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

Abstract

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.

Avaliação in silico e in vivo do perfil de metabolismo e toxicidade hepática de alcaloides β-carbolínicos sintéticos com prévia atividade antimalárica

“…As amostras biológicas utilizadas neste trabalho foram provenientes de experimentos prévios realizados no Núcleo de Pesquisa em Parasitologia da UFJF (CEUA n° 022/2020). Para tal, foram utilizadas fêmeas de camundongos da linhagem C57BL/6, com 6 a 8 semanas de idade, as quais foram infectadas com Plasmodium berghei ANKA, cepa indutora de malária cerebral, como detalhadamente descrito em Alves et al 18…”

“…Tabela 1: Grupos experimentais e seus respectivos esquemas de tratamento, dose e tamanho amostral (n) utilizados no teste antiplasmodial curativo dos alcaloides sintéticos 1, 2 e 3 no estudo conduzido por Alves et al 18 . enquanto a AST encontra-se bem distribuída pelos tecidos e órgãos.…”

“…[14][15][16][17] Nesse contexto, os alcaloides β-carbolínicos são ótimos candidatos ao estudo de potenciais novos compostos com atividade antiplasmodial.Em um estudo prévio, nosso grupo de pesquisa avaliou vinte derivados de alcaloides β-carbolínicos sintetizados no Centro de Pesquisa em Química Biológica (NQBio) da Universidade Federal de São João Del-Rei (UFSJ) 18. Por meio de ensaios in silico, in vitro e in vivo,Figura 1: Estrutura química dos alcaloides β-carbolínicos 1, 2 e 3.…”

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

“…Due to the importance of all PTMs in parasite life, the related proteins and enzymes have been proposed as targets for antimalarials for some time [ 213 ]. Several candidates have been under study for decades, while some emerged recently and are under intense study now [ 9 , 13 , 213 , 293 , 294 ]. Here, we compiled some examples of protein PTM targeting by antimalarials.…”

“…P.f. kinase PfPK7 inhibitors imidazopyridazines and, recently, β-carbolines alkaloids were proposed as antimalarial substances [ 294 , 301 , 302 , 303 ].…”