1282041-94-4

DSM265 belongs to a promising class of antimalarials that inhibit the plasmodium dihydroorotate dehydrogenase enzyme required for pyrimidine biosynthesis. Its good in-vitro efficacy, activity on blood and liver stages, pharmacokinetic profile suitable for single dosing, and good tolerability and safety profiles in phase 1 clinical assessments make it one of the most promising drug candidates in the global antimalarial portfolio.^[1]

DSM265, inhibits the growth of P. falciparum 3D7 parasites with an EC50 of 4.3 nM. It is also a PfDHODH inhibitor with an IC50 of 8.9 nM.

DSM-265 has been synthesized by cyclocondensation of ethyl acetoacetate (I) with aminoguanidine hydrochloride (II) in the presence of NaOEt in refluxing EtOH to give 2,3- diamino-6-methylpyrimidin-4(3H)-one (III). Intermediate (III) upon cyclization with ethyl 2,2-difluoropropanoate (IV) using NaOEt in refluxing EtOH and subsequent treatment with HCl yields triazolopyrimidine derivative (V). Compound (V) reacts with POCl3 providing 7-chloro-2-(1,1-difluoroethyl)- 5-methyl[1,2,4]triazolo[1,5-a]pyrimidine (VI), which is finally condensed with 4-aminophenylsulfurpentafluoride (VII) in EtOH at 50 °C.^[2]

Plasmodium

[1] SABINE BÉLARD   Michael R. DSM265: a novel drug for single-dose cure of Plasmodium falciparum malaria.[J]. The Lancet. Infectious diseases, 2018: 819-820. DOI:10.1016/S1473-3099(18)30374-8.
[2] R. THAKARE. DSM-265. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor, Treatment of malaria[J]. Drugs of The Future, 2019, 1 1. DOI:10.1358/DOF.2019.44.2.2941689.