# Design of Hybrid Quinoline–Chalcone Compounds Against Leishmania amazonensis Based on Computational Techniques: 2D- and 3D-QSAR with Experimental Validation

## TL;DR

This paper describes the design and testing of new hybrid compounds that show promise in fighting a tropical disease caused by Leishmania amazonensis.

## Contribution

The study introduces a novel hybrid quinoline–chalcone compound design guided by computational and experimental methods for antileishmanial drug discovery.

## Key findings

- A CoMSIA model combining steric and hydrogen-bond acceptor fields was identified as the most robust predictor of antileishmanial activity.
- Four hybrid compounds showed inhibitory activity comparable to amphotericin B, a standard treatment for leishmaniasis.
- The most active compounds exhibited favorable biocompatibility and drug-like properties based on physicochemical and in silico pharmacokinetic analyses.

## Abstract

Background: Leishmania amazonensis, one of the causative agents of cutaneous leishmaniasis, is responsible for a neglected tropical disease affecting nearly one million individuals worldwide. Although clinical treatments are available, their effectiveness is often compromised by high toxicity and limited selectivity. Methods: From a database, 64 chalcone derivatives were studied using Comparative Molecular Similarity Indices Analysis (CoMSIA) and Hansch analysis (2D-QSAR) to construct predictive computational models. Internal and external validation criteria were applied to identify structural determinants associated with antileishmanial activity. Based on these insights, twelve novel quinoline–chalcone hybrids were designed, synthesized, and biologically evaluated against L. amazonensis. Results: The most robust CoMSIA model combined steric and hydrogen-bond acceptor fields (CoMSIA-SA), while Hansch analysis highlighted electronic descriptors—specifically LUMO energy and the global electrophilicity index—as critical for parasite growth inhibition. Guided by these computational findings, a new series of 12 hybrid quinoline–chalcone derivatives (E001–E012) was synthesized through a two-step procedure, achieving overall yields of 43–71%. Biological assays demonstrated that four compounds displayed inhibitory activity comparable to amphotericin B. Furthermore, physicochemical profiling and in silico pharmacokinetic predictions for the most active compounds (E003, E005, E006, and E011) indicated favorable biocompatibility and drug-like properties. Conclusions: These results underscore the value of an integrative computational–experimental approach in the rational design of next-generation L. amazonensis inhibitors, reinforcing chalcone-based scaffolds as promising pharmacophoric frameworks for antileishmanial drug discovery.