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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

Recent Advances in the Medicinal Chemistry of Phenothiazines, New Anticancer and Antiprotozoal Agents

Author(s): Alonzo González-González, Lenci K. Vazquez-Jimenez, Alma D. Paz-González, María Laura Bolognesi and Gildardo Rivera*

Volume 28, Issue 38, 2021

Published on: 05 April, 2021

Page: [7910 - 7936] Pages: 27

DOI: 10.2174/0929867328666210405120330

Price: $65

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.

Keywords: Antiprotozoal, anticancer, drugs, phenothiazine, scaffold, biological activities.


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