Predictive Comparative QSAR Modeling of 4-Pyridones as Potent Antimalarials

Motivation. Malaria is one of the most life threatening diseases in tropical developing world. Chloroquine resistance occurs due to mutation in protozoal genes. It has got significance to synthesize new drugs for targeting specific enzyme or bind with receptor or to disrupt the life cycle of P. falciparum. Principal component regression analysis (PCRA), stepwise regression, factor analysis multiple linear regression (FA–MLR), partial least squares (PLS) and factor analysis partial least squares (FA–PLS) techniques were applied on some 4– pyridones to find structurally significant quantitative structure–activity relationship (QSAR) models developed using different descriptors for further improved antimalarial activity. Method. Comparative QSAR study was performed on some 4–pyridones by using PCRA, stepwise regression, FA–MLR, PLS and FA–PLS techniques to find structural requirements for further improved antimalarial activity. Results. The QSAR study shows significances of electrotopological state atom index (ETSA) indices as well as frontier electron density at atom numbers 1 and 9, grid surface area and molecular volume. These may be beneficial for the potent antimalarial activity. It also reveals that at atom numbers 1 and 9 electrophilic attack may be favorable for higher antimalarial activity. Electrostatic potential at the atom number 1 may also play pivotal role in the antimalarial activity of 4–pyridones. Conclusions. Electrophilic substitution as well as electronic interactions at atom 1 and 9 and increasing molecular volume and grid surface area of 4–pyridones may be beneficial for higher antimalarial activity.