QSAR studies of anti-malarial agents: 2,4-diamino pyrimidine derivatives

The discovery and development of a novel target site to treat malaria is still continued worldwide. The bifunctional enzyme dihydrofolate reductase-thymidylate synthetase (DHFR-TS) is found in malarial parasite. The DHFR domain of the enzyme plays an important role in nucleic acid synthesis, which acts as an attractive target for designing antimalarial compounds. The 2,4-diaminopyrimidine derivatives have been reported to be antimalarial agents, by virtue of their inhibition of DHFR. The physico-chemical descriptors, indicator variables and biological activity (TM4, K1CB1) of 2,4-diaminopyrimidine derivatives were considered for quantitative structure activity analysis. Highly correlated significant equations were obtained from the multiple regression analysis and are taken for further analysis as represented below. TM4: -log IC50 = 0.523751(+/- 0.493089)pi - 0.0391451(+/- 0.0372016)MR - 1.64545(+/- 1.32314)I-R1 + 1.20497(+/- 0.887005)I-R5 - 0.735828(+/- 0.755899) n = 28, r = 0.668, r(2)- = 0.447, F-test = 4.6562, s = 0.642, Q(2) = 0.314 K1CB1: -log IC50 = -0.677(+/- 0.613)sigma(m) - 0.595(+/- 0.434)sigma(p) + 0.478(+/- 0.317)I-R2 + 0.628(+/- 0.791)IR1 - 1.058(+/- 0.247) n = 26, r = 0.763, r(2) = 0.583, F-test = 7.355, s = 0.362 The results show that for activity against wild type (TM4) pf DHFR, hydrophobicity of the substituents (pi) and substituent at position R-5 was important (positive correlation) whereas substituent at R, position and a higher electron polarizability, the value of the substituent (MR) would be detrimental to the activity (negative correlation). On the other hand, the activity against S 108N mutant form (K1CB1) of pf DHFR, substituents at R, and R, would be beneficial whereas the electronic property of the molecule was found to be detrimental to the activity.