Novel β‐Carboline‐Quinazolinone Hybrid as Antileishmanial Agents: Targeting Leishmania donovani Trypanothione Reductase

Abstract

Trypanothione reductase (TR) is essential for the survival of the protozoan parasite Leishmania, and, therefore, offers a promising target for the development of selective new drugs against Leishmaniasis. Herein, we report the synthesis of novel β-carboline-quinazolinone hybrids that are able to inhibit Leishmania donovani TR (LdTR) and subsequently inhibit cell growth. A molecular modeling approach based on docking studies and subsequent binding free energy estimation was performed in the active site of LdTR to understand their possible binding site. With the enzymatic assay on LdTR, we were able to identify six hit compounds that were all found to be the competitive inhibitors of TR with Ki value the range of 0.8 - 9.2 µM. The activity of compounds was further tested against the intracellular amastigotes of L. donovani and their cytotoxicity against the Vero cell. The whole-cell screening assay confirmed on-target activity of the compounds and highlighted compound (I) as the most active compounds with IC50 = 4.4 µM and SI >91.32. These investigations revealed that this group of compounds is extremely useful leads to further explore the trypanothione pathway in kinetoplastids and in the development of new antiparasitic agents.