Phenothiazine Derivatives in Anticancer Drug Discovery: Recent Synthetic Advances and Therapeutic Potential

ABSTRACT

Phenothiazine, a versatile tricyclic heterocycle, has gained increasing interest for its emerging anticancer potential. Its sulfur–nitrogen core, electron‐rich rings, and modifiable substituents enable the design of diverse derivatives with improved activity. Advances in electrophilic substitution, cyclization, microwave‐ and ultrasound‐assisted methods, and multicomponent reactions have accelerated the synthesis of structurally varied phenothiazine analogues with better drug‐like properties. Phenothiazine derivatives show potent cytotoxicity against breast, lung, colon, prostate, liver, and leukemia cell lines through mechanisms including apoptosis induction, mitochondrial dysfunction, tubulin inhibition, kinase pathway modulation, and overcoming P‐glycoprotein–mediated drug resistance. Hybrid phenothiazine–heterocycle architectures (e.g., pyridine, triazole, thiazole, quinoline) further enhance potency and target selectivity. This mini‐review outlines recent synthetic trends and anticancer evaluations, offering mechanistic insights for the rational design of next‐generation phenothiazine‐based anticancer agents.