Friday, April 3, 2015

Novel Antimalarial Scaffolds From Astrazeneca

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]


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-diamine

(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.

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.