QSAR Studies of Anti-malarial Agents: 2,4-DiaminoPyrimidine Derivatives

Abstract

The discovery and development of a novel target site to treat malaria is still continued worldwide. The bifunctional enzyme dihydrofolate reductase-thymidylate synthetase (DHFRTS) 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)π – 0.0391451(±0.0372016)MR                                  – 1.64545(±1.32314) I_RI + 1.20497(±0.887005)I_R5                                  – 0.735828(±0.755899)                     n = 28, r = 0.668, r² = 0.447, F_test = 4.6562, s = 0.642, Q² = 0.314            K₁CB₁:            –log IC₅₀ = – 0.677(±0.613)σ_m – 0.595(±0.434)σ_p + 0.478(±0.317) I_R2                                  + 0.628(±0.791) I_RI – 1.058 (±0.247)                     n = 26, r = 0.763, r² = 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 (π) and substituent at position R₅ was important (positive correlation) whereas substituent at R₁ 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 S108N mutant form (K₁CB₁) of pf DHFR, substituents at R₁ and R₂ would be beneficial whereas the electronic property of the molecule was found to be detrimental to the activity.