Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic beta-Lactams

文献类型： 外文期刊

第一作者： Zhai, Lijuan

作者： Zhai, Lijuan;He, Lili;Liu, Yuanbai;Myo, Ko Ko;Iqbal, Zafar;Sun, Jian;Ji, Jinbo;Ji, Jingwen;Mu, Yangxiu;Gao, Yuanyu;Tang, Dong;Yang, Haikang;Yang, Zhixiang;Myo, Ko Ko

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关键词： Monobactams; synthesis; anitbacterial resistance; antibiotics; beta-lactams; aztreonam

期刊名称：MEDICINAL CHEMISTRY （ 影响因子：2.329； 五年影响因子：2.404 ）

ISSN： 1573-4064

年卷期： 2022 年 18 卷 5 期

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收录情况： SCI

摘要： Background: Mononcyclic beta-lactams are regarded as the most resistant class of beta-lactams against a series of beta-lactamases, although they possess limited antibacterial activity. Aztreonam, being the first clinically approved monobactam, needs broad-spectrum efficacy through structural modification. Objective: We strive to synthesize a number of monocyclic beta-lactams by varying the substituents at N1, C3, and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. Methods: Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using the broth microdilution method against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime, and meropenem, existing clinical antibiotics. Results: All compounds 23a-g showed higher antibacterial activities (MIC 0.25 mu g/mL to 64 mu g/mL) against tested strains as compared to aztreonam (MIC 16 mu g/mL to >64 mu g/mL) and ceftazidime (MIC >64 mu g/mL). However, all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains compared to meropenem. Conclusion: Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 mu g/mL to 2 mu g/mL) to meropenem (MIC 1 mu g/mL to 2 mu g/mL) in the case of seven bacterial species. Therefore, compound 23d may be a valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.

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