Synthesis, Biological Evaluation, Molecular Docking and DFT Study of Potent Antileishmanial Agents Based on the Thiazolo[3, 2-a]pyrimidine Chemical Scaffold

Abstract

A series of 20 compounds having thiazolo[3, 2-a]pyrimidine chemical scaffold were synthesized and evaluated for their antileishmanial activity against promastigotes of Leishmania donovani. Amongst all, two compounds showed promising antileishmanial activity in comparison to other compounds. Inhibitory concentration 50% (IC50) was calculated as 42.1 μM and 25.1 μM with selectivity index of 8.3 and 6.05, respectively against Miltefosine (reference drug) 37.78 μM with selectivity index of 2.05. To confirm the target of the these molecules, we modelled Leishmania donovani Ca2+ ion channel (LdCC) protein and performed the docking analysis of the best antileishmanial activity exhibiting inhibitors. The free energy of binding was observed as −10.2 and −9.6 kcal mol−1 in comparison to reference drug −6.2 kcal mol−1. It also makes several hydrogen bonds with our conserved residue Ser1655, Tyr1598 and Asn927. Furthermore, several hydrophobic contacts were also observed within the pocket. Finally, computational work employing density functional theory (DFT) was also carried out to investigate the electronic properties of the synthesized compounds. The in vitro and in silico activities conclusively revealed that our lead compounds may be used as a novel therapeutics against leishmaniasis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim