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IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-17 eCollection Date: 2025-03-13 DOI:10.1021/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, Kelly Chibale

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引用次数: 0

摘要

我们合成了含有联吡啶和酰基硫脲配体的混合配体铂（II）配合物，并评估了它们对人类恶性疟原虫（Pf）的体外生长抑制活性。通过改变四个不同位点的取代基来确定该系列的结构-活性关系。大多数复合物都显示出强大的 PfNF54 活性，IC50 值在纳摩尔范围内，并具有良好的细胞毒性特征。五种复合物（C1、C11、C12、C15 和 C17）对无性血液寄生虫和有性寄生虫（配子体）阶段的寄生虫都具有活性，另一种复合物（C8）仅对晚期配子体具有活性。此外，这两种复合物对 PfK1 多重耐药菌株的 ABS 效力相当。研究还测定了一种类似物（C6）的药动学参数，该类似物具有良好的溶解性和小鼠微粒体代谢稳定性。这项工作证明了酰基硫脲铂(II)复合物作为选择性、多阶段活性抗疟药物的潜力，是寻找新抗疟药物的一部分。

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

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.