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Natural alkaloids have long been recognized for their potent biological activities, particularly their antimicrobial properties. This review comprehensively explores the antibacterial and antifungal potential of alkaloid-based compounds, with a special emphasis on indole-derived frameworks. It discusses the natural antibacterial mechanisms of alkaloids and delves into the synthetic strategies employed to develop indole-based antibacterial agents. The structure-activity relationships (SAR) governing these activities are critically examined to understand the key molecular features influencing their efficacy. In the context of antifungal activity, this review highlights both natural and synthetic developments, including synthetic methodologies and SAR insights that guide the design of effective antifungal agents. Special attention is given to recent advances in synthetic chemistry that address current limitations, such as metal-catalyzed reactions, cross-coupling strategies, multi-component reactions, and organocatalysis, which offer promising routes for the development of novel antimicrobial agents. Finally, the review outlines the existing challenges and proposes future directions for biological evaluation, emphasizing the need for deeper mechanistic studies to better understand the action of both antibacterial and antifungal agents. By integrating synthetic innovation with biological insight, this review aims to guide future research toward the development of more effective and targeted antimicrobial therapies.
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