Semi-síntese de derivados da elipticina e atividade antimalárica de isolados e infusões de Aspidosperma vargasii

Abstract

The growing number of cases of resistance to the common antimalarials chloroquine and the ACTs (artemisinin-based combined therapy) favors the search for new substances with antiplasmodial activity. In 2007, the Amazonian Active Principles Laboratory (LAPAAM) at the National Institute for Amazon Research (INPA) discovered the in vitro antimalarial activity of the indole alkaloid ellipticine (10) against Plasmodium falciparum. A bibliographic search revealed that many indole alkaloids of relatively simple structure exhibited in vitro and in vivo antimalarial activity. In the present study, substances that are structurally related to 10 were obtained by isolation or semi-synthesis and their in vitro antimalarial activity was investigated. 10 and 2-methyl-1, 2, 3 ,4-tetrahydroellipticine (12) were isolated from the alkaline extracts of the bark of carapanaúba (Aspidosperma vargasii, Apocynaceae) by column chromatography. UPLC-MS analysis revealed the presence of 10 and 12 in an infusion of A. vargasii bark. Nitration (HNO3/AcOH) and bromination (Br2/CHCl3) reactions using 10 as starting material formed electrophilic aromatic substitution products 7-nitroellipticine (20, new substance) and a 3:1 mixture of 7,9-dibromoellipticine (17, a new substance) and 9-bromoellipticine (18), respectively. All substances inhibited the K1 strain of P. falciparum in vitro as evidenced by IC50 values 0,19 (10), 1,10 (12), 0,43 (20) and 0,30 (17+18) μg/mL. Compounds 10, 12, 17, 18 and 20 were not cytotoxic to human fibroblasts (IC50 > 50 μg/mL). 10 administered by mouth was highly active in the 4 day suppressive test against Plasmodium berghei in mice and inhibited parasitemia by 92% on the 5th day at a dose of 10 mg/kg/day. In the future, 17, 18 and 20 will be prepared in larger quantity and evaluated for in vivo antimalarial activity.