The widespread emergence and dissemination of Plasmodium falciparum (Pf) strains resistant to conventional antimalarial drugs has intensified the efforts to discover and develop novel, structurally diverse drugs against multidrug-resistant Plasmodium strains. This situation is further aggravated by the emergence of Pf strains resistant to artemisinin derivatives in various part of Asia [1].
Scaffolds disclosed:
1. Triaminopyrimidine [1]
2. Aminoazabenzimidazoles [2]
3. N-Aryl-2-Aminobenzimidazoles [3]
Triaminopyrimidine
Authors report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (named as compound 12) is efficacious in a mouse model of Pf malaria with an ED99 less than 30-mgkg-1 in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days.
Compound 12, IUPAC name: (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1, 5-dimethyl-1H-pyrazol-3-yl)-5-(3, 4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamineScaffolds disclosed:
1. Triaminopyrimidine [1]
2. Aminoazabenzimidazoles [2]
3. N-Aryl-2-Aminobenzimidazoles [3]
Triaminopyrimidine
Authors report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (named as compound 12) is efficacious in a mouse model of Pf malaria with an ED99 less than 30-mgkg-1 in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days.
Procedure:
(A) Pyridine, microwave, 150 °C, 45 min.
(B) (i) POCl3, reflux, 6 h
(ii) sodium carbonate, di-tert-butyl dicarbonate, room temperature, 16 h.
(C) N,N-Diisopropylethylamine (DIPEA), ethanol, microwave, 110 °C, 1 h.
(D) (i) Potassium tert-butoxide, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), pd2(dba)3, toluene, reflux, 12 h.
(E) HCl (4 N) in dioxane, 15-30 min.
(F) Compound 9, DIPEA, dichloromethane, formaldehyde (HCHO), sodium cyanoborohydride, 15 min.
References:
1. Sambandamurthy, V. K.; et. al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 2015, 6, Article number: 6715 doi:10.1038/ncomms7715
2. Hameed, P. S.; et. al. Aminoazabenzimidazoles, a novel class of orally active antimalarial agents. J Med Chem 2014, 57(13), 5702-5713.
3. Ramachandran, S.; et. al. N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds. J Med Chem 2014, 57(15), 6642-6652.
2. Hameed, P. S.; et. al. Aminoazabenzimidazoles, a novel class of orally active antimalarial agents. J Med Chem 2014, 57(13), 5702-5713.
3. Ramachandran, S.; et. al. N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds. J Med Chem 2014, 57(15), 6642-6652.
