Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines

Bioorganic & Medicinal Chemistry Letters
Derek C MartynJon Clardy

Abstract

Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R(2) significantly affecting activity. A subsequent series addressed high LogD values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R(1)/R(2). A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF(3), however antiplasmodial activity decreased without any improvement in clearance. The C6-CF(3) group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.

References

Nov 23, 2006·Antimicrobial Agents and Chemotherapy·Mary Lynn BanieckiJon Clardy
Mar 17, 2009·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Benoit WitkowskiF Benoit-Vical

Citations

Jul 3, 2013·European Journal of Medicinal Chemistry·Kamaljit SinghJan Balzarini
Mar 26, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Libao XuSong Li
Sep 26, 2012·Expert Opinion on Drug Discovery·Sara SadlerGraham B Jones

Related Concepts

2,4-diaminopyrimidine
KCNH1 protein, human
Antimalarials
Microsomes, Liver
Plasmodium falciparum
Pyrimidines
Structure-Activity Relationship
Ether-A-Go-Go Potassium Channels
Benzyl Compounds
Fluorouracil

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