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

Abstract

Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral beta-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-3beta) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC(50) 0.7-1.0microM) 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.

Figure 1

β-Carboline alkaloids with potential biological activities.

Figure 2

Selected HMBC correlations of analogs 2 and 3.

Figure 3

Binding positions of 1–3 within the ATP-noncompetitive binding pocket of GSK-3β (A:1, B:2, C:3). Ligands 1–3 are shown with green carbon; the protein is in ribbon format colored according to secondary structures; the binding pocket interior surface (as detected with the Lee/Richards molecular surface) is in white.

Figure 4

Interactions of 1 (A) and 2 (B) with the GSK-3β ATP-noncompetitive binding pocket residues.

Scheme 1