Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents

•Structure based C-5 and C-6 modifications of 3,4-dihydropyrimidine core.•Modifications were found to have enhanced in vitro inhibition potential.•Compound 8i showed potent in vitro antileishmanial activity.•Molecular docking analysis was carried out.•Drug-like properties was evaluated through in silico ADMET predictions.

In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 μg/ml and 1.5 μg/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis.

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