Structure-based Virtual Screening and Drug Design Development of Leishmanicidal Pyrimidines

Leishmaniasis is a neglected disease caused by parasites of the genus Leishmania sp. that causes approximately 1 million cases and 650,000 deaths annually worldwide. Its treatment has several limitations mainly due to high toxicity and clinical resistance, and the search for alternatives is highly desirable. The present work aimed to design new antileishmanial compounds through a virtual screening of a small in-house library of pyrimidine compounds, never tested against Leishmania, using the active site of trypanothione reductase (TR) as a target model. The compounds showed favorable affinity with the amino acid residues of the active site of TR. Pyr 1-9 were synthesized and tested against Leishmania amazonensis strain. Four derivatives demonstrated activity against promastigote (IC₅₀ value between 11.23 and 91.5 µM) and three other compounds demonstrated discreet activity against amastigote, IC₅₀ value between 81.29 and 153.21 µM. Based on the results obtained in the screening, three new pyrimidines Pyr 10-12 were designed to optimize activity, cytotoxicity, and selectivity. Pyr 10 and Pyr 11 demonstrated good activity against promastigotes, with IC₅₀ of 11.38 ± 9.7 and 20.01 ± 13.55 µM, respectively, and improved cytotoxicity and selectivity. No activity was obtained against amastigotes. Thus, this study contributes important information for the development of new pyrimidines active against Leishmania.