2-N-Methyl modifications and SAR studies of manzamine A

Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral β-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3β) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC50 0.7–1.0 μM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.

Mono- and di-methylated quaternary carbolinium salts of manzamine A were synthesized and evaluated for their antimalarial activity and cytotoxicity and their potential bind with inhibit GSK-3β using docking. These modifications were made based on previous studies suggesting N-alkylation of β-carbolines improves malaria activity and reduces toxicity.Figure optionsDownload as PowerPoint slide