2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

Abstract

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.

Chemistry, Synthesis, and Structure Activity Relationship of Anticancer Quinoxalines

“…Quinoxaline molecules are named benzopyrazines or 1,4-benzodiazines [41][42][43]. There are four benzodiazines: quinoxaline, quinazolines, phthalazines, and cinnolines.…”

Dichloro{4-(4-chlorophenoxy)phthalazin-1-yl} methylphosphonic dichloride

“…In 2020, malaria deaths dramatically increased by 12% from 2019 to a 627,000, among which 77% were children under 5 years old: this was mainly du disruptions during the COVID-19 pandemic. [1] To overcome the resistance o agent Plasmodium to most of the marketed therapies, including the most recen as artemisinin-combination therapies (ACTs), a huge effort has been made new derivatives active against Plasmodium and display original mechanisms o With the aim of developing new antiplasmodial compounds, our laboratory e ferent aza-heterocyclic scaffolds bearing a trichloromethyl group, which was for providing the antiparasitic activity [3][4][5]. We previously obtained a hit mo 2-trichloromethylquinazoline series bearing a 4′-chlorophenoxy substituent a showing micromolar activity against P. falciparum and a low cytotoxicity aga man HepG2 cell line [6] (Figure 1).…”

Efficient Synthesis of Aminoquinolinium and Aminoquinazolinium Salt Series: Amination or N-Alkylation First?

“…As part of our research on antimalarial candidates, [12][13][14] we recently prepared more than forty N-heterocyclic iminium salts with good antiplasmodial activities and a promising mechanism of action. 15 The extensive synthetic work carried out for this project enabled us to identify interesting strategies for the efficient and rapid preparation of aminoquinolinium and aminoquinazolinium salt series.…”