Bharathkumar Inturi

Design, synthesis and 3D-QSAR studies of new diphenylamine containing 1,2,4-triazoles as potential antitubercular agents

A new series of new diphenylamine containing 1,2,4-triazoles were synthesized from 4-arylideneamino-5-[2-(2,6-dichlorophenylamino) benzyl]-2H-1,2,4-triazole-3(4H)-thiones 3a-f. The synthesized compounds were screened for in-vitro antimycobacterial and antibacterial activities. The synthesized compounds 4a, 4e and 4d have shown potential activity against Mycobacterium tuberculosis H37Rv strain with MIC of 0.2, 1.6 and 3.125 μM respectively. To investigate the SAR of diphenylamine containing 1,2,4-triazole derivatives in more details, CoMFA (q(2)-0.432, r(2)-0.902) and CoMSIA (q(2)-0.511, r(2)-0.953) models on M. tuberculosis H37Rv were established. The generated 3D-QSAR models are externally validated and have shown significant statistical results, and these models can be used for further rational design of novel diphenylamine containing 1,2,4-triazoles as potent antitubercular agents.

Recent Advances and Structural Features of Enoyl‐ACP Reductase Inhibitors of Mycobacterium tuberculosis

Mycobacterium tuberculosis enoyl‐ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH‐dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro‐drug that needs activation to form the inhibitory INH‐NAD adduct by KatG coding for catalase‐peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug‐resistant TB (MDR‐TB). Hence, there is a need for new drugs that can combat MDR‐TB. The rationale for the development of new drugs to combat MDR‐TB strains is the design of InhA inhibitors that can bypass bioactivation by KatG. In the present review, special attention was paid to discuss the chemical nature and recent developments of direct InhA inhibitors. The InhA inhibitors reported here have significant inhibitory effects against Mtb InhA. The diphenyl ether derivatives have shown slow onset, a tight‐binding mechanism, and high affinity at the InhA active site. However, some of the diphenyl ethers have significant in vitro efficacy, which fails to transform into in vivo efficacy. Among the InhA inhibitors, 4‐hydroxy‐2‐pyridones have emerged as a new chemical class with significant InhA inhibitory activity and better pharmacokinetic parameters when compared to diphenyl ethers.

Synthesis of 1,3,4-oxadiazoles as promising anticoagulant agents

In the present study, a series of 2,5-disubstituted-1,3,4-oxadiazole derivatives (4a–4k) were designed and subjected to molecular docking simulation studies onto the enzymes vitamin K epoxide reductase (PDB: 3KP9) and factor Xa (PDB: 1NFY) to visualize their binding affinity towards the said target proteins. In silico ADME studies highlighted that the designed compounds are safe enough and have the potential to be considered as drug like molecules, indicating the appreciable ADME property & probable toxicity of the designed compounds. The title compounds were synthesized from (benzo[d]oxazol-2-yl)methanamine and evaluated for in vitro radical scavenging properties and ex vivo anticoagulant activity. The results of the ex vivo anticoagulant evaluation highlighted that the compounds exhibited a significant increase in prothrombin time and clotting time, and a minimal increase in the activated partial thromboplastin time, indicating that the compounds can be considered for promising anticoagulant therapy. The results of the radical scavenging experiments indicated that the compounds have substantial antioxidant activity.

Structural insights of PA-824 derivatives: ligand-based 3D-QSAR study and design of novel PA824 derivatives as anti-tubercular agents

Abstract With the purpose of designing novel chemical entities with improved inhibitory potencies against drug-resistant Mycobacterium tuberculosis, the 3D- quantitative structure–activity relationship (QSAR) studies were carried out on biphenyl analogs of the tuberculosis (TB) drug, PA-824. Anti-mycobacterial activity (MABA) was considered for the 3D-QSAR studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The best CoMFA and CoMSIA models were found statistically significant with cross-validated coefficients (q2) of 0.784 and 0.768, respectively, and conventional coefficients (r2) of 0.823 and 0.981, respectively. The cross-validated and the external validation results revealed that both the CoMFA and CoMSIA models possesses high accommodating capacities and they would be reliable for predicting the pMIC values of new PA-824 derivatives. Based on the models and structural insights, a series of new PA-824 derivatives were designed and the anti-mycobacterial activities of the designed compounds were predicted based on the best 3D-QSAR model. The predicted data results suggest the designed compounds are more potent than existed ones.

Design, synthesis and evaluation of diphenyl ether analogues as antitubercular agents

We herein report the investigation of new diphenyl ethers as Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) inhibitors by structure-based drug design approach. The virtual library of diphenyl ethers was designed and molecules with appreciable physicochemical and ADMET properties were docked. The best ranked molecules based on docking studies were synthesized and characterized by spectral studies. Synthesized compounds were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by Microplate Alamar Blue Assay. Among the tested compounds, DE3 and DE2 exhibited substantial antitubercular potential at 3.125 and 6.25 μg mL−1 concentrations, respectively. The most active compounds were further evaluated for cytotoxicity studies against Vero and HepG2 normal cell lines by microculture tetrazolium assay and ascertained to be safe against normal cell. The molecular dynamic study reveals that the best active compounds show better binding free energy than the reference compounds TCl and JPL at Mtb InhA binding site.