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

• DOI: 10.1016/j.ejmech.2016.03.022
• Publication Date: 2016-03-14T18:39:36Z
• Authors: Umer Rashid; Riffat Sultana; Nargis Shaheen; Syed Fahad Hassan; Farhana Yaqoob; Muhammad Jawad Ahmad; Fatima Iftikhar; Nighat Sultana; Saba Asghar; Masoom Yasinzai; Farzana Latif Ansari; Naveeda Akhter Qu...
• Keywords: Dose-Response Relationship, Drug; Molecular Structure; Chemistry, Pharmaceutical; Antiprotozoal Agents; 01 natural sciences; 0104 chemical sciences; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; Pyrimidines; Parasitic Sensitivity Tests; Drug Design; Drug Screening Assays, Antitumor; Leishmania donovani; Leishmania major

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.