| Identification | Back Directory | [Name]
DSM265 | [CAS]
1282041-94-4 | [Synonyms]
DSM265
DSM265,DSM-265
DSM265;DSM265;DSM265
2-(1,1-Difluoroethyl)-5-methyl-N-[4-(pentafluoro-λ6-sulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine | [EINECS(EC#)]
826-984-9 | [Molecular Formula]
C14H12F7N5S | [MDL Number]
MFCD28502125 | [MOL File]
1282041-94-4.mol | [Molecular Weight]
415.33 |
| Hazard Information | Back Directory | [Description]
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] | [Uses]
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. | [Synthesis]
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]
 | [in vivo]
DSM265 (0.5 to 75 mg/kg; Oral administration; twice daily; for 4 days; NOD-scid IL-2Rγnull (NSG) mice) has potent in vivo antimalarial activity with 90% effective dose (ED90) of 3 mg/kg per day (1.5 mg/kg twice daily). The maximum rate of parasite killing occurred at and above a dose of 13 mg/kg per day (6.4 mg/kg twice daily).
DSM265 has moderate terminal elimination half-life (t1/2) of 2-4 hours for mice (0.5 to 75 mg/kg, oral) [2]. | Animal Model: | NOD-scid IL-2Rγnull (NSG) mice (23-36 g)[2] | | Dosage: | 0.5 to 75 mg/kg | | Administration: | Oral administration; twice daily; for 4 days | | Result: | Had potent antimalarial activity with 90% effective dose (ED90) of 3 mg/kg per day (1.5 mg/kg twice daily).
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| [IC 50]
Plasmodium | [References]
[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. |
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