Discovery and optimization of a novel carboxamide scaffold with selective antimalarial activity

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI:10.1016/j.ejmech.2025.117572

Alicia Wagner , Roger Trombley , Maris Podgurski , Anthony A. Ruberto , Meng Cui , Caitlin A. Cooper , William E. Long , Gia-Bao Nguyen , Adriana A. Marin , Sarah Lee Mai , Franco Lombardo , Steven P. Maher , Dennis E. Kyle , Roman Manetsch

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Abstract

Artemisinin combination therapies (ACTs) are critical components of malaria control worldwide. Alarmingly, ACTs have begun to fail, owing to the rise in artemisinin resistance. Thus, there is an urgent need for an expanded set of novel antimalarials to generate new combination therapies. Herein, we have identified a 1,2,4-triazole-containing carboxamide scaffold that, through scaffold hopping efforts, resulted in a nanomolar potent deuterated picolinamide (110). The lead compound of this class (110) displays moderate aqueous solubility (13.4 μM) and metabolic stability (CLint_app HLM 17.3 μL/min/mg) in vitro, as well as moderate oral bioavailability (%F 16.2) in in vivo pharmacokinetic studies. Compound 110 also displayed activity against various P. falciparum isolates with different genetic backgrounds and a slow-to-moderate rate of killing (average parasite reduction ratio 2.4), making the series appealing for further development.

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具有选择性抗疟活性的新型羧酰胺支架的发现和优化

青蒿素联合疗法是全球疟疾控制的关键组成部分。令人震惊的是，由于青蒿素耐药性的上升，以青蒿素为基础的联合疗法已经开始失败。因此，迫切需要一套扩大的新型抗疟药，以产生新的联合疗法。在此，我们确定了一种含有1,2,4-三唑的carboxamide支架，通过支架跳跃的努力，产生了纳米摩尔的强效氘化picolinamide（110）。该类先导化合物（110）在体外具有中等的水溶性（13.4 μM）和代谢稳定性（CLintapp HLM 17.3 μL/min/mg），在体内具有中等的口服生物利用度（% F 16.2）。化合物110对多种不同遗传背景的恶性疟原虫分离株也显示出活性，且杀灭速度缓慢至中等（平均寄生虫减少率为2.4），表明该系列具有进一步开发的潜力。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.