Study of antiplasmodial activity, toxicity, pharmacokinetic profiles of n-methyl-isatin (CH3ISACN) derivative

IF 1.4 4区 医学 Q3 PARASITOLOGY
Cinthia Rodrigues Melo , Caliandra Maria Bezerra Luna Lima , Brenna Marceliane de Melo Marcelino , Claudio Gabriel Lima-Júnior , Abrahão Alves de Oliveira Filho , Igor Gabriel da Silva Ramalho , Kardilandia Mendes de Oliveira , Gabriela Tafaela Dias , Giciane Carvalho Vieira , Valter Ferreira de Andrade-Neto , Margareth de Fátima Formiga Melo Diniz
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Abstract

One of the main factors that have made it difficult to control malaria is the large number of parasites that are resistant to the usual antimalarial drugs. Therefore, the development of new drugs that are more effective and with low toxicity for humans is necessary. In this work, we evaluated the adduct 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylonitrile, also called CH3ISACN, as a potential antimalarial through in vitro studies, and evaluated its effects in silico and in vivo toxicology. For this, the compound CH3ISACN was exposed to P. falciparum W2 strain in infected human erythrocytes. The results showed that the CH3ISACN adduct showed good antiplasmodial activity, moderate cytotoxicity, and good cell viability. In addition, it has been shown to have good theoretical oral bioavailability and did not pose a risk of toxicity in in-silico studies. Through the in vivo study, acute toxicity was evaluated, in which doses of 300 mg/kg and 2000 mg/kg of the test substance were administered to adult female Wistar rats. CH3ISACN did not cause death in any of the animals, thus presenting a high LD50 and therefore low toxicity. There was no behavioral change in the animals, as well as in the other parameters evaluated; the highest dose tested did not cause any significant change. Only a reduction in urea concentration, but that did not bring relevant clinical significance. Through the histological study, no changes were found that would indicate intoxication in the organs of the animals. Finally, the CH3ISACN adduct presents itself as a promising drug candidate for the treatment of malaria.

Abstract Image

n-甲基isacn (CH3ISACN)衍生物的抗疟原虫活性、毒性和药代动力学研究。
使疟疾难以控制的一个主要因素是大量寄生虫对通常的抗疟疾药物具有耐药性。因此,开发对人体更有效、毒性更低的新药是必要的。本研究通过体外实验对加合物2-(3-羟基-1-甲基-2-氧吲哚-3-基)丙烯腈(CH3ISACN)作为一种潜在的抗疟药物进行了评价,并对其在硅和体内的毒理学作用进行了评价。为此,将化合物CH3ISACN暴露于感染的人红细胞中的恶性疟原虫W2株。结果表明,CH3ISACN加合物具有良好的抗疟原虫活性、中等的细胞毒性和良好的细胞活力。此外,它已被证明具有良好的理论口服生物利用度,并且在硅研究中不构成毒性风险。通过体内实验,对成年雌性Wistar大鼠分别给予300 mg/kg和2000 mg/kg剂量,进行急性毒性评价。CH3ISACN未引起任何动物死亡,因此具有高LD50,因此毒性低。动物的行为和其他被评估的参数都没有改变;测试的最高剂量没有引起任何显著变化。仅能降低尿素浓度,但未带来相关临床意义。通过组织学研究,没有发现动物器官出现中毒的变化。最后,CH3ISACN加合物是一种很有前途的治疗疟疾的候选药物。
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来源期刊
Experimental parasitology
Experimental parasitology 医学-寄生虫学
CiteScore
3.10
自引率
4.80%
发文量
160
审稿时长
3 months
期刊介绍: Experimental Parasitology emphasizes modern approaches to parasitology, including molecular biology and immunology. The journal features original research papers on the physiological, metabolic, immunologic, biochemical, nutritional, and chemotherapeutic aspects of parasites and host-parasite relationships.
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