QSAR and QSTR study of pyrimidine derivatives to improve their therapeutic index as antileishmanial agents

Abstract

In the treatment of leishmaniasis, chemotherapy is expensive and has various side effects. The major side effects are due to multiple injections that are required over a course of several weeks and non-selectivity of the drugs. In addition, there is no fully effective drug available against the cutaneous form of the disease. Experimental data of pyrimidine derivatives show that they are potent inhibitors of Leishmania growth. In the current study, a series of 2-pyridyl pyrimidine derivatives with Plasmodium falcipa- rum methionine aminopeptidase 1b inhibitory activity was subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analy- ses to identify the ideal physicochemical characteristics of potential anti Leishmania activity with limited cytotoxic effects. We also determined the physicochemical charac- teristics that affect antiparasitic activity and cytotoxicity to identify the best relationship model related to these two parameters. 2-Pyridyl pyrimidines with desirable properties were built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Different descriptors were calculated using Dragon and HyperChem software. Multi- linear regression was used as a chemometric tool for QSAR and QSTR modeling and the developed models were shown to be statistically significant according to the vali- dation parameters. Based on our computational studies, using lipophilic and electronegative moieties can improve the therapeutic index of pyrimidine derivatives.