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

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.