The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL ACS Infectious Diseases Pub Date : 2024-09-13 Epub Date: 2024-08-14 DOI:10.1021/acsinfecdis.4c00461

Savannah J Watson, Mariëtte E van der Watt, Anjo Theron, Janette Reader, Sizwe Tshabalala, Erica Erlank, Lizette L Koekemoer, Mariska Naude, Marianna Stampolaki, Feyisola Adewole, Katie Sadowska, Pilar Pérez-Lozano, Andreea L Turcu, Santiago Vázquez, Jihee Ko, Ben Mazurek, Davinder Singh, Satish R Malwal, Mathew Njoroge, Kelly Chibale, Oluseye K Onajole, Antonios Kolocouris, Eric Oldfield, Lyn-Marié Birkholtz

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Abstract

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC₅₀) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

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结核病候选药物 SQ109 及其类似物对恶性疟原虫具有多阶段活性。

为了将抗结核临床候选药物 SQ109 重新定位为抗疟药，我们研究了类似物的结构-活性关系，以确定其对人类恶性疟原虫致病型无性血液阶段以及可传播的有性阶段配子细胞的活性。我们的研究表明，对无性阶段和有性阶段都能达到 100-300 nM 范围内的等效活性（IC50），而且大多数化合物对耐多药菌株都能保持活性。多阶段活性特征依赖于金刚烷头基的高亲脂性，而抗虫体活性则主要取决于二胺连接体。前导化合物对基因多样的南部非洲临床分离株显示出一致的活性。此外，我们还验证了这一系列化合物可以阻断蚊虫传播，这标志着这些化合物是具有多级抗疟活性的新型化学类型。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.