Antimalarial Dibenzannulated Medium-Ring Keto Lactams.

ABSTRACT: We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5H-dibenzo[b,g]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD_7.4 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_7.4 values of <2) had the best metabolic stability (CL_int values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC₅₀ values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC₅₀ values of 4.2 to 9.4 nM and in vitro selectivity indices

SUBMITTER: Ren R 

PROVIDER: S-EPMC10860121 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature