Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria
Fernanda de Moura Alves,
Jessica Correa 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 K. G. Scopel
Affiliations
Fernanda de Moura Alves
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Jessica Correa Bezerra Bellei
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Camila de Souza Barbosa
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Caíque Lopes Duarte
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Amanda Luisa da Fonseca
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Ana Claudia de Souza Pinto
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Felipe Oliveira Raimundo
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Bárbara Albuquerque Carpinter
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Ari Sérgio de Oliveira Lemos
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Elaine Soares Coimbra
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Alex Gutterres Taranto
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Vinícius Novaes Rocha
Research Center of Pathology and Veterinary Histology, Departament of Veterinary Medicine, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Fernando de Pilla Varotti
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Gustavo Henrique Ribeiro Viana
Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil
Kézia K. G. Scopel
Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil
Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria (CM) and is responsible for deaths and significant neurocognitive sequelae throughout life. In this context and considering the emergence and spread of drug-resistant P. falciparum isolates, the search for new antimalarial candidates becomes urgent. β-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds has 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, being synthesized and evaluated for in vitro antiplasmodial activity. Among them, compounds 3–6 and 10 inhibited the growth of the W2 strain at µM concentrations, with low cytotoxicity against the human cell line. In silico physicochemical and pharmacokinetic properties were found to be favorable for oral administration. The compound 10 provided the best results against CM, with important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and suppressive (82%) assays. Furthermore, this compound was able to elongate mice survival and protect them against the development of the experimental model of CM (>65%). Compound 10 also induced reduction of the NO level, possibly by interaction with iNOS. Therefore, this alkaloid showed promising activity for the treatment of malaria and was able to prevent the development of experimental cerebral malaria (ECM), probably by reducing NO synthesis.
