Recent Advances in the Medicinal Chemistry of Phenothiazines. New Anticancer and Antiprotozoal Agents
Background: Molecules that have a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities: antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, among others. First discovered in the 19th century as a histochemical dye, methylene blue, phenothiazine derivatives have been studied, discovering their activities, and repurposing them. Objective: This review is aimed at describing the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities that have been reported during the second decade of the 2000’s (2010-2020) Results: A variety of studies of phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. Structure analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity. Conclusion: The phenothiazine scaffold is favorable for developing of anticancer agents, especially those bearing halogens and electron withdrawing groups bound at 2-position with enhanced biological activities with a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.