Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria

• DOI: 10.3390/pathogens11121529
• Publication Date: 2022-12-14T06:52:34Z
• Authors: Fernanda de Moura...; Jessica Correa Be...; Camila de Souza B...; Caíque Lopes Duarte; Amanda Luisa da F...; Ana Claudia de So...; Felipe Oliveira R...; Bárbara Albuquerq...; Ari Sérgio de Oli...; Elaine Soares Coi...; Alex Gutterres Ta...; Vinícius Novaes R...; Fernando de Pilla...; Gustavo Henrique ...; Kézia K. G. Scopel
• Keywords: Cerebral Malaria; Antimalarial Agent

Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection caused by Plasmodium falciparum, which can lead to development cerebral malaria (CM) and responsible for deaths significant neurocognitive sequelae throughout life. In this context considering the emergence spread drug-resistant P. falciparum isolates, search new antimalarial candidates becomes urgent. β-carbolines alkaloids are good since a wide range biological activity these compounds has been reported. Herein, we designed 20 chemical entities performed silico virtual screening against pool molecular targets, Brazilian Molecular Targets (BRAMMT). Seven structures showed potential interact with PfFNR, PfPK7, PfGrx1, PfATP6, being synthesized evaluated vitro antiplasmodial activity. Among them, 3–6 10 inhibited growth W2 strain at µM concentrations, low cytotoxicity human cell line. physicochemical pharmacokinetic properties were found be favorable oral administration. compound provided best results CM, important values parasite inhibition on 5th day post-infection both curative (67.9%) suppressive (82%) assays. Furthermore, was able elongate mice survival protect them experimental model CM (>65%). Compound also induced reduction NO level, possibly interaction iNOS. Therefore, alkaloid promising treatment prevent (ECM), probably reducing synthesis.