Hydroxylated derivatives of NPC1161: theoretical insights into their potential toxicity and the feasibility and regioselectivity of their formation.

ABSTRACT: For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the S-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water. The derivative hydroxylated at N1' (8-amino) was found to have the smallest IP of ∼ 430 kJ/mol, predicting that it would be the most hemotoxic. The calculated IPs of the derivatives hydroxylated at the C2 and C7 positions were ∼ 475 a

SUBMITTER: Ding Y 

PROVIDER: S-EPMC4216223 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature