Sinha, Kumardip2024-05-222024-05-222024-05-22http://hdl.handle.net/10393/46269https://doi.org/10.20381/ruor-30365The escalating challenge of antibiotic resistance in clinical settings underscores the urgent need for novel antimicrobial strategies. This thesis presents a concerted effort to address this crisis by targeting bacterial metabolism, specifically the biotin biosynthetic pathway. Biotin, a crucial vitamin for bacterial growth, is synthesized through a pathway involving the enzyme BioA. Our research focuses on MAC13772, a synthetic acetohydrazide identified as a potential inhibitor of BioA, which plays a pivotal role in this pathway. Originating from SAR studies at McMaster University, MAC13772 exhibited promising antibacterial properties, albeit with limitations in potency and potential toxicity that necessitated further optimization. The primary objective of this study was to enhance the antibacterial efficacy of MAC13772 against Gram-negative pathogens through structural modification and optimization. A comprehensive series of analogs were synthesized, aiming to overcome the limitations of MAC13772 by improving its potency and metabolic stability. Notably, a trifluoromethyl derivative emerged as significantly more potent against Acinetobacter baumannii, achieving a four-fold increase in efficacy. Moreover, dichloro-substituted analogues demonstrated a remarkable improvement in inhibitory concentration values against BioA, with up to a 90-fold enhancement. Additionally, a benzimidazole derivative was identified for its superior metabolic stability in liver microsomes, indicating a potential for increased in vivo efficacy. This research not only advances our understanding of the biotin biosynthetic pathway as a viable target for antibiotic intervention but also highlights the successful application of SAR studies in the development of more potent and stable antibacterial agents. By addressing the pharmacokinetic shortcomings of MAC13772 and its analogs, this work lays a foundational step towards the identification of new antibacterial drugs capable of combating the growing threat of drug-resistant bacteria.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/antibiotic resistancebiotin biosynthetic pathwayacetohydrazide derivativesGram-negative pathogensThesis