Flavonoids in treatment of tuberculosis: from molecular mechanisms to structure activity relationships

Tuberculosis (TB) being caused by M. tuberculosis is a major global health burden especially in low and middle income countries especially with the rise of drug resistant (MDR/RR- TB) strains and poor treatment outcomes. Limitations of traditional anti-TB treatment, such as toxicity, cost and emerging drug resistance mean that the development of alternative therapy approaches is needed. Flavonoids are a diverse group of plant-derived polyphenolic compounds which have received considerable attention because of their remarkable potent anti- mycobacterial and host directed therapeutic properties. This review provides a comprehensive overview of the mechanisms underlying the antitubercular effects of flavonoids such as reducing oxidative stress, disruption of integrity of mycobacterial cell wall, inhibition of efflux pumps, modulation of the MAPK/ERK signaling pathway, Interference of DNA replication, nucleic acid synthesis and energy metabolism. Their multi-targeted actions increase therapeutic ability and reduce the chances of the development of resistance. The clinical translation of flavonoids is constrained by a number of pharmacokinetic & safety-related problems, including low oral bioavailability, metabolic stability, toxicity, and poor water solubility, which can limit their systemic exposure. However, structural modifications to flavonoids have served to overcome these shortcomings and make them efficient in combating bacterial infections. The SAR studies underscore the fact that biological activity is strongly affected by the pattern of hydroxylation, molecular planarity, and lipophilicity. Key aspects like C₂ = C₃ double bond, B-ring catechol moieties and lipophilic substitutions increase target binding and cellular permeability whereas excessive methylation or glycosylation decreases activity. Overall, flavonoids are promising inexpensive and less toxic candidates to develop novel anti-TB treatments, although it is important to conduct further research to optimize bioavailability and clinical applicability.