Bestatin analogs-4-quinolinone hybrids as antileishmanial hits: Design, repurposing rational, synthesis, in vitro and in silico studies

Amongst different forms of leishmaniasis, visceral leishmaniasis caused by L. donovani is highly mortal. Identification of new hit compounds might afford new starting points to develop novel therapeutics. In this lieu, a rationally designed small library of bestatin analogs-4-quinolone hybrids were prepared and evaluated. Analysis of SAR unveiled distinct profiles for hybrids type 1 and type 2, which might arise from their different molecular targets. Amongst type 1 bestatin analog-4-quinolone hybrids, hybrid 1e was identified as potential hit inhibiting growth of L. donovani promastigotes by 91 and 53% at 50 and 25 mu M concentrations, respectively. Meanwhile, hybrid 2j was identified amongst type 2 bestatin analog-4-quinolone hybrids as potential hit compound inhibiting growth of L. donovani promastigotes by 50 and 38% at 50 and 25 mu M concentrations, respectively. Preliminary safety evaluation of the promising hit compounds showed that they are 50-100 folds safer against human derived monocytic THP-1 cells relative to the drug erufosine. In silico study was conducted to predict the possible binding of hybrid 1e with methionine aminopeptidases 1 and 2 of L. donovani. Molecular dynamic simulations verified the predicted binding modes and provide more in depth understanding of the impact of hybrid 1e on LdMetAP-1 and LdMetAP-2.

Automated summary

Visceral leishmaniasis caused by L. donovani is highly fatal, and the discovery of new hit compounds can lead to the development of novel therapeutics. A small library of bestatin analogs-4-quinolone hybrids was designed and evaluated, revealing distinct profiles for different types of hybrids. Hybrid 1e and hybrid 2j were identified as potential hits that inhibit the growth of L. donovani promastigotes, and they showed excellent safety profiles in comparison to the drug erufosine. In silico studies and molecular dynamics simulations provided insights into the binding mode and impact of hybrid 1e on LdMetAP-1 and LdMetAP-2.