Abstract
Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against the parasite and with low toxicity. Silent information regulator 2 (Sir2) enzymes, or sirtuins, have emerged as attractive targets for the development of novel antitrypanosomatid agents. In the present work, we evaluated the inhibitory effect of natural compounds isolated from cashew nut (Anacardium occidentale, L. Anacardiaceae) against the target enzymes TcSir2rp1 and TcSir2rp3 as well as the parasite. Two derivates of cardol (1, 2), cardanol (3, 4), and anacardic acid (5, 6) were investigated. The two anacardic acids (5, 6) inhibited both TcSir2rp1 and TcSir2rp3, while the cardol compound (2) inhibited only TcSir2rp1. The most potent sirtuin inhibitor active against the parasite was the cardol compound (2), with an EC50 value of 12.25 µM, similar to that of benznidazole. Additionally, compounds (1, 4), which were inactive against the sirtuin targets, presented anti-T. cruzi effects. In conclusion, our results showed the potential of Anacardium occidentale compounds for the development of potential sirtuin inhibitors and anti-Trypanosoma cruzi agents.
Highlights
Chagas disease is a neglected parasitic disease caused by infection with the protozoan Trypanosoma cruzi (Trypanosomatidae)
We evaluated six different compounds derived from anacardic acid, cardol, and cardanol classes isolated from A. occidentale, and determined their in vitro inhibitory activity against TcSir2rp1 and
All extracts were analyzed by HPLC-PDA to localize the expected cardol, cardanol, and anacardic acid derivatives previously described from the cashew nut [26]
Summary
Chagas disease is a neglected parasitic disease caused by infection with the protozoan Trypanosoma cruzi (Trypanosomatidae). Sirtuins have been proposed as potential anti-parasitic targets for drug development [15]. T. cruzi epimastigote growth and viability, control of parasite infection in vitro and in vivo, induce activation of apoptosis and autophagy, and when overexpressed, they protect the parasite against sirtuin inhibitors [8,9,13,16]. Molecular docking composed of a small library of phytochemicals has previously identified a restricted number of scaffolds that potentially interact with the modeled TcSir2rp and TcSir2rp enzymes including an anarcadic acid derivative obtained from the cashew nut shell liquid (CNSL), which exhibited the best overall docking results in both parasitic sirtuins [17]. We evaluated six different compounds derived from anacardic acid, cardol, and cardanol classes isolated from A. occidentale, and determined their in vitro inhibitory activity against TcSir2rp and.
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