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<p>The global burden of tuberculosis is on the rise and continues to be alarmingly high, with a notable prevalence of multidrug-resistant disease. Despite a promising drug development pipeline, the levels of resistance to these therapeutics remain significant, underscoring the need for new, innovative drugs to tackle this clinical issue. Benzoxadiazoles and their derivatives have become a valuable foundation for the development of next-generation antibacterial, antifungal, and anticancer agents. Herein, we explore the benzoxa-[2,1,3]-diazole scaffold as a promising framework for antimycobacterial development. Building on prior work, thirty-two amino acid hydrazide derivatives were synthesised using a modular approach, allowing variation of both the aryl hydrazine and amino acid moieties. These analogues were evaluated for activity against wild-type, isoniazid-resistant, and multidrug-resistant mycobacterial strains using the REMA assay, with several analogues demonstrating notable inhibitory activity. Overall, the series of novel benzoxa-[2,1,3]-diazole amino acid hydrazides demonstrates that through manipulation and optimisation of the amino acid hydrazide moieties, it is feasible to engineer potent compounds with improved antimycobacterial activity against both wild-type bacteria and, crucially, drug-resistant strains of the disease.</p><p></p>

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Benzoxa-[2,1,3]-diazole substituted amino acid hydrazides as therapeutics for drug-resistant Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月3日

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  • Ahmed K. B. Aljohani,
  • Yucheng Lu,
  • Kelly J. Jackson,
  • Paul G. Waddell,
  • Jason H. Gill,
  • Alistair K. Brown,
  • Jonathan D. Sellars

摘要

The global burden of tuberculosis is on the rise and continues to be alarmingly high, with a notable prevalence of multidrug-resistant disease. Despite a promising drug development pipeline, the levels of resistance to these therapeutics remain significant, underscoring the need for new, innovative drugs to tackle this clinical issue. Benzoxadiazoles and their derivatives have become a valuable foundation for the development of next-generation antibacterial, antifungal, and anticancer agents. Herein, we explore the benzoxa-[2,1,3]-diazole scaffold as a promising framework for antimycobacterial development. Building on prior work, thirty-two amino acid hydrazide derivatives were synthesised using a modular approach, allowing variation of both the aryl hydrazine and amino acid moieties. These analogues were evaluated for activity against wild-type, isoniazid-resistant, and multidrug-resistant mycobacterial strains using the REMA assay, with several analogues demonstrating notable inhibitory activity. Overall, the series of novel benzoxa-[2,1,3]-diazole amino acid hydrazides demonstrates that through manipulation and optimisation of the amino acid hydrazide moieties, it is feasible to engineer potent compounds with improved antimycobacterial activity against both wild-type bacteria and, crucially, drug-resistant strains of the disease.