Novel β-carboline-quinazolinone hybrid as inhibitor of Leishmania donovani Trypanothione Reductase: Synthesis, molecular docking and bioevaluation

Abstract

Trypanothione reductase (TR) is a vital enzyme in the trypanothione based redox metabolism of trypanosomatid parasites. It is one of only a handful number of chemically validated targets for Leishmania. 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 with compounds, we were able to identify six hit compounds (8j-8o) that were all found to be the competitive inhibitors of TR with Ki in the range of 0.8 - 9.2 µM. The whole-cell screening assay highlighted analogues 8k, 8l and 8n as the most active compounds with IC50 4.4, 6.0 and 4.3 µM respectively along with adequate selectivity index (SI) of >91, 36, 24 respectively.