Antimycobacterial pyrroles: Synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies

A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5-33) were tested in vitro against Mycobacterium tuberculosis C IP 103471. The majority of rested compounds were efficient antimycobacteria l agents showing MIC values ranging from 0.5 to 32 mu g/mL. A 3-D-QSAR stud y has been performed on these pyrrole derivatives to correlate their chemic al structures with their observed inhibiting activity against M. tuberculos is. Due to the absence of information on a putative receptor responsible fo r this activity, classical quantitative structure-activity relationships (Q SAR) and comparative molecular field analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemic al structures of pyrrole derivatives 5-33 has been developed which is poten tially helpful in the design of novel and more potent antituberculosis agen ts. The combination of CoMFA with classical QSAR descriptors led to a bette r hybrid 3-D-QSAR model, that successfully explains the structure-activity relationships (r(2) = 0.86) of the training set. A comparison between the Q SAR, CoMFA and mixed QSAR-CoMFA models is also presented. The hybrid model is to be preferred, however, because of its lowest values of the average ab solute error of prediction toward a limited external test set. (C) 2000 Els evier Science Ltd. All rights reserved.