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3-(1,3,4-Thiadiazole-2-yl)quinoline derivatives: Synthesis, characterization and anti-microbial activity
Abstract
A new series of thiadiazoles and intermediate thiosemicarbazones were synthesized from the chloroquinone molecule, with an aim to explore their effect on in vitro growth of microorganisms causing microbial infection. The chemical structures of the compound were elucidated by elemental analysis, FTIR, 1H and 13C NMR and ESI-MS spectral data. In vitro anti-microbial activity was performed against Staphylococcusaureus, Streptococcuspyogenes, Salmonellatyphimurium, and Escherichiacoli. The MIC was detected using the double dilution method. The results were compared by calculating percent inhibit area/μg of the compounds and the standard "amoxicillin". The selected compounds were tested for cytotoxic results using MTT assay H9c2 cardiac myoblasts cell line and the results showed that all the compounds offered remarkable >80% viability to a concentration of 200 μg/mL.
... Five-membered heterocycles like thiadiazolidine have found wide applications in the fields of pharmaceutical chemistry and have stimulated much interest in the field of medicinal and biological chemistry. The value of thiadiazolidine derivatives is significant among various heterocycles, as they are found to possess antibacterial [1][2][3][4], anti-inflammatory [5,6], antiviral [7], antiparasitic [8], antifungal [9][10][11] and other diverse biological activities [12]. Many thiadiazolidines are used for the production of anticonvulsant drugs [13,14] and in the treatment of depression also [15]. ...
... To substituted benzalaniline (0.02 mol) taken in 250 mL conical (8:2) as an eluent to afford pure 4-imino-3-phenyl-2-substitutedphenyl-5-tolyl-2H,3H,5H [1,2,5]thiadiazolidin-1-oxide derivatives 8a-i. 1620cm -1 (C=N); 1598cm -1 (C=C); 1023cm -1 (S=O); 1 H-NMR (400 flask were added ethanol (50 mL) and glacial acetic acid (5-6 mL). ...
... Then to the solution of N-α-cyanoamine in dry toluene a catalytic amount of triethylamine was added followed by the addition of N-sulphinyl-4-toluidine 7 (which itself was synthesized using toluidine and thionyl chloride Scheme 3) to provide the desired five-membered heterocyclic compound (Scheme 4) which have been characterized as 4-imino-3-phenyl-2-substitutedphenyl-5-tolyl-2H,3H,5H [1,2,5] thiadiazolidine-1-oxide derivatives as evidenced by thin layer chromatography (TLC) showing the regioselectivity of these 1,3-dipolar cycloadditions. ...
An atom economic and facile synthesis of novel thiadiazolidine-1-oxides has been achieved via using 1,3-dipolar cycloaddition reactions. The salient features of synthetic procedure are characterized by the good yields, high regio- and stereoselectivity, one-pot procedure, and operational simplicity. The regiochemistry and structures of the cycloadducts were determined by using various spectroscopic techniques (IR, 1H-NMR, ESI-MS) and elemental analyses data.
... The impact of extra binding sites, N4 substitution, and metal ion complexation on biological behavior has been studied [80]. 83 84 The Mn(II) complexes (85)(86)(87)(88) with four semicarbazide and thiosemicarbazide-based ligands such as 2-formyl pyridine semicarbazone (L1), 2-formyl pyridine thiosemicarbazone ( L2), 5-methyl 2-formyl pyridine semicarbazone (L3), and 5-methyl 2-formyl pyridine thiosemicarbazone (L4). The twisted octahedral geometry of complexes has been proposed based on IR electronic and EPR spectral data [81]. ...
... Both the ligands and their palladium derivatives have been shown to have anti-amoebic action against the protozoan parasite Entamoeba histolytica [82]. antitubercular, antifungal, anthelmintic, anticancer, antimalarial, and other valuable chemical and biological processes are found in semicarbazide and thiosemicarbazide derivatives [83][84][85][86][87][88][89][90]. They are physiologically and pharmacologically active compounds that have also been effective in the CNS and cardiovascular disorders. ...
Organic compounds have plays vital role in biological chemical activities and also use for increase people's quality of life. Semicarbazide and thiosemicarbazide are sulfur and nitrogencontaining organic compounds with diverse biological activities. They are Schiff’s bases formed by the condensation product of aldehydes or ketones with different amines. These derivatives are urea and thiourea derivatives depend on the attached aldehydes or ketones moiety. Antibacterial, antifungal, anticonvulsant, antitubercular, antimalarial, anticancer, analgesic, antipyretic, anti-inflammatory, antioxidant, antiviral, and other biological activities are all possible with semicarbazide and thiosemicarbazide derivatives. The addition of hydrazides to various isocyanates and isothiocyanates is one
of the most convenient methods for the synthesis of semicarbazide and thiosemicarbazide derivatives, but they also used as a starting material for the synthesis of various Schiff’s bases, metal chelating complexes, and anticorrosion agents.
Various biological activities of semicarbazide and thiosemicarbazide derivatives, and their uses in the drug development phases, are the subject of this study.
... The impact of extra binding sites, N4 substitution, and metal ion complexation on biological behavior has been studied [80]. 83 84 The Mn(II) complexes (85)(86)(87)(88) with four semicarbazide and thiosemicarbazide-based ligands such as 2-formyl pyridine semicarbazone (L1), 2-formyl pyridine thiosemicarbazone ( L2), 5-methyl 2-formyl pyridine semicarbazone (L3), and 5-methyl 2-formyl pyridine thiosemicarbazone (L4). The twisted octahedral geometry of complexes has been proposed based on IR electronic and EPR spectral data [81]. ...
... Both the ligands and their palladium derivatives have been shown to have anti-amoebic action against the protozoan parasite Entamoeba histolytica [82]. antitubercular, antifungal, anthelmintic, anticancer, antimalarial, and other valuable chemical and biological processes are found in semicarbazide and thiosemicarbazide derivatives [83][84][85][86][87][88][89][90]. They are physiologically and pharmacologically active compounds that have also been effective in the CNS and cardiovascular disorders. ...
Organic compounds have plays vital role in biological chemical
activities and also use for increase people's quality of life.
Semicarbazide and thiosemicarbazide are sulfur and nitrogencontaining organic compounds with diverse biological activities. They are Schiff’s bases formed by the condensation product of aldehydes or ketones with different amines. These derivatives are urea and thiourea derivatives depend on the attached aldehydes or ketones moiety. Antibacterial, antifungal, anticonvulsant, antitubercular, antimalarial, anticancer, analgesic, antipyretic, anti-inflammatory, antioxidant, antiviral, and other biological activities are all possible with semicarbazide and thiosemicarbazide derivatives. The addition of hydrazides to various isocyanates and isothiocyanates is one of the most convenient methods for the synthesis of semicarbazide and thiosemicarbazide derivatives, but they also used as a starting material for the synthesis of various Schiff’s bases, metal chelating complexes, and anticorrosion agents.
Various biological activities of semicarbazide and thiosemicarbazide derivatives, and their uses in the drug development phases, are the subject of this study.
... Multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (S. aureus), penicillin resistant Streptococcus pneumoniae (S. pneumoniae), and vancomycin-resistant Enterococci, compounded problems in the therapeutics [2,3] . Quinolines and its derivatives have been known to possess diverse pharmacological activities such as antibacterial, antifungal, antimycobacterial, antidepressant, antimalarial, anticonvulsant, antiviral, anticancer, hypotensive and antiinflammatory activities [4][5][6][7][8][9][10][11] . Quinine, which is extracted from Cinchona bark, has provided the basis for the development of synthetic quinoline-containing drugs, and many of them are presently available such as chloroquine, amodiaquine and mefloquine [12]. ...
... In addition to NMR, the compounds were subjected to ESI-MS analysis for detecting the molecular mass of the compounds. Results obtained for structure elucidation of all the synthesized compounds provide strong recommendation for the complete conversion of these compounds and also supported by the reported literature [9,10,25]. Physicochemical calculations exhibited that all the compounds were found to compliance with Lipinski's rule of five similar to the results obtained by Verma [40]. The bioactivity score was calculated for GPCR ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor and enzyme inhibitor. ...
Objective: To deal with the anti-uropathogenic and in silico screening of (E-)-N′-(substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide analogues in order to search the potential anti-uropathogenic agents.
Methods: Three (E-)-N′-(substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide analogues were synthesized. Structure elucidation was done using various spectroscopic techniques including infrared radiation, 1hydrogen-nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, etc. Physicochemical score, bioactivity score and molecular docking studies were carried out using Lipinski's rule of five, Molinspiration (web based software), Autodock 4.2 tools. In vitro anti-uropathogenic activity was carried out against four pathogens named as Staphylococcus aureus (S. aureus), Staphylococcus epidermidis, Proteus mirabilis and Escherichia coli by disc diffusion method and macro-dilution test following their morphological and biochemical characterization.
Results: The formation of (E-)-N′-(substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide is confirmed from the spectroscopic results. All the compounds were found in compliance with Lipinski's rule of five and exhibited bioactivity score from −0.50 to 0.00. Docking results revealed that compound-1 is forming one hydrogen bond with TYR 576 and two hydrogen bond with GLU 569, while compound-2 is forming one hydrogen bond with ARG 599, and compound-3 forming 0 hydrogen bond. The anti-uropathogenic evaluation exhibited that compound one exhibited better activity against S. aureus, while it was found to possess moderate to good activity against both Gram-positive bacteria and Gram-negative bacteria excluding S. aureus.
Conclusions: Our study revealed that compound one exhibited better activity than the standard in case of S. aureus and moderate to good activity against rest of the pathogens. Molecular docking, physicochemical and bioactivity studies strongly supported the experimental results. From the well obtained results it was concluded that compound-1 can lead as potential anti-uropathogenic agents.
... Infections caused by pathogenic microorganisms like bacteria can bring human morbidity and mortality [1][2]. Even though the efforts regarding research for antibiotics has somehow improved mankind's health condition, but still the emergence of bacterial resistance has become a serious problem for the clinical management worldwide [3][4][5][6]. Infections are usually treated by utilizing antimicrobials chemotherapy [7]. Nitroimidazoles (such as secnidazole, metronidazole) and their derivatives have been extensively used as antimicrobial drugs [8][9][10] and has been accepted as drug of choice for anti-infectious therapy to kill microbials in host tissues and organs [11]. ...
... Thus the structural modification at the hydroxyl group of alkyl chain of secnidazole has received our attention and then we synthesized the representative hydrazones of nitroimidazole. A total of seven hydrazones of nitroimidazole (2)(3)(4)(5)(6)(7)(8) were synthesized and evaluated for their antimicrobial activities. To the best of our knowledge, all the synthesized derivatives in this study are new. ...
5-Nitroimidazole derivatives 2-8 were synthesized from secnidazole. The syntheses were accomplished in two steps which start from the oxidation of secnidazole to the secnidazolone 1. Secnidazolone 1 was converted into its hydrazone derivative 2-8 by treating with different substituted acid hydrazide. Compounds 2-8 were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria, compounds 3 and 4 showed the significant activity against Staphylococcus epidermidis, however, compound 2 showed good inhibitions against Corynebacterium diphtheria when compared with the standard. Compound 3 showed good inhibitory potential against tested Gram-negative bacterial strains i.e. Enterobacter aerogene, Escherichia coli, Salmonella typhi, Salmonella paratyphi A, Shigella flexeneri and Vibrio choleriae. All synthetic derivatives were also tested against eight fungal stains, however, they were weekly active against Aspergillus flavus and Candida albican. The synthesized compounds were characterized by different spectroscopy techniques.
... They have remarkable physiological effects (9), which help to use them as pharmaceuticals, stimulants, and narcotics. These nitrogen in a negative oxidation state which is of limited distribution among living organisms (10). Alkaloids represent group of molecules with a relatively large occurrence in nature. ...
... They have remarkable physiological effects (9), which help to use them as pharmaceuticals, stimulants, and narcotics. These nitrogen in a negative oxidation state which is of limited distribution among living organisms (10). Alkaloids represent group of molecules with a relatively large occurrence in nature. ...
Qualitative and quantitative analysis of alkaloid component in seeds from Peganum harmala L. extracts Abstract: Peganum harmala L. represents the major rich plant of alkaloids harmine and harmanline. In this study, one of these alkaloids was detected qualitatively and quantitatively using different extraction methods: aqueous, methanol, and alkaloid. In comparison between standard harmine and the three extracted using TLC technique, different spots were appeared from the three extraction methods and the color looked like the standard. While when run the extracts on HPLC in comparison to standard harmine, three peaks were observed and retention time of each extract was recorded to calculate the concentration of alkaloid. The best extraction method was the alkaloid extraction that give two peaks quite similar to that in the standard and almost the same retention time. This study shows that there are many important compounds in the alkaloid extraction of P. harmala of Iraqi species.
... It is one of the most prominent heterocyclic nucleus, has been known for more than 150 years, and it is the structural skeleton of several natural products, synthetic pharmaceuticals [133]. Thiadiazole are known to show significant pharmacological activities, such as antimicrobial [134,135], antitumor [136], antiviral [137], and anti-inflammatory [138], anticancer [139], anticonvulsant, and antioxidant activities [140]. -2-p-tolyl-1H-imidazo[1,2-a]pyridine-3-yl)methyl-N-phenyl-1,3,4 thiadiazol-2-amine-Thiosemicarbazide (0.005 mol) was taken in 50 ml borosilicate glass beaker with 10 mL of 2 N sodium hydroxide solution. ...
Monocyclic heterocyclic compounds are regarded as a promising class of bioactive compounds that exhibit a range of biological activities like anti-microbial, anti-diabetic, anti-proliferative, anti
... They found antifungal activity against C. albicans, antibacterial activities against S. aureus (Gram-positive), and E. aerogenes (Gram negative). Bhat and co-workers studied antimicrobial activities of 3-(1,3,4-thiadiazole-2-yl)quinoline derivatives [35]. They found antibacterial activities against S. typhimurium (Gram negative). ...
Novel 1,3,4-thiadiazole derivatives were prepared by cyclization reaction of thiophene-2-carboxylic acid with N-arylthiosemicarbazides and POCl3. The antibacterial activities of the synthesized compounds were tested against Gram-negative bacteria (Salmonella enteritidis, Salmonella typhimurium, Enterobacter aerogenes, Salmonella infantis, Salmonella kentucky, and Escherichia coli), Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Enterococcus durans), and the fungus Candida albicans using the disk diffusion method. Selected 1,3,4-thiadiazole derivatives exhibited effective antimicrobial activity against S. aureus, C. albicans, S. typhimurium, E. aerogenes, and S. kentucky. Therefore, 1,3,4-thiadiazole derivatives can be considered as bioactive agents for pharmacological and medicinal applications. The synthesized compounds were characterized by using IR, ¹H NMR, and ¹³C NMR spectroscopies and elemental analysis.
... Compounds N-4-acetyl-5-(2,8-dichloroquinolin-3-yl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)-N-o-tolylacetamide and N-4-acetyl-5-(2-chloroquinolin-3-yl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)-N-(2,5-difluorophenyl)acetamide showed excellent inhibitory results against S. aureus at 16 µg/mL. similarly N-4-acetyl-5-(2-chloroquinolin-3-yl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)-N-o-tolylacetamide and N-4-acetyl-5-(2-chloroquidnolin-3-yl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)-N-p-tolylacetamide showed good effects for S. pyogenes at 32 µg/mL [77] (Scheme 65). ...
Heterocyclic compounds are well known for their different biological activity. The heterocyclic analogs are the building blocks for synthesis of the pharmaceutical active compounds in the organic chemistry. These derivatives show various type of biological activity like anticancer, antiinflammatory, anti-microbial, anti-convulsant, anti-malarial, anti-hypertensive, etc. From the last decade research showed that the quinoline analogs plays a vital role in the development of newer medicinal active compounds for treating various type of disease. Quinoline reported for their antiviral, anticancer, anti-microbial and anti-inflammatory activity. This review will summarize the various synthetic approaches for synthesis of quinoline derivatives and to check their biological activity. Derivatives of quinoline moiety plays very important role in the development of various types of newer drugs and it can be used as lead compounds for future investigation in the field of drug discovery process.
... Thiadiazoles represent a class of compounds having immense importance in medicinal chemistry due to their mesoionic nature and good lipophilicity [1][2][3]. They are very useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest including antibacterial [4,5], antifungal [6][7][8], anti-inflammatory [9, 10], antimicrobial [10][11][12][13], antitubercular [14][15][16], anticancer [17][18][19][20][21][22], anti-helicobacter pylori [23,24] and anticonvulsant [25] properties. In recent years, we have synthesized a series of new naphthalene derivatives bearing 1,3,4-thiadiaziole backbone as potetial anti-HIV agents [26], meanwhile Ijichi et al. [27] reported that 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-B Shahid Hameed shameed@qau.edu.pk ...
A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a–4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a–2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a–3f. Treatment of 2a–2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a–4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 μM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 μM and could be a promising antiproliferative agent.
... Antibacterial activity of 3-(1,3,4-thiadiazoline-2-yl)quinolines 27 was found to be strongly depended on substitution at C-5 and C-2 of thiadiazoline. Thiadiazoline derivatives substituted with N-(2-methylphenyl) acetamide 27a and N-(4-methylphenyl)acetamide 27b groups at C-2 and 2,8dichloroquinoline and 2-chloroquinoline at C-5 showed better activity against S. aureus and S. pyogenes, respectively [25]. ...
Introduction:
Four isomeric structures of thiadiazole motifs have outstanding pharmacological inhibitory applications are reported in this review. Thiadiazole nucleus is present in several biologically active natural products and commercial drugs. Most of thiadiazoles reported herein are emphasized to have broad spectrum of medicinal activities. Areas covered: This review represents the recent inhibitory activities of thiadiazole isomeric scaffolds and their broad-spectrum biological applications published as full texts during 2010-2016 as well as the patents published during 2005-2016. The inhibition areas covered included anti-inflammatory, antimicrobial, antitumor, antioxidant, antitubercular, antiviral, antileishmanial, anticonvulsant, herbicidal and algicidal activities in addition to enzymes, human platelet aggregation and neuroprotective inhibitors. Expert opinion: This survey revealed very interesting data about the applications of thiadiazoles, where some synthetic or natural thiadiazole derivatives were components of drugs available in the market. Many thiadiazole derivatives can be considered as lead compounds for drug synthesis. The most inhibitory active 1,3,4-thiadiazole compounds are those incorporating secondary alkyl(aryl)amido- and/or benzylthio(mercapto) groups at positions 2 and 5. Several thiadiazole derivatives demonstrated higher antibacterial, antitumor and antiviral activities than the standard drugs. Some thiadiazole derivatives exhibited high selective enzymes inhibitory activities based on the electronic properties of the substituents at positions 2 or 5.
... The incorporation of oxygen, nitrogen, and sulfur donor atoms in the macrocycles markedly affect their complexing properties because of the hard (O, N) and soft (S) character of the donor atoms and the exodentate tendency of the sulfide linkages [4]. During recent years there has been intense investigation of different classes of thiadiazole compounds, many of which known to possess interesting biological properties such as antimicrobial [5] S containing two carbon atoms, three hydrogen, two nitrogen and one sulphur [3]. ...
Thiadiazole and their derivatives have been studied colossally because of their wide range of biological activity. They are found to be effectual as antibacterial, antimalarial, antiviral, anti-inflammatory, anticancer and antianthelminthic agents. Distinct biological activities, such as antibacterial, anti-inflammatory, and antiviral have been consort with 1, 3, 4-thiadiazole derivatives. The substituted 1, 3, 4 Thiadiazole nucleus is particularly ubiquitous, and found in some marketed drugs such as acetazolamide, Methazolamide and antibacterial such as Sulphamethazole, antibiotic like Cefazoline. The synthesis of 1, 3, 4 Thiadiazole derivatives has allured widespread attention due to their diverse biological activities, including antimicrobial, anti-inflammatory, analgesic, and antianthelmintic. These reviews focused on various biological activities consorted with thiadiazole nucleus. © 2015, International Journal of Pharmacy and Pharmaceutical Science. All rights reserved.
... The versatile and eminent biological profiles of 1,3,4-thiadiazoles and their analogs are well known. 14 Because of the presence of a toxophoric N=C-S moiety, 1,3,4-thiadiazoles exhibit a broad spectrum of biological activities. Recent literature suggests that 1,3,4thiadiazole derivatives exhibit antibacterial and antitubercular activities. ...
In a green, one-pot approach, several 5-naphthalen-1-yl-5,10-dihydro-1H-pyrimidoi-[4,5-b]-iquinoline-2,4-dionesi (4a-k) were synthesized via a three-component reaction comprising substituted anilines, naphthaldehyde, and barbituric acids. The reaction conditions were optimized by testing different catalysts (PTSA, CF3COOH, and L-proline) and different solvents. Most of the tested reaction conditions influenced the synthetic reaction. L-proline was more effective with water as a solvent in synthesizing the targeted compounds with high yields. All the synthesized compounds underwent antiepileptic screening using in vivo and in silico methods. In vivo, screening has been performed following the maximal electroshock seizure (MES), and subcutaneous pentylenetetrazole (scPTZ) animal screening methods. The antidepressant screening of the most potent antiepileptic compounds has been tested through a locomotor impairment test (using an actophotometer). The in silico molecular docking and simulation studies were determined by utilizing AutoDock 4.2 version and Gromacs. Among all, compounds 4b, 4d, 4e, and 4j have demonstrated significant antiepileptic activity with effective antidepressant properties. In silico studies (calculation of ADME parameters, molecular docking, and MD simulation) established that targeted molecules have good ADME parameters (good for oral use), the possible mechanism involved interactions primarily with GABAA receptors while interactions with other receptors like VGSCs and NMDA also took place.
A diverse set of 4,7‐dihydro‐[1,2,3]thiadiazolo[5,4‐b]pyridine‐6‐carboxamides 4(a–o) was synthesized via a one‐pot reaction of 5‐amino‐[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4 e demonstrated superior efficacy against the Salinivibrio proteolyticus strain of Gram‐negative bacteria compared to ciprofloxacin. Compound 4 d exhibited the highest potency against the fungal strain Candida albicans, surpassing amphotericin B. The physicochemical characteristics of 4 d and 4 e were assessed. According to docking analysis, DHTDAPy 4 e shows a higher binding affinity of −7.2 kcal/mol in the binding cavity of the receptor. These findings illustrate the safety, tolerability, and potency of the newly synthesized DHTDAPy compounds against fungal and bacterial infections. image
A series of substituted spiro 4‐thia‐1,2,6,9‐tetraazaspiro[4.4]non‐2‐ene‐7,8‐diones were synthesized with good yields through 1,3‐dipolar substituted hydrazonoylchloride's substituted 2‐thioxoimidazolidin‐4,5‐diones under mild conditions as described. This switchable C−S and C−N bond connection with simple execution and broad substrate scope. In this study, the synthesized compounds 3 a–q were screened against four distinct cancer cell lines (PANC‐1, MIA PaCa‐2, MDA MB231 and DU145) along with a standard cell line HEK‐293, to determine their in vitro anticancer activities, and assessed using the Sulphorhodamine B assay to determine their viability
Quinoline and its derivatives have been utilized and marketed as antibacterial, antimalarial, anticancer, hypertension, asthma (COPD), etc. The diverse pharmacological properties of quinolone are related to its chemical structure. Nowadays, it is common practice to combine at least two pharmacophores to create a single molecule with powerful pharmacological effects. This helps to synergize pharmacological qualities, enables interaction with several targets, or lessens the negative effects related to them. Various synthetic approaches which have been used in recent times for the synthesis of quinoline and its derivatives are listed in the manuscript with their merits and demerit. The structure-activity relationship relating various pharmacological actions with molecular structure and interaction with several targets has also been highlighted to provide a good comprehension to the researchers for future studies on quinoline.
Quinoline derivatives are widely utilized in a variety of applications, including medicine and materials. In this work our previously developed bioactive fluorine-containing 2,3-diarylquinolines (1a, 1b and 1c) were investigated theoretically and compared with the experimental data. DFT was used to investigate the optimized geometry and geometric parameters using the B3LYP/6-311++G (d,p) basis set. DFT studies demonstrated a high degree of concordance of the predicted ¹H, ¹³C NMR, and FT-IR spectroscopic data with the experimental results. The DFT technique was used to explore HOMO-LUMO energies, global reactive parameters, NLO, NPA, and NBO characteristics using the aforementioned level of theory and basis set. HOMO-LUMO analysis revealed that compound 1c has a slightly narrower energy gap (4.3355 eV) than compounds 1a (4.4626 eV) and 1b (4.4645 eV) suggesting all three compounds have significantly comparable NLO properties. The reported compounds have polarizability in the range 40.17 - 42.53 × 10⁻²⁴ esu. Strong delocalization interactions between Lewis bonding and antibonding orbitals have been confirmed by NBO analysis.
Compounds containing both ketone and amide carbonyl groups were reduced with sodium borohydride (NaBH4). In this way, secondary alcohols, which are very important compounds for the synthesis of drugs, agricultural chemicals, food chemicals, and other chemicals, were obtained with regioselectivity. To do this, the starting compound 2-(5-amino-1,3,4-thiadiazol-2-yl)thio)-1-(3,4-dichlorophenyl)ethanone (3) was obtained. Subsequently, 10 ketone derivatives (5a-j) were synthesized from the reaction of 3 with the appropriate substituted acyl halide derivatives (4a-j). Then, secondary alcohol derivatives (6a-j), which came from the regioselective reduction of the ketone derivatives (5a-j), were synthesized with NaBH4. The molecular structures of ketone and alcohol derivatives were elucidated using ¹H NMR, ¹³C NMR, FTIR, and MS. In the last step of the study, binuclear metal complexes of all alcohol and ketone derivatives were synthesized in DMF and characterized using FTIR and MS. The magnetic properties and thermal stability of these complexes were investigated using magnetic susceptibilities and determined using a Gouy magnetic susceptibility apparatus and a TGA analyzer, respectively. The complexes are distorted octahedral low-spin (S = 3/2) Co(II) and distorted octahedral (S = 1) Ni(II). Finally, the metal ratios of the complexes were determined by using ICP-AES.
(2-Chloroquinolin-3-yl)-1,3,4-thiadiazole-2-carboxamides were synthesized from hydrazones obtained via the reaction of 3-formyl-2-chloroquinoline with oxamic acid thiohydrazides.
Heterocycles form by far the largest of classical divisions of organic chemistry and are of immense importance biologically and industrially, and about one half of over six million compounds recorded in chemical abstracts are heterocyclic. The majority of pharmaceuticals and biologically active agrochemicals are heterocyclic while countless additives and modifiers used in industrial applications ranging from cosmetics, reprography, information storage and plastics are heterocyclic in nature. One striking structural feature inherent to heterocycles, which continue to be exploited to great advantage by the drug industry, lies in their ability to manifest substituents around a core scaffold in defined three-dimensional representations. Among the approximately 20 million chemical compounds identified by the end of the second millennium, more than two-thirds are fully or partially aromatic and approximately half are heterocyclic. The presence of heterocycles in all kinds of organic compounds of interest in electronics, biology, optics, pharmacology, material sciences and so on is very well known. Between them, nitrogen-containing heterocyclic compounds have maintained the interest of researchers through decades of historical development of organic synthesis. In the present work, focus on the literature survey of chemical diversity (piperidine 1, pyridine 2, quinoline 3, [1,3,4]-thiadiazole 4, pyrazole 5 and [1,2,4]-triazole 6) in the molecular framework in order to get a complete information regarding pharmacologically interesting compounds of widely different composition.
In present study, a series of 3-[(5-methyl-1,3-benzoxazol-2-yl)amino]-2-phenyl-2,3-dihydro-4H-1,3- benzothiazin-4-ones (6a-n) were synthesized and elucidated by elemental, FT-IR, 1H & 13C NMR and LC-MS studies. The in vitro antibacterial screening against Gram-positive bacterial strains such as B. subtilis, S. aureus, S. epidermidis and Gram-negative bacteria such as E. coli, P. aeruginosa was carried in comparison with tetracycline as reference standard. Antifungal activities against different fungal strains namely R. oryzae, A. niger, A. favus, C. albicans and S. cerevisiae have been evaluated by comparing with fluconazole as reference standard. Compounds 6b, 6c, 6e, 6j, 6m and 6n emerged as highly potent antimicrobial agents. The DPPH radical scavenging assay of the synthesized moieties showed good antioxidant potency comparable to standard ascorbic acid. The molecular docking simulation studies of all the title compounds in their active conformation analogues with target proteins (PDB ID 2XCT-antibacterial, PDB ID 1IYL-antifungal, PDB ID 2HCK- antioxidant) exhibited good binding interactions in top scoring poses. The pharmacokinetic properties prediction by ADMET descriptors and Lipinski′s rule of five endorse the properties of newly synthesized compounds to a drug molecule. The results of the docking protocols were compatible with the in vitro studies which validates the potency of the molecules.
Unusual reaction proceeding via the electrophilic activation of nitroalkanes in the presence of polyphosphoric acid has been discovered. Subsequent nucleophilic attack with semicarbazides or thiosemicarbazides allows to access 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles, respectively.
Four novel Cu (II) chelates were synthesized by reacting hydrated CuCl2 and Cu (CH3COO)2 with two derivatives of 1,3,4‐thiadiazolethiosemicarbazone. The structures and geometries of the synthesized complexes were deduced applying the alternative analytical and spectral tools confirming the complexes to have the formulae [(LH)Cu (Cl)]•0.5H2O, [(LH)Cu (OAc)(H2O)2]•0.5H2O, [(LCl)Cu (Cl)(H2O)2]•H2O and [(LCl)Cu (OAc)]; where LH and LCl are phenyl and p‐chlorophenyl derivatives of 1,3,4‐thiadiazolethiosemicarbazone ligands, respectively (deprotonated form). IR spectral data confirmed the coordination of the ligands to the copper center as monobasic tridentate in the thiol form. Thermal analysis, UV–Vis spectra and magnetic moment assured the geometry around the copper center to be square planar, trigonal bipyramid and octahedral which have been confirmed by the computational studies. The two ligand derivatives and their copper complexes were applied to evaluate their binding modes with SS‐DNA via UV–Vis spectral titration and viscosity measurements. The DNA‐binding constant (kb) values of the investigated derivatives were calculated and compared with ethidium bromide in order to assess their mode of binding with DNA. Moreover, docking study of these complexes was carried out to recognize the drug–DNA interactions and to calculate their binding energies.
Owing to manifold applications in agrochemical, biological, material and pharmaceutical industry, 1,3,4-thiadiazoles represent one of the most studied class of five-membered heterocycles. This review covers developments achieved in theoretical methods (molecular calculations, molecular geometry, electronic structures), experimental structural methods (X-ray, neutron and electron diffraction, microwave, NMR, UV, CV, ESR, fluorescence, IR and Raman spectroscopy, mass spectrometry), thermodynamic aspects (physical properties, aromaticity, tautomerism), reactivity, synthesis and future outlook of 1,3,4-thiadiazoles.
The aim of the present protocol is to develop a facile route for the synthesis of novel ionic liquid (IL) functionalized graphene nano sheets (IMD-Si/FeCl4ˉ@GNS). An imidazolium IL with iron chloride as an anion (IMD-Si/FeCl4ˉ) was used to reduce graphene oxide. IMD-Si/FeCl4ˉ@GNS was well characterized by various techniques such as Fourier Transform Infrared (FTIR), Raman, Ultraviolet-Visible Diffuse Reflectance Spectroscopy (UV-VIS DRS), Scanning Electron Microscope/Energy Dispersive X-ray (SEM/EDX), Elemental mapping, Transmission Electron Microscope (TEM), Powder X-ray diffraction (XRD), Thermal Gravimetric (TG), Electron Paramagnetic Resonance (EPR), and X-Ray Photoelectron Spectroscopy (XPS) analyses. The IL functionalized material was investigated for its catalytic property and found to be an efficient catalyst for the synthesis of (E)-selective substituted thiosemicarbazone derivatives. The (E)-selectivity was confirmed by the DFT calculations which showed that the (E)-isomer was stabilized by 4.90 kcal/mol more than the (Z)-isomer. The catalyst maintained its catalytic activity for six successive runs.
New 1,3,4-thiadiazole-based compounds were designed, synthesized, and their anticancer effects were assessed by MTT assay against PC3 (prostate cancer), HT-29 (colon cancer), and SKNMC (neuroblastoma) cell lines. The results were compared to that of doxorubicin. According to MTT assay, some of the synthesized compounds exhibit higher cytotoxic activity (IC 50 , μM range) than doxorubicin against PC3 and SKNMC cells but not HT29 cells. According to the analysis of structure – activity relationship, compounds with methoxy group as an electron donating moiety rendered higher activity than nitro group as an electron withdrawing group. Compound 4d with ortho position of methoxy moiety activated caspases 3 and 9 in both PC3 and HT-29 cell lines.
Background: In a search for new antioxidant agents, a series of eleven diversely substituted quinoline containing chalcone derived from a quinoline scaffold were synthesized and evaluated as antioxidant agents.
Methods
Compounds were prepared via Claisen-Schmidt condensations of 2, 6-dichloroquinoline-3-carbaldehyde with appropriately substituted acetophenones. All the synthesized compounds were characterized by spectral (FT-IR, mass and 1HNMR) and elemental analysis. The synthesized compounds were investigated for their in vitro antioxidant activity by FRAP assay method.
Results
Among the screened compounds QHM-1, QH-1, QDB-1 and QE-1 exhibited significant antioxidant activities.
Conclusion
It can be predicted that electron releasing groups with higher resonating structures makes the compound more potent than the compounds with electron releasing group and less resonating structures. The electron releasing behavior of compounds proved them good terminators of radical chain reactions.
A series 1,2,4-triazole piperine analogues (TP1-TP6) were designed and synthesized. The structures were confirmed using 1H NMR and 13C NMR. Antibacterial study was done using Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram-negative micro-organisms (E. coli and Pseudomonas aeruginosa) by disc diffusion method. Compound containing chloro substitution (TP6) showed the highest effect, while compound TP1, TP3, TP4, TP5 showed the moderate activity.
In the present study, a series of substituted 1,3,4-thiadiazole derivatives 4(a–o), 5(a–m) and 6(a–j) were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and mass spectroscopic technique. The synthesized compounds were evaluated for their in vitro anti-mycobacterial activity against the Mycobacterium tuberculosis H37Rv and resistance MDR-TB strain. Among the compounds tested N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)furan-2-carboxamide (4h) showed significant inhibitory activity with MIC of 9.87 μM (H37Rv strain) and 9.87 μM (MDR-TB strain) compared to isoniazide [MIC of 3.64 μM (H37Rv) and >200 μM (MDR-TB strain)] and rifampin [MIC of 0.152 μM (H37Rv) and 128 μM (MDR-TB strain)]. In addition, these compounds have also been assessed for their cyto-toxicity to a mammalian Vero cell line using the MTT assay. The result shows that these compounds exhibit anti-tubercular activity at non-cytototoxic concentrations.
A series of new 1,2-substituted tetrazole derivatives were synthesized and evaluated on MCF-7 (ER positive), MDA-MB-231 and ZR-75 (ER negative) breast cancer cell lines. Out of the fourteen compounds, three compounds 10, 12 and 14 showed higher inhibitory effects on MCF-7 cells. Whereas, compound 8 exhibited higher inhibition in MDA-MB-231 and ZR-75 cells at 10 À5 M concentration. Total RNA was extracted and effect of compounds on different marker genes was studied. The gene expression of CD44, BRAC and BAX were significantly affected. The compounds were screened against the HepG2 cell line, to know if they are selectively targeting specific cancers and only 1e10 percent inhibition was found at 10 À5 M concentration.
New derivatives of 2,5-dimercapto-1,3,4-thiadiazole substituted both at one or two exocyclic sulfur atoms with a series of aroyl or ethoxycarbonyl groups were synthesized in reactions of 2,5-dimercapto-1,3,4-thiadiazole salts with appropriate acid chlorides or ethyl chloroformate in mild conditions. The products were characterized by spectroscopy (¹H NMR, ¹³C NMR, IR, and HRMS). Some from the synthesized compounds were screened in vitro and in vivo for antibacterial and antifungal activities against a panel of reference strains of microorganisms. The study revealed that ethyl S-(5-mercapto-1,3,4-thiadiazol-2-yl) carbonothioate seems to be the most active and versatile compound against Gram-positive bacteria, Gram-negative bacteria, and plant pathogenic fungi.
Background: Infectious pathogenic bacteria are the key virulence in our daily life. Especially diseases produced by multidrug resistant Staphylococcus aureus (MRSA) still contributing in morbidity and mortality in humans. Discovery of new and safer antibiotics is an upmost task in current medicinal research. Methods: By keeping in mind the considerable antimicrobial activities of coumarin scaffold, 3-substituted coumarin derivatives 1-24 were synthesized by Knoevenegel condensation reaction. Different aryl aldehydes were treated with β-keto esters in the presence of organic base piperidine. All synthetic compounds were characterized by different spectroscopic techniques such as EI-MS, HREI-MS, ¹H-NMR, and ¹³C-NMR. Compounds were screened to check for their in vitro anti-MRSA (multidrug resistant Staphylococcus aureus) activity against different strains of bacteria such as MRSA-252, EMRSA-16, EMRSA-17 and local clinical isolate. Micro-plate alamar blue assay (MABA) was used for this activity. Oxacillin, streptomycin, clindamycin and vancomycin were used as standards. Results: Results were reported as percent inhibition at 20 μg/mL concentration. Amongst all four standard drugs, only vancomycin was showed 19%, 24%, 21% and 40% inhibitions in case of MRSA-252, EMRSA-16, EMRSA-17 and local clinical isolate, respectively, at 20 μg/mL concentration. Most of the synthetic compounds were showed a weak to good inhibition as compared to standard, vancomycin. Conclusion: Newly identified compounds may serve as lead for future research in order to get the more powerful antibacterial agents.
Quinolines are nitrogen-containing bicyclic compounds that are widely found throughout Nature in various forms. Quinoline derivatives are utilized in the areas of medicine, food, catalysts, dyes, materials, refineries, electronics, etc. The quinoline nucleus is present in numerous biological compounds, e.g., antimalarial, antimicrobial, antimycobacterial, antidepressant, anticonvulsant, antiviral, anticancer, antihypertensive, platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) inhibitory, antiinflammatory, antioxidant, and anti-human immunodeficiency virus (HIV) agents. However, owing to the swift development of new molecules containing this nucleus, many research reports have been generated in a brief span of time. There therefore seems to be a requirement to collect recent information in order to understand the current status of the quinoline nucleus in medicinal chemistry research, focusing in particular on the numerous attempts to synthesize and investigate new structural prototypes with more effective antimalarial, antimicrobial, and anticancer activity.
A new series of structurally diverse 2-chloro-8-methyl quinoline imides (2a-g) were synthesized by conversion of 2-chloro-8- methyl quinoline-3- carboxaldehyde (1) to its amide (2) followed by coupling of different benzoyl chlorides. The newly synthesized compounds were characterized by spectral and elemental analysis and studied for their antioxidant properties by three in vitro assays like 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, microsomal lipid peroxidation (LPO) assay and ferric reducing power assay. Butylated hydroxy anisole (BHA) was used as a reference antioxidant and the comparative study with newly synthesized compounds was also done. Among the analogues compound (2f), bearing three hydroxyl groups showed predominant activity.
Two classes of addition/cycloaddition cascade reactions of hydrazinecarbodithioate (1) have been developed under mild reaction conditions. Reaction of hydrazinecarbodithioate (1) with formaldehyde solution (2) and propiolic acid (3) gives 3-propargyl-5-thiol-2,3-dihydro-1,3,4-thiadiazoles (5) via a decarboxylative coupling/cycloaddition domino sequence. When propiolic acid (3) is switched to phenyl boronic acid (4), a Petasis/cycloaddition domino reaction is instead observed, in which 3-benzyl-5-thiol-2,3-dihydro-1,3,4-thiadiazoles (6) are obtained. Both of these two reactions show a wide range of functional-group compatibility for propiolic acids and aryl boronic acids, and give the corresponding products in moderate to good yields.
A new cis-dioxo molybdenum(VI) complex was obtained by reaction of 2,4-dihydroxybenzylidene(5-N,N-methylphenylamino-1,3,4-thiadiazol-2-yl)hydrazone as ligand and [MoO2(acac)2] in methanol and was characterized by elemental analyses, 1H NMR, IR, and electronic spectroscopic studies. The complex was also analyzed by single-crystal X-ray diffraction. The structure determination revealed a distorted octahedral coordination geometry around molybdenum in which the tridentate NNO donor (L2-) is bonded to [MoO2]2+ through phenolic oxygen, hydrazinic nitrogen, and thiadiazole nitrogen. The sixth coordination site is occupied by a weakly bonded methanol. The complex was tested as a catalyst for homogeneous epoxidation of olefins using tert-butyl hydrogen peroxide as an oxidant. In the homogeneous catalytic system, the reactions are efficiently carried out with high yields and selectivity.
A library of thiosemicarbazones (III) and thiadiazoles (V) is prepared with the aim to explore their effect on the growth of microorganisms.
The compounds styryl 1,3,4-thiadiazoles were prepared adopting one and two step methodologies to optimize the yield of the products. The two-step methodology via benzohydrazide followed by treatment with Lawesson’s reagent in the presence of Propylphosphonic anhydride and triethylamine produced styryl 1,3,4-thiadiazoles in excellent yields. The olefin moiety in these compounds is utilized to develop pyrazole and isoxazole rings by 1,3-dipolar cycloaddition methodology followed by oxidation.
A glance at standard reference works shows 1,3,4-thiadiazole has been investigated more than other isomers. The 1,3,4-thiadiazole ring is a very weak base due to the inductive effect of the sulfur atom and possesses relatively high aromaticity. In addition, the ring is also shown to be very electron deficient due to the electron-withdrawing effect of the nitrogen atoms and relatively inert toward electrophilic substitution but susceptible to nucleophilic attack, whereas when substitutions are introduced into the 2' or 5' position of this ring, it would be highly activated and readily react to yield diverse derivatives. Thus, possessing these properties, 1,3,4-thiadiazole derivatives are applied widely in pharmaceutical, agricultural, and materials chemistry. In particular, the 1,3,4-thiadiazoles display a broad spectrum of biological activities including antimicrobial, antituberculosis, antioxidant, anti-inflammatory, anticonvulsants, antidepressant and anxiolytic, antihypertensive, anticancer, and antifungal activity.
A series of 2-Styryl-5-Nitroimidazole derivatives (25-48) have been synthesized and their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus subtilis and Bacillus thuringiensis as potential FabH inhibitors. All the compounds were structurally determined by 1H NMR, MS, and elemental analysis. E. coli β-ketoacyl-acyl carrier protein synthase III inhibitory assay and docking simulation indicated that compound 33 with IC50 of 9.0-36.4 μg/mL and compound 47 with IC50 of 6.3-34.3 μg/mL against bacterial strains were most potent inhibitors of E. coli FabH. And more, compounds 33 and 47 which possessed a broad-spectrum of antibacterial activities didn't exhibit any toxicity towards macrophage.
Cyclization of oxime with different aldehydes and ketones under basic condition led to the formation of new dioxazole derivatives and the structure was elucidated by spectral data. The effects of diaoxazoles on the inhibition of growth of Entamoeba histolytica and Giardia intestinalis in vitro have been determined, and selected compounds further investigated for their toxicity. SAR showed that the compounds with 5-nitrothiophene group at the 3-postion of the diaoxazole ring were more active than those with the p-toluene group at the same position. It is interesting to note that the compounds found active against E. histolytica were not found active against G. intestinalis. Toxicity studies showed that the compound 8 and 9 were non-toxic against Vero cell line ATCC CCL-81.
Over the course of a 20-month period, in a hospital respiratory ward in which ciprofloxacin was often used as empirical antimicrobial
therapy for lower respiratory tract infections (LRTIs), 16 patients with chronic bronchitis developed nosocomial LRTIs caused
by penicillin- and ciprofloxacin-resistant Streptococcus pneumoniae (serotype 23 F). The minimum inhibitory concentration (MIC) of ciprofloxacin for all isolates from the first 9 patients was
4 µg/mL, in association with a parC mutation. Isolates from the subsequent 7 patients all had a ciprofloxacin MIC of 16 µg/mL, in association with an additional
mutation in gyrA. The MICs for this isolate were 8 µg/mL of levofloxacin (resistant), 2 µg/mL of moxifloxacin and gatifloxacin (intermediately
resistant), and 0.12 µg/mL of gemifloxacin. This outbreak demonstrates the ability of S. pneumoniae to acquire multiple mutations that result in increasing levels of resistance to the fluoroquinolones and to be transmitted
from person to person.
In this study, eight original N-phenyl-N′-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl] thiourea derivatives were synthesized and tested for antituberculosis activity. Antituberculosis activities of the synthesized compounds were screened in vitro using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv at 6.25 μg/ml. The highest inhibition observed with the synthesized compounds is 67% for N-phenyl-N′-[4-(5-cyclohexylamino-1,3,4-thiadiazole-2-yl)phenyl] thiourea. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
Cardiac myocytes, upon exposure to increasing doses of norepinephrine (NE), transit from hypertrophic to apoptotic phenotype. Since reactive oxygen species (ROS) generation is attributed to both phenomena, the authors tested whether an elevation in intracellular ROS level causes such transition. H9c2 cardiac myoblasts upon treatment with hypertrophic and apoptotic doses of NE (2 and 100 microM, respectively) transiently induced intracellular ROS at a comparable level, while 200 microM H(2)O(2), another proapoptotic agonist, showed robust and sustained ROS generation. Upon analysis of a number of redox-responsive transcription factors as the downstream targets of ROS signaling, the authors observed that NE (2 and 100 microM) and H(2)O(2) (200 microM) were ineffective in inducing NF-kappaB while both the agonists upregulated AP-1 and Nrf-2. However, the extents of induction of AP-1 and Nrf-2 were not in direct correlation with the respective ROS levels. Also, AP-1 activities induced by two doses of NE were intrinsically different, since at 2 microM, it primarily induced FosB, and at 100 microM it activated Fra-1. Differential induction of FosB and Fra-1 was also reiterated in adult rat myocardium injected with increasing doses of NE. Therefore, NE induces hypertrophy and apoptosis in cardiac myocytes by distinct redox-signaling rather than a general surge of ROS.
Ausgehend von o′-Toluidin (I) wird das Thiosemicarbazid (II) dargestellt und mit den aromatischen Aldehyden (III) zu den Thiosemicarb- azonen (IV) mit tuberkulostatischer und antibakterieller Aktivität umgesetzt.
The synthesis and biological activities (anti-inflammatory and antibacterial) of a number of 2,5-substituted 1,2,4-triazole, 1,3,4-thiadiazole/oxadiazole and 2,3-substituted-4-thiazolidinone derivatives are described. The anti-inflammatory activity was carried out on 2-amino/mercapto oxadiazole and 2-substituted aryl 1,3,4-oxadiazoles 10a-e. These compounds show anti-inflammatory activity from 22.34 to 72.36% whereas reference drug ibuprofen shows 80.85% inhibition at 100 mg/kg oral dose in this test. The antibacterial activity has been carried out on triazole, thiadiazole, 4-thiazolidinone and few oxadiazole derivatives 6a-b. All these compounds show significant antibacterial activity when compared with standard drug ofloxacin against S.aureus and E. coli.
Several thieno [3,2-d]pyrimidin-4-ones (4a-i) were conveniently prepared by the thio-claisen rearrangement of 5-prop-2-ynylsulfanyl pyrimidin-4-ones derivatives. The constitution of the products was supported by IR, PMR and mass spectral study. The compounds synthesized were tested in vitro against gram positive microorganisms, Bacillus subtilis, Bacillus cereus, Staphlococus aureus, Enterococcus faecalis and gram negative microorganism Eseherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Klabsiella pneumoniae and Shigella sonnei. Standard drugs were also tested under identical conditions for comparing the results.
The synthesis of the first bis-ferrocenyl-substituted core-modified porphyrins, 5,20-bis{2-{[(alkyl)(alkyl′)amino]methyl}ferrocen-1-yl}-10,15-diphenyl-21,23-dithiaporphyrin derivatives 6a–6j, via a multistep route is reported (Schemes 1, 2, and 4). The synthesis was carried out through acid-catalyzed (BF3⋅Et2O) condensation of 1,1″-[thiophene-2,5-diylbis(hydroxymethyl)]bis[2-{[(alkyl)(alkyl′)amino]methyl}ferrocenes] 4a–4j with 2,2′-[thiophene-2,5-diylbis(phenylmethylene)]bis[1H-pyrrole] (5b) in presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (=4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile; DDQ). Characterization of the compounds was done at each step by means of various spectroscopic techniques. The final compounds were screened for in vitro anti-amoebic activity against the strain HM1 : IMSS of E. histolytica (Table 2).
Novel synthesis routes for the promising antimalarial agents 4(3-hydroxypyrrolidin-1-yl) and 4(3-hydroxypiperidine-1-yl)-2,8-bis(trifluoromethyl)quinoline
have been developed.
A novel series of 1,4-bis(6-(substituted phenyl)-[1,2,4]-triazolo[3,4-b]-1,3,4-thiadiazoles (5a-b) and 4-bis(substituted phenyl)-4-thiazolidinone derivatives (7a-c) have been synthesized from terephthalic dihydrazide (1) through multistep reaction sequence. 1,4-Bis(5-aryl-1,3,4-oxadiazole-2yl) benzene derivatives (2a-f) and bis-substituted terephthalohydrazide (6a-e) were also synthesized from terephthalic dihydrazide by cyclization with various aromatic acids and aldehydes. Terephthalic dihydrazide (1) was obtained from poly(ethylene terephthalate) waste from reaction with hydrazine hydrate in good yield (86%). All the synthesized compounds were screened for their antibacterial activities against various bacteria and fungi strains. Several of these compounds showed potential antibacterial activity.
With the aim of determining selectivity and the possible target(s) of nitroheteroaryl-1,3,4-thiadiazoles considered as possible leads for the development of anti-leishmanial agents, we studied 5-nitroimidazole, 5-nitrofuran and 5-nitrothiophene analogs of N-substituted-piperazinyl-1,3,4-thiadiazoles. We investigated 21 representative compounds 1-3(a-g) for the following properties: selectivity and efficiency against different Leishmania wild type species and intracellular parasite, toxicity against host cells and inhibition of topoisomerases I and II. Our results indicate that the nitroimidazole analogs 1a and 1f, and nitrofuran derivatives 2a, 2b, 2c, 2f, and 2g exhibited low toxicity against the host cells (IC(50)> or =80 microM), but high selectivity against intracellular amastigotes (selectivity index>12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC(50) doses of compounds against Leishmania). Our findings showed that at least part of leishmaniacidal effect of the compounds could be attributed to disruption DNA-relaxed activities of topoisomerases I and II, and cleavable-complex formation.
A novel series of 1,2,3-thiadiazole thioacetanilide (TTA) derivatives have been designed, synthesized and evaluated for its anti-HIV activities in MT-4 cells. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Among them, 2-[4-(2,4-dichlorophenyl)-1,2,3-thiadiazol-5-ylthio]-N-(2-nitrophenyl)acetamide 7d2 was identified as the most promising compound (EC(50)=0.059+/-0.02 microM, CC(50)>283.25 microM, SI>4883). The structure-activity relationship (SAR) of these novel structural congeners is discussed.
Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.
The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.
This review focuses on published information on the experimental as well as clinical data on the emergence of quinolone resistant isolates. In the course of clinical use of fluoroquinolones, only a sporadic emergence of quinolone resistance has been noted. The resistant organisms emerged particularly in certain clinical settings where large numbers of organisms frequently causing chronic infections are present and/or in loci where quinolone concentrations may not be optimal. In terms of occurrence in individuals, quinolone resistance has emerged most frequently in hospitalized and nursing-home patients with identifiable risk factors. Epidemiological studies revealed that in nearly all the cases studied one or one predominating quinolone resistant clone was selected that was horizontally transmitted. Thus, the emergence of quinolone resistance is not due to an independent selection of resistant strains in a number of patients, but to the clonal spread of one strain once it has acquired quinolone resistance. Therefore, the rate of quinolone resistance is very likely to be lower than reported.
To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.
New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
Antibiotic resistance is a worldwide concern. Over the past several decades, antibiotic resistance has increased to many respiratory pathogens as well as aerobic gram-negative bacilli. Recently, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have become important hospital pathogens. Antibiotic resistance is not related to a particular antibiotic structure and is not dependent upon mechanism of antibiotic action. The volume of use per se does not increase antimicrobial resistance. This article discusses control strategies and identifies which antibiotics are associated with the emergence of resistant organisms.
Methicillin-resistant S. aureus are the major cause of nosocomial bacteremias showing a high morbidity rate in intensive care units. These strains are often resistant against almost all antibiotics in clinical use with the exception of vancomycin. However, the first isolation of a S. aureus strain with a diminished susceptibility to vancomycin from a hospitalized patient in Japan has been reported very recently. Therefore, current antibiotic therapy is difficult and expensive, often a combination of several antibiotics has to be used. For this reason novel antibiotics to combat staphylococcal bacteremias, which prevent further spread of resistance are urgently needed. One approach might be the investigation of the mechanism of methicillin resistance, which is mediated by PBP2a, an additional penicillin-binding protein present in resistant strains with low affinity to ss-lactams. Beside PBP2a other housekeeping genes, the so called fem factors, are involved in expression of methicillin resistance. Two of these fem factors, the FemAB proteins, have been shown to participate in the formation of the pentaglycine crossbridge, which is a unique staphylococcal cell wall component. The biosynthesis of the pentaglycine side chains is not fully elucidated, but follows an interesting novel mechanism with unusual glycyl-tRNA as a substrate. Furthermore, inactivation of femAB, which have been reported as essential for bacterial growth, causes a completely restoration of antibiotic susceptibility in MRSA strains. Thus, these proteins might serve as attractive novel anti-staphylococcal targets for a small-range antibiotic.
Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 microM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 microM and inhibited COX-1 activity in platelets with an IC50 of 3.1 microM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7. 1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.
A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities. Preliminary results indicated that most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Among them, 1-(4-amino-2-fluorophenyl)-6-fluoro-1,4-dihydro-7-[4-[2-(4-methoxyphenyl)-2-hydroxyiminoethyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid (11d) and its ketone precursor 10d exhibited significant activities against Klebsiella pneumoniae, methicillin-resistant S. aureus, erythromycin- and ampicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. Due to strong cytotoxicities of 11d (a mean log GI(50) of -5.40), compound 10d, with good antibacterial activities and low cytotoxicities (a mean log GI(50) of -4.67), is a more potential drug candidate.
New 1-acylderivatives of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazole (5c-f, 6d-f) were synthesized by the acylation of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazoles (3, 4) with acyl chlorides. The compounds 3, 4 were obtained by the alkylation of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol (2) sodium salt with alkyl iodides. Compound 2 and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole (8) were prepared by the treatment of 3,4-dimethoxybenzoylthiosemicarbazide (1) with sodium hydroxide or acetyl chloride (and then sodium hydroxide), respectively. Related 2-acylamino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazoles (7c, e, f) were synthesized by the acylation of compound 8 with acyl chlorides. 3-(3,4-Dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (9) was N-acylated with acyl chlorides or S-methylated with iodomethane to give 1-acyl-3-(3,4-dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H- 1,2,4-triazole-5-thiones (10a, b) or 3-(3,4-dimethoxyphenyl)-5-methylthio-4-phenyl-4H-1,2,4-triazole (11) respectively. The synthesized compounds 6d, 7a, c, 10a, b, 11 exhibit anti-inflammatory activity.
The MICs of 13 antimicrobial agents including seven fluoroquinolones (ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, gatifloxacin, moxifloxacin and clinafloxacin) for Streptococcus pneumoniae isolates obtained from all regions of Hong Kong in the year 2000 were determined by the Etest. Overall, 39.4% of 180 isolates were susceptible to penicillin, 11.7% were intermediate and 48.9% were resistant. The overall prevalence of fluoroquinolone non-susceptibility (levofloxacin MIC > or = 4 mg/L) was 13.3% but increased to 27.3% among the penicillin-resistant isolates. For the fluoroquinolone non-susceptible isolates, within-class cross-resistance was common. For the fluoroquinolone non-susceptible isolates, the median MICs of clinafloxacin, gatifloxacin, moxifloxacin, sparfloxacin and grepafloxacin were, respectively, six-, 24-, 32- 84- and 128-fold higher than those for the susceptible isolates. All fluoroquinolone non-susceptible strains were derived from adults. The prevalence of fluoroquinolone resistance was higher in isolates from older patients (17.1% among those > or = 65 years of age versus 9.1% among those 18-64 years of age, P < 0.001) and from adults with chronic obstructive pulmonary disease (24.6% versus 9.3%, P = 0.01). All fluoroquinolone non-susceptible strains were non-susceptible to penicillin (MIC range 2-4 mg/L), cefotaxime (MIC range 1-4 mg/L) and erythromycin (MIC range 4- > or = 256 mg/L). The fluoroquinolone non-susceptible isolates were genetically related to the Spain(23F)-1 clone when analysed by pulse-field gel electrophoresis and multilocus sequence typing. In conclusion, a rapid increase in the prevalence of fluoroquinolone resistance among S. pneumoniae was found in Hong Kong. Typing analysis suggests that this is due to the pan-regional dissemination of a fluoroquinolone-resistant variant (designated Hong Kong(23F)-1) of the globally distributed Spain(23)F-1 clone.
In this study, we have synthesized several compounds and examined their cytotoxic effects on human non-small cell lung cancer A549 cells. We found that GO-13 ((E,E)-2,5-bis[4-(3-dimethyl-aminopropoxy)styryl]-1,3,4-thiadiazole) is the most effective one by the MTT assay. Furthermore, the GO-13-induced apoptotic reaction was identified based on several criteria, such as negative release reaction of lactate dehydrogenase and positive labeling of annexin V and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) techniques. GO-13 induced the apoptosis in A549 cells in a concentration- and time-dependent manner. The data demonstrate that the regulations of p38 mitogen-activated protein kinase and protein kinase C was not involved in the GO-13-mediated mechanism. However, GO-13 significantly induced a down-regulation of Bcl-X(L) expression in a short-term treatment (less than 3hr), whereas stimulated up-regulation of Bax expression in a long-term treatment (24hr) indicating their involvement in GO-13 action. GO-13-mediated apoptosis is also positively correlated with the increase in caspase-3 activity. Worth noting is the fact that GO-13 did not modify the phosphorylation level of Akt/protein kinase B (PKB) until a 24-hr exposure was carried out indicating that the inhibition of Akt/PKB activation was involved in the late-phase apoptosis. Besides the anticancer activity, GO-13 also showed equivalent anti-angiogenic activity in the nude mice angiogenesis model. In summary, we conclude that GO-13 is the most effective anticancer compound in our screening tests. It induced the early-phase apoptosis in A549 cells via the Bcl-X(L) down-regulation, and that of the late-phase through up-regulation of Bax expression as well as inhibition of Akt/PKB activation.
A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized, the compounds structures were elucidated and screened for the antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Among the tested compounds, 2-phenylamino-5-(4-fluorophenyl)-1,3,4-thiadiazole 22 showed the highest inhibitory activity. The relationships between the structures of compounds and their antituberculosis activity were investigated by the Electronic-Topological Method (ETM) and feed forward neural networks (FFNNs) trained with the back-propagation algorithm. As a result of the approach, a system of pharmacophores and anti-pharmacophores has been found that effectively separates compounds of the examination set into groups of active and inactive compounds. The system can be applied to the screening and design of new active compounds possessing skeletons similar to those used in the present study.
In this study, a series of 5-aryl-3-alkylthio-1,2,4-triazoles and corresponding sulfones were prepared with the objective of developing better analgesic-antiinflammatory compounds with minimum ulcerogenic risk. The structures of the compounds were elucidated by spectral and elemental analysis. The compounds were assayed per os in mice for their antiinflammatory and analgesic activity as well as the ulcerogenic risk and acute toxicity. Several of these compounds showed significant activity. Alkylsulfone derivatives were found to be much more potent analgesic-antiinflammatory agents than the corresponding alkylthio analogs. Compounds 9 and 11 were the most active of the series in both analgesic and antiinflammatory activity tests. In contrast to reference compound acetyl salicylic acid, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic/antiinflammatory activity.
A novel series of 4-substituted 1-{[4-(10,15,20-triphenylporphyrin-5-yl)phenyl]methylidene}thiosemicarbazide, 4a-4n, was synthesized in 9-21% yield by the condensation of 4-(10,15,20-triphenylporphyrin-5-yl)benzaldehyde (3) with various substituted thiosemicarbazides in presence of catalytic amount of AcOH. These compounds were assayed for in vitro antiamoebic activity, and the results showed that out of 14 compounds 9 were found with IC(50) values lower than metronidazole corresponding to 1.05- to 4.7-fold increase in activity. MTT Assay showed that all the compounds are nontoxic to human kidney epithelial cell line. 4-(m-Toluidinyl)-1-{[4-(10,15,20-triphenylporphyrin-5-yl)phenyl]methylidene}thiosemicarbazide (4h) showed the highest antiamoebic activity with least cytotoxicity. Some of the compounds were screened for their antimalarial activities and ability to inhibit beta-haematin formation, but none of them showed an activity better than chloroquine and quinine. Only one compound out of six showed an activity comparable to standard drug.