Avaliação da atividade anti-mycobacterium tuberculosis e antiproliferativa: Piper amalago L. e derivados β-carbolínicos

Abstract

Tuberculosis and cancer are a major public health problem worldwide. Over the years the stage of these diseases has not proven optimistic, due to increased number of cases of drug resistance. Accordingly, there is an urgent need for development of new original molecules active and less toxic than usual antituberculosis and anticancer drugs. The aim of this study was to evaluate in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) and antiproliferative of methanolic extract, fractions and compounds isolated from the leaves of Piper amalago L. and some β-carboline synthetic compounds containing guanidine unit. The Minimum Inhibitory Concentration (MIC) was assessed by the resazurin reduction method in microplates (REMA). The in vitro cytotoxicity (proliferative activities) was investigated against human tumor cell lines using the colorimetric method with Sulforhodamine B (SRB). For acute toxicity study was used in vivo mouse model Swiss females at doses of 175, 560, 1792 and 2000 mg/Kg, as the protocol 425 the Organization for Economic Cooperation and Development (OECD). The methanolic extract obtained from the leaves of P. amalago L. (MEPA) presented moderate antimycobacterial activity with MIC = 45.5 µg/mL. The chloroform fraction (FCPA) resulting from liquid-liquid partitioning had MIC = 15.3 µg/mL. The phytochemical study of the FCPA resulted in the isolation of two piperamides PA-1 and PA-2 with MIC 92.0 µg/mL and 57.0 µg/mL, respectively. MEPA also showed potent antiproliferative activity against PC- 3 prostate (LC50 = 4.34 µg/mL; TGI = 64.72 µg/mL) and OVCAR-3 ovarian cells (LC50 = 9.44 µg/mL). The FCPA acute administration did not cause signs of toxicity in the treated animals. Regarding β-carboline derivatives containing amine group (2a-c, 3a-c) or guanidinium (4a-c) terminal to C-3, compounds 2a (24.9 µg/mL), 2b (26.9 µg/mL) and 4a (27.8 µg/mL), were most active against M. tuberculosis. Regarding antiproliferative activity, eight compounds inhibited cell growth against resistant strain of ovarian NCI-ADR/RES (GI50 ≤ 8.36 mM). Based on these results further studies are needed to explore the mechanism of action and in vivo toxicity of these compounds in detail.