Novel hydroxynaphthalene and quinoline derivatives effective against Trypanosoma and Leishmania

Abstract

Background and purpose: The increasing prevalence of multidrug-resistant parasites, particularly Trypanosoma and Leishmania, together with the limited efficacy of current therapies, highlights the need for new antiprotozoal agents. Current therapeutic options remain limited by toxicity and insufficient efficacy. Building on our previous work on naphthalene and quinoline derivatives with antiparasitic activity, we report new derivatives with potent antiprotozoal activity against both Leishmania mexicana and Trypanosoma brucei. Experimental approach: The synthesized compounds were evaluated for their antiprotozoal activity against Leishmania mexicana and Trypanosoma brucei, cytotoxicity, and metabolic stability in rat and human liver microsomes. To investigate their possible mechanism of action, a comprehensive molecular modelling study was performed, including molecular docking, molecular dynamics simulations (per-residue analysis), and quantum theory of atoms in molecules (QTAIM) calculations. Key results: Some synthesized compounds exhibited inhibitory effects comparable to or greater than those of the reference compounds and showed no significant cytotoxicity. The most active molecules demonstrated high metabolic stability in both rat and human liver microsomes. Molecular modelling provided mechanistic insight into the observed antiparasitic activity and identified trypanothione reductase and arginase as possible molecular targets in Leishmania mexicana. For Trypanosoma brucei, our simulations suggest that trypanothione reductase is the most probable molecular target and that these compounds inhibit this enzyme. Conclusion: The synthesized hydroxynaphthalene and quinoline derivatives represent promising antiprotozoal compounds with favourable metabolic stability and low cytotoxicity. Molecular modelling provided a possible explanation for their biological activity and suggested potential molecular targets that may support their further optimization.