Desenvolvimento de novos derivados 4-aminoquinolínicos, N-acilidrazônicos e N-fenilacetamida com potencial atividade antimalárica

Abstract

Malaria is a tropical disease whose etiological agent comprises more than 100 species of the genus Plasmodium spp. and is considered a relevant global public health problem. Considering the increasing emergence of resistance against drugs currently used in clinical practice and the relevance of the quinoline, hydrazine and acetamide moieties for the design of new compounds active against malaria, this work aims to develop new 4-aminoquinoline, N-acylhydrazone and N-phenylacetamide derivatives with potential antimalarial activity. For this, the three intended series were designed, using classical molecular modification strategies of medicinal pharmaceutical chemistry, such as bioisosterism, retroisosterism, as well as molecular hybridization, expansion and simplification. The synthesis and physicochemical characterization were carried out appropriately, and the chemical structures were elucidated by infrared and 1H and 13C nuclear magnetic resonance spectroscopy, as well as mass spectrometry and in silico study of Density Functional Theory (DFT). The activity of the compounds at fixed concentrations, 1 and 10 μM, against P. falciparum 3D7 (sensitive to chloroquine) was then evaluated, and the 50% inhibitory concentration (IC50) values of the most promising derivatives were determined in strains with different drug sensitivities. After that, cytotoxicity was performed against hamster lung cells (V79) and their possible in silico mechanisms of action were analyzed by molecular docking. As a result, 31 compounds were obtained by different reaction mechanisms, which include condensation, aromatic nucleophilic substitution and possible spontaneous cyclization, originating the 1,2,4-thiazolidine-3-thione ring. In this sense, all synthesized compounds were adequately characterized, however, requiring additional analyses to confirm the absolute and relative configuration of the GLM derivatives. In in vitro antimalarial activity assays, 11 promising compounds were identified, with IC50 of 0.3-4.0 µM against different strains of P. falciparum, with greater potency for GLM derivatives and better resistance profile for AMTAC spiroacridines. In addition, the importance of the 4-aminoquinoline core and the association between N-acylhydrazone and the spiroacridine scaffold were highlighted. Regarding selectivity, only 4 compounds (GLM-01, GLM-09, AMTAC-01 and AMTAC-02) obtained IC50 higher than 20 µM, with lower toxicity in mammalian cells. Finally, regarding the in silico mechanism of action, aminoquinoline derivatives showed greater affinity with the enzymes Lactate and Dihydroorotate Dehydrogenases, while spiroacridines were more promising against Falcipain-2 and Topoisomerase II.