title: Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies.
abstract: A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5-33) were tested in vitro against Mycobacterium tuberculosis CIP 103471. The majority of tested compounds were efficient antimycobacterial agents showing MIC values ranging from 0.5 to 32 microg/mL. A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5-33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents. The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure-activity relationships (r2 = 0.86) of the training set. A comparison between the QSAR, 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 absolute error of prediction toward a limited external test set.
authors.affiliation: Center for Molecular Design, Washington University, St. Louis, MO 63110, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ragno
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
authors.forename: R
authors.initials: R
authors.lastname: Di Santo
authors.forename: R
authors.initials: R
authors.lastname: Costi
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: R
authors.initials: R
authors.lastname: Rompei
authors.forename: M
authors.initials: M
authors.lastname: Artico
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013055:Spectrophotometry, Infrared; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D011758:Pyrroles