Uses
Fexinidazole is a medication used in the treatment of African trypanosomiasis caused by trypanosoma brucei gambiense. An antitrypanosomal agent. It also functions as a medication used against the main species that cause visceral and cutaneous new World leishmaniasis.
Origin
Fexinidazole is a 2-substituted-5-nitroimidazole antiparasitic drug originally synthesised and disclosed in the 1970s by Hoechst AG (now part of Sanofi). The drug was found to be active against Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African trypanosomes) through a joint screening campaign by the Drugs for Neglected Diseases initiative and Sanofi in 2005. This has led to the rediscovery of fexinidazole as a candidate for the treatment of human African trypanosomiasis (HAT, commonly known as sleeping sickness.) In November 2018, the European Medicines Agency (EMA) gave a positive opinion on fexinidazole for the treatment of stage 1 (haemolymphatic) and stage 2 (meningoencephalitic) HAT in adults and children. As the first all-oral treatment for HAT, the World Health Organisation (WHO) added it to its list of essential medicines in 2019.In July 2021, the US FDA approved fexinidazole for the treatment of HAT in patients aged 6 years and older who weigh at least 20kg.
Biological Activity
Anti Trypanosoma, Leishmania agent.', 'Fexinidazole is a potent anti-Trypanosoma agent. Trypanosoma species human protozoan pathogens are responsible for sleeping sickness and Chagas disease. In vivo, fexinidazole is oxidized to sulfoxide and sulfone metabolites th at are effective in blocking the progression of the parasitic disease visceral leishmaniasis. The mechanism of action appears to be by reductive activation via an NADH-dependent nitroreductase expressed by the parasites.
Synthesis
The synthesis of Fexinidazole started with the methylation of nitroimidazole (2.1) using dimethyl sulphate in dioxane to give intermediate 2.2 in 82% yield. The methylated imidazole 2.2 was subsequently reacted with formaldehyde in dimethyl sulfoxide to produce the corresponding imidazolyl methanol derivative 2.3 in 62% yield. Intermediate 2.3 was reacted with dichlorosulfoxide in chloroform to give the corresponding 2-chloromethyl-1-methyl-5-nitroimidazole 2.4, which was then coupled with 4-methylmercaptophenol (2.5) in the presence of acetone and potassium carbonate to produce "wet" fexinidazole hydrochloride (2.6). The final free base of fexinidazole (2) was obtained by neutralisation with 25% aqueous ammonia solution, giving an overall yield of 65% for the entire three-step reaction.
in vivo
Fexinidazole (HOE 239; 20-50 mg/kg/day of IP or 25-100 mg/kg/day of PO; four consecutive days) has antitrypanosomal activities[1].
| Animal Model: | Adult female NMRI mice weighing between 20 and 25 g T. b. rhodesiense[1] |
| Dosage: | 20, 50 mg/kg (IP) or 25, 50, 100 mg/kg (PO) |
| Administration: | IP or PO; daily; four consecutive days |
| Result: | Had antitrypanosomal activities, with 100 mg/kg/day p.o. being 100% curative.
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References
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1015 - 1018
