Instituto Gonçalo Moniz, FIOCRUZ, Salvador, BA 40296-710, Brazil.
School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU, 1, Rue Michel Servet, 1211 Geneva, Switzerland.
Molecules. 2019 Apr 3;24(7):1299. doi: 10.3390/molecules24071299.
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 (, L. Anacardiaceae) against the target enzymes TcSir2rp1 and TcSir2rp3 as well as the parasite. Two derivates of cardol (, ), cardanol (, ), and anacardic acid (, ) were investigated. The two anacardic acids (, ) inhibited both TcSir2rp1 and TcSir2rp3, while the cardol compound () inhibited only TcSir2rp1. The most potent sirtuin inhibitor active against the parasite was the cardol compound (), with an EC value of 12.25 µM, similar to that of benznidazole. Additionally, compounds (, ), which were inactive against the sirtuin targets, presented anti- effects. In conclusion, our results showed the potential of compounds for the development of potential sirtuin inhibitors and anti- agents.
苯硝唑和硝呋替莫是唯一可用于治疗恰加斯病的药物，但疗效有限，并伴有严重的不良反应。因此，迫切需要寻找新的生物靶点，以鉴定针对寄生虫的新型生物活性化合物，且毒性低。沉默信息调节因子 2（Sir2）酶，或称为沉默调节蛋白，已成为开发新型抗锥虫药物的有吸引力的靶点。在本工作中，我们评估了腰果壳油（，漆树科）中分离出的天然化合物对靶酶 TcSir2rp1 和 TcSir2rp3 以及寄生虫的抑制作用。我们研究了两种 cardol 的衍生物（，）、cardanol（，）和 anacardic acid（，）。两种 anacardic acids（，）抑制了 TcSir2rp1 和 TcSir2rp3，而 cardol 化合物（）仅抑制了 TcSir2rp1。对寄生虫最有效的抑制 sirtuin 的化合物是 cardol 化合物（），其 EC 值为 12.25 µM，与苯硝唑相当。此外，对 sirtuin 靶标无活性的化合物（，）具有抗寄生虫作用。总之，我们的研究结果表明这些化合物具有开发潜在的 sirtuin 抑制剂和抗寄生虫药物的潜力。
