Pentacyclic ingamine-type alkaloids, a new antiplasmodial pharmacophore from the marine sponge Petrosid Ng5 Sp5

Abstract

Two new pentacyclic ingamine alkaloids, 22(S)-hydroxyingamine A (2) and dihydroingenamine D (3), together with the known ingamine A (1) have been isolated from marine sponge Petrosid Ng5 Sp5 (Petrosiidae) obtained from the open repository of NCI, USA. The structures of 1-3 were determined using NMR and MS techniques. The absolute configuration of OH-groups at C9 and C22 of 2 was determined as (S) using a modified Mosher esterification method. 1 and 3 showed strong antiplasmodial activity against CQ-sensitive (D6) and -resistant (W2) strains of P. falciparum with IC50 values of 90 and 78ng/mL, and 72 and 57ng/mL, respectively, while 2 was found to be less active. The compounds were found to be devoid of in vitro cytotoxicity against tumor cells of ductal (BT-549), ovary (SK-OV-3), epidermoid (KB) carcinomas and skin melanoma (SK-MEL), and non-cancerous monkey kidney fibroblasts (VERO) and pig kidney epithelial (LLC-PK11) cells, up to a maximum concentration of 10µg/mL. These polycyclic ingamine alkaloids represents the first example of antiplasmodial leads without a β-carboline ring, which is responsible for the cytotoxicity of the antiplasmodial manzamine class of marine alkaloids related to 1-3.