ABSTRACT
In continuation with our previous work in anti-TB research area, in the present study we have demonstrated the structural diversity of quinolylhydrazides as potent anti-tuberculars. The compound library was synthesized by molecular hybridization approach and tested in vitro against Mycobacterium tuberculosis H37Rv strains. Among the designed conjugates, the most promising molecules were found to exhibit 100% Growth Inhibition (GI) at MIC <6.25 µg/mL. Moreover, several analogs in the designed series were also turned out as excellent anti-tuberculars. To probe the structural characteristics influencing on the SAR, the classification model was generated using a binary QSAR approach termed recursive partitioning (RP) analysis. The significant features outlined by the RP model act as a guide in order to design the 'lead' compound.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Hydrazines/chemistry , Hydrazines/pharmacology , Mycobacterium tuberculosis/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Drug Design , Humans , Microbial Sensitivity Tests , Quantitative Structure-Activity RelationshipABSTRACT
Control and prevention of tuberculosis is a major challenge, as one-third of the world's population is infected with Mycobacterium tuberculosis. The resurgence of tuberculosis and the emergence of multidrug-resistance strains of mycobacteria, necessitate the search for new class of antimycobacterial agents. As a part of investigation of new antitubercular agents in this laboratory, we describe the syntheses of various hydrazides of comarins, quinolones and pyrroles and screening against M. tuberculosis (Mtb) H37(Rv) by using rifampin as a standard drug. Among the designed molecules, the most prominent compounds 2a-g, 4a and 9a showed >90% GI at MIC<6.25 µg/mL. Finally, these studies suggests that compounds 2a-g, 4a and 9a may serve as promising lead scaffolds for further generation of new anti-TB agents.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Hydrazines/pharmacology , Mycobacterium tuberculosis/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Hydrazines/chemical synthesis , Hydrazines/chemistry , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4-(arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 µg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r²) and cross-validated q². The values of r²(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained.
