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Keywords: antimalarial; characterisation; Diversinate™; fluorine; triazolopyrazine; scaffold; Open Source Malaria
Abstract
Nine new fluorinated analogues were synthesised by late-stage functionalisation using Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4). The structures of all analogues were fully characterised by NMR. UV and MS data analysis; three triazolopyrazines were confirmed by X-ray crystal structure analysis. The inhibitory activity of all compounds against the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and the cytotoxicity against a human embryonic kidney (HEK293 ) cell line were tested. Some of the compounds demonstrated moderate antimalarial activity with IC50 values ranging from 0.2 to >80 uM: none of the compounds displayed any cytotoxicity against HEK293 cells at 80 uM. Antimalarial activity was significantly reduced when C-8 of the triazolopyrazine scaffold was substituted with CF3 and CfriH moieties. whereas incorporation of a CfriMe group at the same position completely abolished antiplasmodial effects.
Introduction
Malaria is an infectious disease caused by Plasmodium parasites and is a major global threat to human health. The WHO World Malaria Report 2021. estimates 241 million cases of malaria and 627.000 deaths globally in 2020. an increase of 12% from the previous year [1]. The increase was mainly from countries in the WHO African region, which accounted for about 95% of malaria cases and deaths, and was associated with service disruptions during the COVID-19 pandemic [1]. Infants and young children are at a disproportionately high risk of severe malaria and death, as 80% of deaths in this region were children under five [1]. Whilst there are drugs available for the treatment of malaria infections, most have now succumbed to parasite drug resistance and thus reduced clinical efficacy [2.3]. Consequently, new antiplasmodial drugs with novel malaria targets are urgently needed to combat the global problem of parasite drug resistance. For more than 10 years, the Open Source Malaria (OSM) consortium [4] has had an interest in identifying and developing novel antimalarial compounds that belong to a variety of chemotypes, one of which includes the l,2,4-triazolo[4,3-a]pyrazine scaffold [5]. This particular series, known as OSM Series 4, has demonstrated significant potency against various strains of Plasmodium falciparum (Pf) with IC50 values as low as 16 nM. The series also showed decent in vitro...