Novel β-carboline–quinazolinone hybrid as an inhibitor of Leishmania donovanitrypanothione 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 the few 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 sites. 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 K_i in the range of 0.8–9.2 μM. The whole-cell screening assay highlighted the analogues 8k, 8l and 8n as the most active compounds with IC₅₀ of 4.4, 6.0 and 4.3 μM, respectively, along with an adequate selectivity index (SI) of >91, 36 and 24, respectively.