Cinnamon-derived Phenylpropanoids against Candida: Multi-target Mechanisms and Medicinal Chemistry Perspectives

Invasive candidiasis, particularly caused by drug-resistant strains, has emerged as a significant contributor to morbidity and mortality among hospitalized patients worldwide, posing a serious public health challenge. With the rising resistance to conventional antifungal agents such as azoles and echinocandins, the search for novel, effective, and low-toxicity antifungal lead compounds from natural products has become increasingly urgent. Cinnamon (Cinnamomum spp.), an ancient spice and medicinal plant, is rich in active components, notably cinnamaldehyde, eugenol, and cinnamic acid, which exhibit broad-spectrum and potent inhibitory effects against various Candida species, including clinically resistant strains. This review provides a systematic and updated synthesis of the anti-Candida mechanisms of these cinnamon-derived bioactive constituents, offering three distinctive contributions. First, a medicinal chemistry perspective was integrated, summarizing structure-activity relationships and physicochemical limitations that guide rational lead optimization. Second, a multi-target antifungal network encompassing cell wall/membrane disruption, biofilm and hyphal inhibition, metabolic interference, oxidative stress, and transcriptional modulation was delineated. Third, basic research to clinical translation was bridged by reviewing advanced formulation strategies, including nanoparticles, liposomes, nanofibers, and gels, alongside earlyphase clinical trial data. This multi-level integration, from molecular targets to delivery systems to human studies, provides a unique and actionable roadmap for developing cinnamon-derived nextgeneration anti-Candida therapeutics.