Novel hydroxynaphthalene and quinoline derivatives effective against Trypanosoma and Leishmania

Original scientific paper

Authors

  • Tomas Gonec Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-3712-8641
  • Tomas Strharsky Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0001-9291-5424
  • Marcela Vettorazzi Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis. IMIBIO-CONICET, Ejército de los Andes 950 (5700) San Luis, Argentina. https://orcid.org/0000-0002-5810-748X
  • Lucas Gutierrez Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis. IMIBIO-CONICET, Ejército de los Andes 950 (5700) San Luis, Argentina https://orcid.org/0000-0003-2776-517X
  • Martina Cudova Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0009-0004-8929-8022
  • Tereza Kauerova Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-2854-511X
  • Michaela Simurdova Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic https://orcid.org/0009-0003-0726-480X
  • Michal Oravec Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic https://orcid.org/0000-0002-2506-5826
  • Jiří Kos Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic https://orcid.org/0000-0002-3589-4361
  • Peter Kollar Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-2265-1528
  • Bohuslav Drahos Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, 779 00 Olomouc, Czech Republic https://orcid.org/0000-0003-4298-4530
  • Jan Jurica Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic https://orcid.org/0000-0002-0257-6711
  • Ondrej Zendulka Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic https://orcid.org/0000-0001-5038-4899
  • Jana Gregorova Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic https://orcid.org/0000-0002-3639-6559
  • Ondrej Pes Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic https://orcid.org/0000-0002-1325-0418
  • Joelle Quetin-Leclercq Louvain Drug Research Institute, Université de Louvain (UCLouvain) of Louvain, Avenue E. Mounier, 72, B1.7203, B-1200 Brussels; Belgium https://orcid.org/0000-0002-2278-6206
  • Josef Jampilek Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic https://orcid.org/0000-0003-2003-9052
  • Ricardo D. Enriz Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis. IMIBIO-CONICET, Ejército de los Andes 950 (5700) San Luis, Argentina https://orcid.org/0000-0002-4846-9452

DOI:

https://doi.org/10.5599/admet.3520

Keywords:

Carboxanilides, antiprotozoal activity, structure-activity relationship, metabolic stability, molecular modelling, cytotoxicity

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.

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20-08-2026

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Vol. 14 (2026)

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Medicinal chemistry

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Copyright (c) 2026 Tomas Gonec, Tomas Strharsky, Marcela Vettorazzi, Lucas Gutierrez, Martina Cudova, Tereza Kauerova, Michaela Simurdova, Michal Oravec, Jiří Kos, Peter Kollar, Bohuslav Drahos, Jan Jurica, Ondrej Zendulka, Jana Gregorova, Ondrej Pes, Joelle Quetin-Leclercq, Josef Jampilek, Ricardo D. Enriz

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Novel hydroxynaphthalene and quinoline derivatives effective against Trypanosoma and Leishmania: Original scientific paper. (2026). ADMET and DMPK, 14, Article 3520. https://doi.org/10.5599/admet.3520

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