is the rapid resistance development of MRSA to any approved antibiotics, including vancomycin. The development of new, efficient, and nontoxic drug candidate to fight against MRSA isolates is the need of the hour. The intriguing molecular structure and versatile bioactive pyrazole core attracting to development required novel antibiotics. This review presents the decade developments of pyrazole-containing derivatives with a broad antibacterial movement against diverged bacterial strains. In specific, we correlated the efficacy of structurally diversified pyrazole analogs against MRSA and discussed different angles of structure-activity relationship (SAR). The current survey highlights pyrazole hybrids' present scenario on MRSA studies, covering articles published from 2011 to 2020. This collective information may become an excellent platform to plan and develop new pyrazole-based small MRSA growth inhibitors with minimal side effects.
A new thiadiazole ligand, N-ethyl-5- (benzo[b]thien-2-yl-)-1,3,4-thiadiazol-2-amine (BTH), was prepared from 3-methyl-1-benzofuran-2-carboxylic acid and N-ethylhydrazinecarbothioamide precursors. Corresponding silver(I) complex, tetrakis(N-ethyl-5-(benzo[b]thien-2-yl-)-1,3,4-thiadiazol-2-amine)silver(I) nitrate [Ag2(BTH)4](NO3)2 (1), was prepared. The structures of BTH and 1 were characterized by ¹H-NMR, ¹³C-NMR, FT-IR, elemental analysis and HR-MS techniques. Furthermore, molecular structure of 1 was illuminated by X-ray crystallography. Owing to strong anagsotic interaction, crystal structure of the complex revealed an intriguing asymmetric monomer unit even with two same ligands in 2:1 metal-to-ligand stoichiometry. Photoluminescence properties of the complex were investigated by solid and solution media emission measurements. Excited and emissive state behavior of the complex was further analyzed by quantum chemical TD-DFT calculations and natural transition orbital (NTO) analyses.
The current study in this article concerned with construction of five‐membered heterocycles with multiple heteroatoms as nitrogen and sulfur from readily available starting materials and reagents. Treatment of 1‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one with each of phenylisothiocyanate in alcoholic potassium hydroxide and carbon disulfide in basic medium gave rise to a thioanilide and methylthio derivatives, respectively. Treatment of the latter compounds with a variety of hydrazonoyl halides resulted in construction of thiadiazole moiety linked to pyrazole ring. Furthermore, triazole derivatives were synthesized from the thioanilide derivative through its reaction with methyl iodide followed by reaction with hydrazonoyl halides. 5α‐Reductase inhibition activity for the prepared compounds was investigated against the reference drug anastrozole, and the results showed that the inhibition activity of compounds 5g and 11g is more potent than anastrozole. Also compounds bearing triazole moiety is more potent than compounds bearing thiadiazole one. Moreover, the anti‐prostate cancer screening anti‐androgenic bioassay in human prostate cancer cells for the tested compounds was evaluated, and the results showed great inhibition growth and potential antiandrogens.
Background
Thiazoles and pyridines are versatile synthetic scaffolds possessing wide spectrum of biological effects including potential antimicrobial activity.
Objective
In the efforts to develop suitable antimicrobia drugs, medicinal chemists have focused on thiazole derivatives. A novel series of 2-thiazolyl pyridines was prepared in a one-pot three-component reaction using 2-bromoacetyl pyridine as a starting precursor.
Method
Structure of the synthesized compounds was elucidated by spectral data (FT-IR, 1H NMR, 13C NMR, and mass) and elemental analyses. The prepared compounds were screened for their in vitro antimicrobial activity.
Results
The results revealed that compounds 4a,b,e-g and 12 showed promising activity. Molecular docking studies using MOE software were carried out for compounds 4a and 4b which exhibited potent activities indicated by the diameter zones (4a; 3.6, 4.0, 1.2 mm) (4b; 4.2, 3.5, 1.5 mm) and the binding affinities (4a; -5.7731, -5.3576, -4.6844 kcal mol-1) (4b; -5.9356, -2.8250, -5.3628 kcal mol-1) against Candida albicans, Bacillus subtilis and Escherichia coli, respectively.
Conclusion
This paper describes a facile and efficient MCR for synthesis of 2-thiazolyl pyridines from reaction of 2-bromoacetyl pyridine with different reagents. There was an agreement between the values of binding affinities and interactions and the data obtained from the practical antimicrobial screening of the tested compounds.
A novel class of 5‐amino‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐1H‐pyrazole‐4‐carbohydrazides and 8‐(pyridin‐4‐yl)pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidin‐5(1H)‐ones was synthesized from reaction of 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐acetohydrazide and 7‐(pyridin‐4‐yl)‐2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐one with the appropriate hydrazonoyl halides. Moreover, 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)‐ethylidene)‐acetohydrazide was used for the synthesis of 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐acrylohydrazides and 2‐oxo‐2‐(2‐(1‐(pyridin‐4‐yl)ethylidene)‐hydrazinyl)‐acetohydrazonoyl cyanides. The structures of the newly prepared compounds were confirmed by both elemental and spectral analyses as well as by alternate synthesis. The anticancer activities of the prepared compounds were screened against the hepatocellular carcinoma (HepG2) cell line, and the results showed that most of the compounds exhibit considerable activities.
5-Amino-3-methyl-4-phenylazo-1H-pyrazole and ethyl cyanoacetate reacted in solvent-free media at 150°C to produce 7-amino-3-phenylazo-2-methyl-4H-pyrazolo[1,5-a]pyrimidine-5-one (3). A series of aromatic amines was coupled using this compound (3) and nitrous acid to produce new pyrazolo[1,5-a] pyrimidine derivatives with two arylazo groups 4(a-m). The structures of these dyes were determined via UV–vis, Fourier transform infrared, proton nuclear magnetic resonance, high-resolution mass spectral data, and elemental analysis. After synthesis, the solvent and acid–base effects of the dyes were investigated within the UV–vis region. The antimicrobial properties of the dyes were also studied. All dyes exhibited activity against Gram-positive and Gram-negative bacteria, and even against fungi. The results were compared to conventional reference results from the antibiotics ciprofloxacin and ketoconazole. Antioxidant potentials were analyzed using in vitro antioxidant models on the basis of DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activities. Most of the compounds exhibited excellent antioxidant activities. In particular, compound 4b had a higher activity than Vitamin C.
Ten novel fluorescent azo disperse dyes 2a–e (open forms) and 3a–e (closed forms) were obtained by the coupling reaction of carbocyclic amine based diazonium chloride with compounds 2 and 3. The synthesized dyes were characterized by elemental analysis, high-resolution mass spectrometry, Fourier transform infrared, and NMR spectral techniques. Moreover, we investigated the substituent effect and solvatochromic properties of the dyes on absorption and fluorescence spectra. At the same time, the absorption and emission spectral data of the closed form dyes 3a–e were compared with the open form dyes 2a–e due to more planarity of the closed form dyes that lead to the extension of the π–electron conjugation.
Fourteen potentially bioactive pyridines, pendant to pyrazole moiety, were synthesized and evaluated in vitro for their antimicrobial potential. Treatment of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone with pyridine afforded the corresponding pyridinium bromide salt. Reaction of the latter salt with α,β-unsaturated ketones yielded the corresponding 2,4,6-trisubstituted pyridine derivatives. The structures of the synthesized products were confirmed by all possible spectral data. The antimicrobial activity of some selected products was evaluated by using well-diffusion agar assay and minimum inhibitory concentration determination, and the results revealed good-to-moderate activities compared with reference drugs.
The novel compound namely ethyl 3-(1-(2-(2-cyanoacetyl)-hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate 3 was used as key intermediate for synthesizing the thioanilide derivative 4 and the arylidene derivatives 6. The reaction of 4 with a number of haloketones and haloesters furnished the respective thiazole derivatives 8, 10 and 11a,b. Moreover, the reaction of 4 with N-aryl-2-oxopropane hydrazonoyl chloride 13 and ethyl (N-arylhydrazono)chloroacetate 17 in absolute ethanol in the presence of triethylamine at reflux afforded a new series of thiadiazoles 15 and 19, respectively. The mechanisms that account for formation of products 15 and 19 were discussed. Also, the structures of all the newly synthesized products were confirmed based on elemental analysis, spectral data and by alternative methods..
The synthesis of a novel series of pyridine and bipyridine derivatives is described via one-pot multicomponent reaction of 5-acetylimidazole, malonitrile (or ethylcyanoacetate or diethylmalonate), substituted benzaldehyde (or terephthaldehyde), and ammonium acetate in good yields. The structures of all the new compounds were elucidated on the basis of elemental analysis and spectral data. The antimicrobial activities of the synthesized compounds were screened and the results showed that most of such compounds exhibit considerable activities. Furthermore, some of the newly synthesized compounds were screened for their anticancer activity against human breast cell line (MCF-7) and liver carcinoma cell line (HEPG2) in comparison to doxorubicin. Most of the tested compounds exhibited promising activity.
A series of alkyl α-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetic acid esters 6a–e were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H37Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The antituberculosis data indicated that methyl, propyl, buthyl and benzyl esters showed a significant in vitro antimycobacterium tuberculosis activity (MIC=0.39–0.78 μg/ml) and the ethyl analogue did not show a good activity (MIC>6.25 μg/ml, %inhibition=58). The most active compound of the series was n-propyl α-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetate (6c) with MIC value of 0.39 μg/ml.
A series of novel thiosemicarbazone based molecular tweezers were synthesized and studied as anion-binding receptors. Contrasting our former work, some of these receptors not only have considerable selectivity to H2PO4 , as well as F and CH3COO. When adding F, CH3COO and H2PO4 anions to their solutions respectively, the color has shown striking changes from colorless to yellow or dark yellow. The binding abilities of the receptors are according with the acidities of the N-H groups on the thiourea moiety, which are determined by the electronegativity of subgroups on them. Job plot indicated that 1:1 stoichiometry complex are formed between receptors and anions.
A practical and scaleable synthesis of 2-chloro-5-(pyridin-2-yl) pyrimidine, an intermediate in the synthesis of a selective PDE-V inhibitor, was developed. A Negishi cross-coupling between the in situ prepared 2-pyridylzinc chloride and 5-iodo-2-chloropyrimidine catalyzed by Pd(PPh3)4 afforded the product in one step. Development of a convenient purification did away with the necessity of chromatography, allowing the preparation of the product on kilogram scale.
A series of Co(II), Ni(II) and Cu(II) complexes of the type ML2 have been synthesized with Schiff bases derived from methylthiosemicarbazone and 5-formyl-6-hydroxy coumarin/8-formyl-7-Hydroxy-4-methylcoumarin. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMF indicate that, the complexes are non-electrolytes in nature. In view of analytical, spectral (IR, UV–vis, ESR, FAB-mass and fluorescence), magnetic and thermal studies, it has been concluded that, all the metal complexes possess octahedral geometry in which ligand is coordinated to metal ion through azomethine nitrogen, thione sulphur and phenolic oxygen atom via deprotonation. The redox behavior of the metal complexes was investigated by using cyclic voltammetry. The Schiff bases and their complexes have been screened for their antibacterial (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi) and antifungal activities (Aspergillus niger, Aspergillus flavus and Cladosporium) by Minimum Inhibitory Concentration method. The DNA cleavage is studied by agarose gel electrophoresis method.
Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.
To review acute administration of drugs in epilepsy for indications other than status epilepticus.
This review looks into the application of acute drug administration (ADA) against febrile and prolonged nonfebrile seizures in children, seizure clustering (habitual or at drug withdrawal), catamenial epilepsy, response to seizure "warnings", and prophylaxis of seizures at perceived increased risk (reflex epilepsies, long-distance travel, lifestyle, and social occasions). The drugs most commonly used for ADA are the benzodiazepines diazepam (oral or rectal), clobazam and buccal or nasal midazolam, and lorazepam. Others include valproic acid, nitrazepam, acetazolamide, chloral hydrate, pyridoxine, and antipyretics.
The best evidence for the efficacy of ADA exists in febrile and nonfebrile childhood seizures, whereas the evidence in catamenial epilepsy is weak. Prevention of clusters is a well-proven principle but its application has been little studied. Prevention of imminent seizures predicted by well-established triggers, defined risk factors, or premonitory minor seizure activity seems to be at the same time the most intelligent and the least investigated application of ADA and would deserve to be better studied.
The tetrahydroquinoline ring system is a very common structural motif and is found in numerous biologically active natural products and pharmacologically relevant therapeutic agents. variety of novel 1,2,3,4-tetrahydroquinoline-based natural products, some of which showed interesting biological activities, were reported during the 1995-2010 period. A couple of novel pyrroloquinoline alkaloids, martinellic acid 2a and martinelline 2b, was isolated from the roots of the tropical plant Martinella iquitosensis,8 and they have become synthetic. Tetrahydroquinolines having hydrogenation patterns different from the 1,2,3,4-tetrahydro-one are rarely present in natural products. Some tetrahydroquinolines are also active against antibacterial targets, including DNA gyrase and methionyl tRNA synthetase which has been proposed as an important target in the treatment of infections because of the Gram-positive bacteria resistant to conventional antibiotic therapy. Some tetrahydroquinoline derivatives have interesting activities on ion channels.
Progress made in the preparation of substituted pyrazoles from 2000 to mid-2010 both in solution and on solid phase is presented. The search for new and efficient procedures for the synthesis of pyrazole derivatives has experienced an unprecedented growth during this period. One-pot procedures and the use of new reaction conditions have made it possible to overcome limitations such as the preparation of the starting materials or the lack of regioselectivity in the synthesis of substituted pyrazoles. The Michael-type addition of N-monosubstituted hydrazones to nitroolefins, reported for the first time in 2006, has emerged as a versatile method for the regioselective synthesis of a plethora of alkyl-, aryl-, and heteroaryl-substituted pyrazoles. Stille, Sonogashira, Negishi, and Heck C-C cross-coupling reactions have been applied to the regioselective introduction of alkenyl, alkynyl, acyl, and (het)aryl substituents at the C-3, C-4, and C-5 positions of prepared pyrazoles bearing adequate heteroatoms containing functionalities.
Hemiplegic migraine is a rare form of migraine with aura that involves motor aura (weakness). This type of migraine can occur as a sporadic or a familial disorder. Familial forms of hemiplegic migraine are dominantly inherited. Data from genetic studies have implicated mutations in genes that encode proteins involved in ion transportation. However, at least a quarter of the large families affected and most sporadic cases do not have a mutation in the three genes known to be implicated in this disorder, suggesting that other genes are still to be identified. Results from functional studies indicate that neuronal hyperexcitability has a pivotal role in the pathogenesis of hemiplegic migraine. The clinical manifestations of hemiplegic migraine range from attacks with short-duration hemiparesis to severe forms with recurrent coma and prolonged hemiparesis, permanent cerebellar ataxia, epilepsy, transient blindness, or mental retardation. Diagnosis relies on a careful patient history and exclusion of potential causes of symptomatic attacks. The principles of management are similar to those for common varieties of migraine, except that vasoconstrictors, including triptans, are historically contraindicated but are often used off-label to stop the headache, and prophylactic treatment can include lamotrigine and acetazolamide.
Although the formation of cystine stones is seen in only a small fraction of all patients with urolithiasis, this disease is associated with a pronounced morbidity. The difficult clinical management of these patients, with the aim of arresting or decreasing the rate of recurrent stone formation, is well recognized. This review summarizes some recent knowledge.
An early and correct diagnosis of cystinuria is fundamental for a successful course of the disease in these patients. Formation starts early in life, and attention to this diagnosis is necessary for the paediatric stone formers. New radiological and biochemical improvements seem useful in this respect. A combination of medical tools is usually necessary to influence the very often, troublesome stone-forming activity. Urine dilution, alkalization and chelating therapy have remained the cornerstones of the therapeutic approach. The importance of a high urine pH has been further emphasized, and the possibility to use acetazolamide is a promising improvement of the medical treatment. In order to increase the compliance and reduce the need of active stone removal, special stone clinics seem to be of particular value. The understanding of the genetic background might open future treatment alternatives.
Patients afflicted by cystine stone disease need an aggressive medical treatment, gentle stone-removing surgery and careful follow-up.
The clinical importance of obstructive sleep apnea (OSA) is gradually rising to the extent that many clinicians now consider OSA as an underlying etiology or precipitating factor for many cardiovascular and pulmonary events. Although the incidence and pathophysiology underlying these cardiopulmonary structural and functional abnormalities are not well defined, various mechanisms are hypothesized. These include but are not limited to sympathetic activation, oxidative stress, inflammation, and endothelial dysfunction. Given the rising awareness of OSA, it is timely to review the effects of OSA on cardiovascular complications like arrhythmias and ventricular remodeling. In the later part of the review, we focused on the role of therapeutics in the management of patients with OSA. Although the role of medical therapeutics is not well defined, we reviewed the available literature focusing on the available options, supporting evidence and their role in specific subgroup of patients with OSA.
An overview of the chemical and physical properties of 2-thiazolines is studied, including new methodologies for their preparation, and applications. 2-Thiazoline derivatives are prepared from either β-amino thiols or β-amino alcohols. Condensation of β-amino thiols with nitriles or carboxylic acid derivatives is a straight forward route to 2-thiazolines. The new thiazolines are efficiently prepared either from amino thiols or from amino alcohols. New synthetic methodologies, which use the convenient thiocarbonyl, provide a fantastic opportunity to create structural diversity and efficiently tune the properties of these compounds. The first study using thiazolines was reported by Helmchen in 1991, where he studied the efficiency of C 2-symmetric bis(thiazolines) in the rhodium-catalyzed asymmetric hydrosilylation of acetophenome. Thiazolines should be considered as a new family of compounds and not only as sulfur analogues of oxazolines.
Congenital myasthenic syndromes (CMS) are classified in terms of the located defect: presynaptic, postsynaptic, and synaptic. They are inherited disorders caused by various genetic defects, all but the slow-channel CMS by recessive inheritance. To date, 10 different CMS are known and further CMS subtypes and their genetic cause may be disclosed by future investigations. Prognosis in CMS is variable and largely depends on the pathophysiological and genetic defect. Subtypes showing progression and life-threatening crises with apneas are generally less favorable than others. Therapeutic agents used in CMS depend on the underlying defect and include acetylcholinesterase inhibitor, 3,4-diaminopyridine, quinidine sulfate, fluoxetine, acetazolamide, and ephedrine. Although there are no double-blind, placebo-controlled clinical trials for CMS, several drugs have shown convincingly positive clinical effects. It is therefore necessary to start a rational therapy regime as early as possible. In most CMS, however, mild and severe clinical courses are reported, which makes assessment on an individual basis necessary. This review emphasizes therapeutic strategies in CMS.
The 1,3-dipolar cycloaddition of nitrile imines to 9H-thioxanthone-9-thione and 9H-xanthone-9-thione afforded novel spiro-thioxanthene-9',2-[1,3,4]thiadiazoles 6a-g and spiro-xanthene-9',2-[1,3,4]thiadiazoles 7a-g in good yields. Some of the newly synthesized compounds were tested for anti-inflammatory and analgesic activities comparable to ibuprofen. Compounds 6a,d,e and 7a,d,e showed significant activity compared to standard drug. The toxicity studies revealed that neither death nor other behavioral or toxicological changes were observed on rats up to a dose as high as 200 mg/kg.
Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.
The synthesis of several new pyrazolo[3,4-b]pyridine, pyrido[2',3':3,4]-pyrazolo[1,5-a]pyrimidine and imidazo[1',2':1,5]pyrazolo[3,4-b]pyridine derivatives is described. The obtained compounds were tested for their antiproliferative activity in vitro. One of them, 4-phenyl-2-(3,4,5-trimethoxy-beta-styrylo)pyrido- [2',3':3,4]pyrazolo[1,5-a]pyrimidine (9), revealed cytotoxic properties against the cells of all three human cancer cell lines applied. Another one, 2,4-dimethyl-pyrido[2',3':3,4]pyrazolo[1,5-a]-pyrimidine (2), revealed weak cytotoxic activity only against the cells of human bladder cancer cell line HCV29T. All other compounds tested did not reveal any cytotoxic activity.
Through this review it is contemplated that acetazolamide (ACZ), an age-old treatment for glaucoma with a myriad of side effects and inadequate topical effectiveness, may be formulated into a topically effective agent by utilizing various newer formulation approaches of ocular drug delivery. Even though it has a poor solubility and penetration power, various studies mentioned in the review indicate that it is possible to successfully formulate topically effective ACZ by using: (i) high concentration of the drug, (ii) surfactant gel preparations of ACZ, (iii) ACZ loaded into liposomes, (iv) cyclodextrins to increase the solubility and hence bioavailability of ACZ, and (v) viscolyzers and other polymers either alone or in combination with cyclodextrins. With the advent of newer topical carbonic anhydrase inhibitors (CAIs) like dorzolamide and brinzolamide, a localized effect with fewer side effects is expected. But whenever absorbed systemically, a similar range of adverse effects (attributable to sulphonamides) may occur upon use. Furthermore, oral ACZ is reported to be more physiologically effective than 2% dorzolamide hydrochloride administered topically, even though in isolated tissues dorzolamide appears to be the most active as it shows the lowest IC(50) values for CA-II and CA-IV [M.F. Surgue, J. Ocular Pharmacol. Ther. 12 (1996) 363-376]. Hence, there exists considerable scope for the development of more/equally effective and inexpensive topically effective formulations of ACZ. The use of various formulation technologies discussed in this review can provide a fresh impetus to research in this area.
For Abstract see ChemInform Abstract in Full Text.