Title:Recent Advances in the Medicinal Chemistry of Phenothiazines, New Anticancer and Antiprotozoal Agents
Volume: 28
Issue: 38
Author(s): Alonzo González-González, Lenci K. Vazquez-Jimenez, Alma D. Paz-González, María Laura Bolognesi and Gildardo Rivera*
Affiliation:
- Laboratorio de Biotecnologia Farmaceutica, Centro de Biotecnología Genomica, Instituto Politecnico Nacional, 88710 Reynosa,Mexico
Keywords:
Antiprotozoal, anticancer, drugs, phenothiazine, scaffold, biological activities.
Abstract:
Background: Molecules with a phenothiazine scaffold have been considered versatile
organic structures with a wide variety of biological activities, such as antipsychotic, anticancer,
antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal,
etc. It was first discovered in the 19th century as a histochemical dye, phenothiazine methylene
blue. Since then, its derivatives have been studied, showing new activities; moreover,
they have also been repurposed.
Objective: This review aims to describe the main synthetic routes of phenothiazines and, particularly,
the anticancer and antiprotozoal activities reported during the second decade of the
2000s (2010 - 2020).
Results: Several studies on phenothiazines against cancer and protozoa have revealed that
these compounds show IC50 values in the micromolar and near nanomolar range. The structural
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 anticancer agents, especially
those bearing halogens and electron-withdrawing groups bound at 2-position with enhanced
biological activities through 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.
