Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-10-28 DOI:10.1021/acs.jmedchem.4c01594

Matheus Andrade Meirelles, Vitor M. Almeida, Jaryd R. Sullivan, Ian de Toledo, Caio Vinicius dos Reis, Micael Rodrigues Cunha, Rachel Zigweid, Abraham Shim, Banumathi Sankaran, Elijah L. Woodward, Steve Seibold, Lijun Liu, Mohammad Rasel Mian, Kevin P. Battaile, Jennifer Riley, Christina Duncan, Frederick R. C. Simeons, Liam Ferguson, Halimatu Joji, Kevin D. Read, Scott Lovell, Bart L. Staker, Marcel A. Behr, Ronaldo A. Pilli, Rafael M. Couñago

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引用次数: 0

Abstract

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

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理性探索 2,4-二氨基嘧啶作为 DHFR 抑制剂对两种新出现的人类病原体--脓肿分枝杆菌和分枝杆菌--的活性

非结核分枝杆菌（NTM）是与严重肺部疾病相关的新型人类病原体。目前的治疗方法需要长期使用多种药物，但往往效果不佳。细菌二氢叶酸还原酶（DHFR）是革兰氏阴性细菌感染中抗生素所针对的一种关键酶。然而，针对革兰氏阴性菌设计的现有 DHFR 抑制剂往往无法抑制分枝杆菌的 DHFR。在此，我们以 P218（一种恶性 DHFR 抑制剂）为基础，详细介绍了非结核菌 DHFR 抑制剂的合理设计。我们发现了化合物 8，这是一种 2,4-二氨基嘧啶，对纯化的 DHFR 和两种主要 NTM 物种的全细胞培养物具有更好的药理特性和活性：分枝杆菌和脓肿分枝杆菌。这项研究强调了化合物 8 作为体内验证 DHFR 有效治疗 NTM 感染的候选药物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.