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.
Highlights
Malaria remains the deadliest parasitic disease; according to the World Health Organisation (WHO) [1], malaria caused an estimated 229 million cases leading to 409,000 deaths in 2019 with 94% of malaria cases and deaths occurring in the sub-Saharan Africa region
Yield variation seems to have no clear correlation with the electrondonating or -withdrawing behavior of the different substituents borne on the phenols
(2a–2t), a chlorination reaction using PCl5 and POCl3 was performed under microwave heating at 100 ◦ C for 30 min, leading to the target analogs of hit B (3a–3t) in low to very good yields (26–85%)
Summary
Malaria remains the deadliest parasitic disease; according to the World Health Organisation (WHO) [1], malaria caused an estimated 229 million cases leading to 409,000 deaths in 2019 with 94% of malaria cases and deaths occurring in the sub-Saharan Africa region. The most lethal species infecting humans is Plasmodium falciparum. The first-line treatment of malaria caused by P. falciparum is based on artemisinin-based combination therapies (ACTs). Despite global efforts, the emergence of parasite resistance to the most effective class of antimalarial drugs, such as artemisinin (ART) [2], has led to treatment failures, in the Greater Mekong Subregion [3]. Molecular markers of artemisinin resistance were described in African regions, leading to a significant public health concern [4]. There are only six new chemical entities in the Medicines for Malaria Ventures (MMV) clinical pipeline [5]
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