1,3,4-Thiadiazole Derivatives. Synthesis, Structure Elucidation, and Structure−Antituberculosis Activity Relationship Investigation (original) (raw)
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Bioorganic & Medicinal Chemistry, 2011
Antituberculosis activity of several 5-(4-aminophenyl)-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones (1-9) and their thiourea derivatives (10-31) were screened for their antimycobacterial activities against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Of the synthesized compounds, 10-12, 30 were the most active derivatives exhibiting more than 90 % inhibition of mycobacterial growth at 12.5 μg/mL. Structure-activity relationships study was performed for the given series by using the Electronic-Topological Method combined with Neural Networks (ETM-NN). A system of prognosis was developed as the result of training associative neural network (ASNN) using weights of pharmacophoric fragments as descriptors. Descriptors were calculated by the projection of ETM compound and pharmacophoric fragments on the elements of Kohonen's self-organizing maps (SOM). From the detailed analysis of all compounds under study, the necessary requirements for a compound to possess antituberculosis activity were formulated. The analysis have shown that any requirements violation for a molecule implies a considerable decrease or even complete loss of its activity.
Medicinal Chemistry, 2006
Antituberculosis activity of several 5-(4-aminophenyl)-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones (1-9) and their thiourea derivatives (10-31) were screened for their antimycobacterial activities against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Of the synthesized compounds, 10-12, 30 were the most active derivatives exhibiting more than 90 % inhibition of mycobacterial growth at 12.5 μg/mL. Structure-activity relationships study was performed for the given series by using the Electronic-Topological Method combined with Neural Networks (ETM-NN). A system of prognosis was developed as the result of training associative neural network (ASNN) using weights of pharmacophoric fragments as descriptors. Descriptors were calculated by the projection of ETM compound and pharmacophoric fragments on the elements of Kohonen's self-organizing maps (SOM). From the detailed analysis of all compounds under study, the necessary requirements for a compound to possess antituberculosis activity were formulated. The analysis have shown that any requirements violation for a molecule implies a considerable decrease or even complete loss of its activity.
2020
A series of novel Schiff bases were designed and synthesized by the condensation of 1,3,4-thiadiazoles that contain aromatic primary amine and variously substituted benzaldehydes. The synthesized compounds were screened for their antituberculosis activity against Mycobacterium tuberculosis H37Rv using BACTEC 460 radiometric system. Among the tested compounds, 2-(4-nitrophenyl)amino-5-[4-(3-(4-phenoxy))benzylideneaminophenyl]-1,3,4thiadiazole (3n) showed the highest inhibitory activity (80%). The activities of the newly synthesized Schiff bases were higher in comparison to those of intermediate products 2-(4-aminophenyl)-5-aryl/alkylamino-1,3,4thiadiazoles (2a-l). The computational studies were also performed to estimate drug-like profile of the compounds by using QikProp analysis.
Some novel 1,3,4-thiadiazole [5-8] and 1,2,4-triazole [9-12] derivatives carrying amino acid moiety were synthesized starting from L-methionine. 1,3,4-Thiadiazole and 1,2,4-triazole scaffolds were prepared by cyclocondensation of the corresponding thiosemicarbazide and finally converted to their thiourea derivatives. Structures of the synthesized compounds [4-12] were confirmed by IR, 1 H-NMR and 13 C-NMR spectral data and elemental analysis. Synthesized compounds were evaluated for their antiviral and antibacterial activity. Of the screened compounds, N-{3-(methylsulfanyl)-1-[5-(phenylamino)-1,3,4-thiadiazole-2-yl]propyl}benzamide [5] was identified as the most potent inhibitor of Influenza A H3N2 virus with an EC 50 value of 31.4 μM, which serves as a lead compound for prospective development. The antituberculosis activity screen of the synthesized compounds revealed 1-[4-(4-chloro-(3-trifluoromethyl)phenyl]-3-[3-(methylsulfanyl)-1-(4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)propyl]thiourea [12] as the most active compound against M. tuberculosis H37Rv strain (MIC : 30.88 µM) but the compound proved not selective.
Journal of Bionanoscience, 2018
Qualitative and Quantitative structure-activity relationship (QSAR) studies have been performed on twenty-three molecules of 1,3,4-Thiadiazole derivatives. The compounds used are among the most tubulin inhibitors. A multiple linear regression (MLR) procedure was used to design the relationships between molecular descriptor and tubulin inhibition of the 1,3,4-Thiadiazole derivatives. The predictivity of the model was estimated by cross-validation with the leave-one-out method. Our results suggest a QSAR model based on the following descriptors: polarizability (POL), molar volume (MV), molar weight (MW), partition coefficient octanol/water (logP) and molar refractivity (MR), for the tubulin inhibitory activity. To confirm the predictive power of the models, an external set of molecules was used. High correlation between experimental and predicted activities values was observed, indicating the validation and the good quality of the QSAR model.
In silico Evaluation of Antimicrobial Activity of Some Thiadiazoles Using Molecular Docking Approach
The 24th International Electronic Conference on Synthetic Organic Chemistry, 2020
Molecular docking studies have been performed to assess the antimicrobial potential of three 1,3,4-thiadiazole derivatives containing azulene rings. The simulations were conducted on Mycobacterium tuberculosis DNA gyrase, Staphylococcus aureus DNA gyrase, and Escherichia coli DNA adenine methylase. The relationships between the structures of compounds and their potential antimicrobial activity were investigated. Interactions with amino acid residues from the active binding site were elucidated and the results of docking are reported in terms of docking score. Better docking scores are obtained for the investigated compounds than for the natural ligand, (4S)-2-methyl-2,4pentanediol, in the case of the Mycobacterium tuberculosis. Two of the studied ligands present better binding affinities against Escherichia coli than the co-crystallized ones. Regarding S. aureus gyrase, the thiadiazole derivatives exhibit lower docking scores and fewer interactions than the aminobenzimidazole urea inhibitor. Our study can be useful to screen and design similar hybrid active compounds.
Synthesis and structure–antituberculosis activity relationship of 1H-indole-2,3-dione derivatives
Bioorganic & Medicinal Chemistry, 2007
New series of 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones 2a-k and 5-fluoro-1-morpholino/piperidinomethyl-1Hindole-2,3-dione-3-thiosemicarbazones 3a-r were synthesized. The structures of the synthesized compounds were confirmed by spectral data, elemental and single crystal X-ray diffraction analysis. The new 5-fluoro-1H-indole-2,3-dione derivatives, along with previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 2l-v, 1-morpholino/piperidinomethyl-5-nitro-1H-indole-2,3dione-3-thiosemicarbazones 4a-l, and 5-nitro-1H-indole-2,3-dione-3-[(4-oxo-1,3-thiazolidin-2-ylidene)hydrazones] 5a-s, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 5-nitro-1Hindole-2,3-dione-3-thiosemicarbazones (2p, 2r, and 2s) and its 1-morpholinomethyl derivatives (4a, 4e, 4g, and 4i) exhibited significant inhibitory activity in the primary screen. The antituberculosis activity of molecules with diverse skeletons was investigated by means of the Electronic-Topological Method (ETM). Ten pharmacophores and ten anti-pharmacophores that have been found by this form the basis of the system capable of predicting the structures of potentially active compounds. The forecasting ability of the system has been tested on structures that differ from those synthesized. The probability of correct identification for active compounds was found as equal to 93% in average. To obtain the algorithmic base for the activity prediction, Artificial Neural Networks were used after the ETM (the so-called combined ETM-ANN method). As the result, only 9 pharmacophores and anti-pharmacophores were chosen as the most important ones for the activity. By this, ANNs classified correctly 94.4%, or 67 compounds from 71.
Journals International Journal of Pharmacy and Pharmaceutical Sciences, 2024
Objective: To design novel series of 1,3,4 thiadiazoles and to evaluate their anti-mycobacterial potency via in silico modeling. Methods: In silico modeling comprising of lipinski rule evaluation, ADMET prediction, Molecular docking and Simulation studies aimed to identify potent 1,3,4 thiadiazoles. Results: The various physiochemical parameters and molecular descriptors of the proposed 1,3,4 thiadiazoles were predicted. And they exhibited good binding score compared with standard drug INH. The simulation studies showed minimal fluctuation of the ligand-receptor complexes. Conclusion: The MD simulation and binding affinity of designed 1,3,4 thiadiazoles proved their efficiency as InhA inhibitors. The potency of the selected derivatives can be confirmed by further in vitro and in vivo experiments.
Journal of Drug Delivery and Therapeutics, 2019
To determine antimycobacterium and dTDP rhamnose inhibitor activity of the synthesized azetidinone, thiazolidinone derivatives of thiazole, we studied different derivatives for the activity. One pot synthesis of 2-amino-4-methylthiazole-5-carboxylic acid ethyl ester has been carried out and synthesized different derivative compounds. Compounds were tested for antimicrobial activity against different strains of microorganism and antitubercular activity against M. tuberculosis H37Rv. Compounds 7c, 7d, 7i, 8d, 8e, 8g and 8h, were showed antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhosa using Gentamycin as standard, while 7b, 7e, 7f, 7i, 8b, 8e, 8f and 8i showed very strong antimycobacterial activity using rifampicine as a standard. Thiazole derivatives especially with carbonyl group scaffold inhibit an enzyme RmlC, which is an essential component for the biosynthesis of dTDP-rhamnose and produce good antimycobacterium and...