Examination of Coligands in Mefloquine–Metal Complexes Reveals the Structural Determinants of Activity against <i>Plasmodium falciparum</i> and <i>Schistosoma mansoni</i>
Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ-metal complexes of the general formula [M(II)(L)(MQ)]PF<sub>6</sub> are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a <i>N</i>,<i>O</i>-bidentate ligand. Biological evaluation against <i>Plasmodium falciparum</i> and <i>Schistosoma mansoni</i> revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ-Pt complexes displayed high <i>in vivo</i> efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.
Authors
- Victor M. Deflon (ORCID: https://orcid.org/0000-0002-5368-6486)
- Ariane Isis Barros (ORCID: https://orcid.org/0000-0002-6857-230X)
- Wilmer Villarreal (ORCID: https://orcid.org/0000-0002-7781-4083)
- Godwin Akpeko Dziwornu (ORCID: https://orcid.org/0000-0003-1668-8818)
- Nicoletta Basilico (ORCID: https://orcid.org/0000-0001-9030-1066)
- Przemysław J. Boratyński (ORCID: https://orcid.org/0000-0002-7139-8568)
- Christina Brandstädter (ORCID: https://orcid.org/0000-0001-8801-2273)
- Mahsa Rahbari
- Helenita Costa Quadros (ORCID: https://orcid.org/0000-0002-7191-4809)
- J. Araújo e Nobrega
- Keabetswe Masike
- Diogo R. M. Moreira
- Legna Colina-Vegas
- Nandi Mehlala
- Sammy Y Aboagye
- Kelly Chibale
- Maribel Navarro
- Dawid Jakub Kucharski
- David L. Williams
- Gabriel H. Ribeiro
- Alzir A. Batista
- Sarah D’Alessandro
Institutions
- Universidade Federal de Juiz de Fora (BR)
- South African Medical Research Council (ZA)
- Wrocław University of Science and Technology (PL)
- Rush University Medical Center (US)
- Universidade Federal do Rio Grande do Sul (BR)
- University of Cape Town (ZA)
- Universidade Federal de São Carlos (BR)
- Universidade de São Paulo (BR)
- University of Milan (IT)
- Justus-Liebig-Universität Gießen (DE)
- Discovery Centre (CA)
- Universidade Federal de Mato Grosso (BR)
- Processos - Soluções de Engenharia (Brazil) (BR)
- Drug Discovery Laboratory (Norway) (NO)
- Instituto de Psicologia Comportamental de São Carlos (BR)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03739
- Primary Topic
- Metal complexes synthesis and properties
- Type
- article
- Field-Weighted Citation Impact
- 0.00