Screening for In Vitro Antimycobacterial Activity and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Study of 4-(arylamino)coumarin Derivatives

摘要

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 C₄- position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv 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.