Hydroxylated Derivatives of NPC1161: Theoretical Insights into Their Potential Toxicity and the Feasibility and Regioselectivity of Their Formation

[Image: see text] 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 and ∼478 kJ/mol, respectively, whereas the calculated IPs of those hydroxylated at all other possible positions were between 480 and 490 kJ/mol. The homolytic bond dissociation energies (HBDEs) of all C–H/N–H bonds in NPC1161a were also calculated. The smaller HBDEs of the C–H/N–H bonds on the 8-amino side chain suggest that these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implies that the N1′ position should be the most reactive center when NPC1161 approaches the heme in CYP450.