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

Abstract

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.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…[22] Quinoline and side-chain analogues contribute a centric role in providing huge quinoline-based medications with a significant contribution in the new anti-malarial drug development. [23] Apart from quinolines, [24] other nitrogen, nitrogen/ sulphur/ oxygen containing heterocycles [11] such as indole, [25] phenothiazine, [26] triazoles, [14] β-carboline, [27,28] have also been well explored.…”

Synthesis, Electronic, and Antibacterial Properties of 3,7-Di(hetero)aryl-substituted Phenothiazinyl N-Propyl Trimethylammonium Salts

“…In addition, among other privileged scaffolds, phenothiazines are considered to be photosensitizers in antimicrobial photodynamic therapy [9]. Derivatives bearing halogens or electron-withdrawing groups have been shown to have anticancer and antiprotozoal effects [10]. Diverse biological activities associated with phenothiazine hybrids make them particularly promising candidates for drug development [11].…”

Synthesis, Characterization and Anticancer Molecular Docking Studies of Phenothiazine Derivatives – A Green Chemical Approach

“…It was proposed that structural changes, primarily through replacement at the nitrogen atom, could improve its cytotoxicity in a targeted manner [7] . Tricyclic heterocycles, like phenothiazine, are perennially significant sources of scaffolding for the development of anti‐cancer drugs [8–10] …”

“…[7] Tricyclic heterocycles, like phenothiazine, are perennially significant sources of scaffolding for the development of anti-cancer drugs. [8][9][10] Due to electron-rich heteroatoms like sulphur and nitrogen, phenothiazine compounds can donate electrons. Phenothiazine-constructed dyes are advantageous as potential sensitizers for effective dye-sensitized solar cells because the molecular aggregation and the production of intermolecular excimers can be avoided since the phenothiazine ring is non-planar with butterfly confirmation in the ground state.…”