Antimalarial Dibenzannulated Medium-Ring Keto Lactams.

We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD values of <2) had the best metabolic stability (CL values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had IC values of 4.2 to 9.4 nM and selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (, , and ) but did have relatively high potency against , with IC values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1)-quinolone transannular condensation products in culture medium and in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.