Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-17 DOI:10.1021/acsmedchemlett.4c0054510.1021/acsmedchemlett.4c00545

Fatima-Zahra Ishmail, Dina Coertzen, Sizwe Tshabalala, Meta Leshabane, Shante da Rocha, Mathew Njoroge, Liezl Gibhard, Lyn-Marie Birkholtz, John G. Woodland, Timothy J. Egan, Kathryn J. Wicht* and Kelly Chibale*,

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Abstract

Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized and evaluated for their in vitro growth inhibitory activity against the human malaria parasite Plasmodium falciparum (Pf). The substituents at four distinct sites were varied to identify structure–activity relationships for this series. Most complexes displayed potent PfNF54 activity with IC₅₀ values in the nanomolar range and favorable cytotoxicity profiles. Five complexes (C1, C11, C12, C15, and C17) exhibited activity against both the asexual blood and sexual (gametocyte) stage parasites, with another complex (C8) exhibiting activity against late-stage gametocytes only. In addition, the complexes showed comparable ABS potency against the PfK1 multidrug-resistant strain. The pharmacokinetic parameters of one analog (C6), which displayed good solubility and mouse microsomal metabolic stability, were measured. This work demonstrates the potential of acyl-thiourea platinum(II) complexes as selective, multistage-active antiplasmodium compounds as part of the search for new antimalarial agents.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.