title: QSAR modeling of a set of pyrazinoate esters as antituberculosis prodrugs.
abstract: Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.
authors.affiliation: Department of Pharmacy, University of São Paulo, SP, Brazil. jpsfer@usp.br
authors.forename: João P S
authors.initials: JP
authors.lastname: Fernandes
authors.forename: Kerly F M
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Veni M A
authors.initials: VM
authors.lastname: Felli
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Ferreira
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Brandt
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004952:Esters; D016018:Least-Squares Analysis; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011355:Prodrugs; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004952:Esters; D011355:Prodrugs; D011718:Pyrazinamide; C005296:pyrazinoic acid