Produção Nacional
Rational-Based Discovery of Novel β-Carbolines Derivatives as Potentials Antimalarials: From in Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria
2022; RELX Group (Netherlands); Linguagem: Inglês
10.2139/ssrn.4215668
ISSN1556-5068
AutoresFernanda de Moura Alves, Jéssica Côrrea Bezerra Bellei, Camila de Souza Barbosa, Caíque Lopes Duarte, Amanda Luisa da Fonseca, Ana Claudia de Souza Pinto, Felipe Oliveira Raimundo, Bárbara Albuquerque Carpinter, Ari Sérgio de Oliveira Lemos, Elaine Soares Coimbra, Alex Gutterres Taranto, Vinícius Novaes Rocha, Fernando de Pilla Varotti, Gustavo Henrique Ribeiro Viana, Kézia KG Scopel,
Tópico(s)Computational Drug Discovery Methods
ResumoMalaria continues a scourge to many countries in the world, having a long spread in tropical underdeveloped regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria, and is responsible for deaths and significant neurocognitive sequelae throughout life, even with the administration of adequate antimalarial treatment. In this context, and considering the emergence and spread of drug resistant isolates of P. falciparum, it becomes urgent the search for new antimalarial candidates that positively aid in conventional drugs to reduce a severe prognostic of infection. β-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds have been reported. Herein, we designed 20 chemical entities and performed an in silico virtual screening against a pool of P. falciparum molecular targets, the Brazilian Malaria Molecular Targets (BRAMMT). Seven structures showed potential to interact with PfFNR, PfPK7, PfGrx1, and PfATP6. Thus, seven compounds were synthetized and evaluated for in vitro antiplasmodial activity. Compounds 3-6 and 10 inhibited the growth of W2 strain at micromolar concentrations with low cytotoxicity against human cell line (WI-26 VA4). In silico physicochemical and pharmacokinetic properties of absorption were found to be favorable for oral administration. Compound 10 showed important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and the suppressive tests (82%). Furthermore, compound 10 was able to elongate mice survival and protect them against the development of experimental model of cerebral malaria (ECM) (>65%) in both treatment regimens. Compound 10 also induced reduction in the synthesis of nitric oxide, possibly by interaction with iNOS. In conclusion, this alkaloid demonstrated promising activity for the treatment of malaria and was able to avoid the development of ECM, probably by the reduction of NO synthesis as one of its pathways of action.
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