Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.
Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.
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DOI：
10.1021/acs.jmedchem.0c01372
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发表时间：
2020-12-24
影响因子：
7.3
通讯作者：
Blaskovich MAT
中科院分区：
文献类型：
--
作者：
Ang CW;Tan L;Sykes ML;AbuGharbiyeh N;Debnath A;Reid JC;West NP;Avery VM;Cooper MA;Blaskovich MAT
Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.
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