π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

Abstract

The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, β-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.

Adsorption to the Surface of Hemozoin Crystals: Structure‐Based Design and Synthesis of Amino‐Phenoxazine β‐Hematin Inhibitors

“…These and other experimental π-delocalized lipophilic cations are thought to accumulate in plasma and mitochondrial membranes. [37] Akin to methylene blue, these compounds exhibit potent antimalarial activity against CQ resistant P. falciparum strains; an EC 50 of 2.8 nM against the K1 strain and IC 50 values < 10 nM against both D6 and W2 strains, have been reported for basic blue and brilliant cresyl blue, respectively. [37][38] Derivatization of the phenoxazinium scaffold has led to the discovery of active compounds with a tetracyclic benzo[a]phenoxazine scaffold.…”

“…[37] Akin to methylene blue, these compounds exhibit potent antimalarial activity against CQ resistant P. falciparum strains; an EC 50 of 2.8 nM against the K1 strain and IC 50 values < 10 nM against both D6 and W2 strains, have been reported for basic blue and brilliant cresyl blue, respectively. [37][38] Derivatization of the phenoxazinium scaffold has led to the discovery of active compounds with a tetracyclic benzo[a]phenoxazine scaffold. [39] Lead compound SSJ-183 was reported with an IC 50 of 7.6 nM against the K1 strain and selectivity index of ~7300 when tested on L6 myoblast cells.…”

Synthetic, biological and optoelectronic properties of phenoxazine and its derivatives: a state of the art review

“…Methylene blue was chosen as an antimalarial agent due to its ability to specifically stain plasmodia which was demonstrated by Celli and Guarnieri, as well as Ehrlich and Leppmann's successful clinical use of this dye to treat neuralgia. Phenoxazine, an isostere of phenothiazine, came into focus over the past few decades with renewed enthusiasm for the development of new antimalarial medications [ 17 , 81 ].…”

“…Guttman and Ehrlich reported the clinical cure of two malaria patients in 1891 following the oral administration of methylene blue which contains a phenothiazine moiety; this dye was well known prior to the discovery of penicillin [ 16 , 17 ]. During the development of antimalarial drugs, phenoxazine, an isostere of phenothiazine, came into the sight again [ 18 ].…”

Discovery of Methyl (5Z)-[2-(2,4,5-Trioxopyrrolidin-3-ylidene)-4-oxo-1,3-thiazolidin-5-ylidene]acetates as Antifungal Agents against Potato Diseases

“…Numerous studies of 1,3-thiazolidine-4-one derivatives are devoted to their biological activity. , There are several publications in the literature concerning the double-bond-linked 1,3-thiazolidine-4-ones with pyrazole, oxazole, 1,3-dithiol, tetrahydropyridine, oxazine, and fused systems . Previously, we described a convenient synthesis method of 2,4,5-trioxopyrrolidin-3-ylidene-4-oxo-1,3-thiazolidin-5-ylidenes .…”