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

被引：0

作者：

Ishmail, Fatima-Zahra ^{[1
]}

Coertzen, Dina ^{[2
]}

Tshabalala, Sizwe ^{[2
]}

Leshabane, Meta ^{[2
]}

da Rocha, Shante ^{[2
]}

Njoroge, Mathew ^{[3
]}

Gibhard, Liezl ^{[3
]}

Birkholtz, Lyn-Marie ^{[2
,4
,5
]}

Woodland, John G. ^{[1
,3
,6
]}

Egan, Timothy J. ^{[1
,6
]}

Wicht, Kathryn J. ^{[1
,3
,6
]}

Chibale, Kelly ^{[1
,3
,6
]}

机构：

[1] Univ Cape Town, Dept Chem, ZA-7701 Rondebosch, South Africa

[2] Univ Pretoria, Inst Sustainable Malaria Control, Dept Biochem Genet & Microbiol, ZA-0028 Hatfield, South Africa

[3] Univ Cape Town, Holist Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South Africa

[4] Univ Pretoria, Inst Sustainable Malaria Control, Sch Publ Hlth & Hlth Syst, ZA-0028 Hatfield, South Africa

[5] Stellenbosch Univ, Dept Biochem, ZA-7602 Matieland, South Africa

[6] Univ Cape Town, Inst Infect Dis & Mol Med, South African Med Res Council Drug Discovery & Dev, ZA-7925 Observatory, South Africa

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2025年 / 16卷 / 03期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

Platinum(II) complexes; antiplasmodium; malaria; gametocyte; acyl-thiourea; bipyridine; ANTIMALARIAL-DRUG RESISTANCE; IN-VITRO; CHLOROQUINE; DERIVATIVES; ANTICANCER; FERROQUINE;

D O I：

10.1021/acsmedchemlett.4c00545

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：428 / 435

页数：8

共 42 条

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