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

<b>Background</b>: <i>Leishmania amazonensis</i>, 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. <b>Methods</b>: 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 <i>L. amazonensis</i>. <b>Results</b>: 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 (<b>E001</b>-<b>E012</b>) 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 (<b>E003</b>, <b>E005</b>, <b>E006</b>, and <b>E011</b>) indicated favorable biocompatibility and drug-like properties. <b>Conclusions</b>: These results underscore the value of an integrative computational-experimental approach in the rational design of next-generation <i>L. amazonensis</i> inhibitors, reinforcing chalcone-based scaffolds as promising pharmacophoric frameworks for antileishmanial drug discovery.