Síntese, estudos in silico e avaliação da atividade tripanocida de sistemas pirazólicos e triazólicos

Abstract

Heterocyclic compounds are a crucial class of compounds with diverse applications, especially in medicinal chemistry. Found in approximately 85% of biologically active substances, nitrogen-containing heterocycles are integral to the structure of many drugs and exhibit a wide range of activities, including trypanocidal activity. Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected tropical disease that affects 6 to 7 million people worldwide, causing 10,000 deaths annually. The only treatments for CD are benznidazole and nifurtimox, both effective in the acute phase but associated with various side effects. Despite extensive research efforts, there remains a pressing need for new trypanocidal agents. Based on the promising results from our research group, this study synthesized and characterized twenty-five compounds, including ten 2-(1-aryl-1H-pyrazol-4-yl)-1H-benzimidazoles 1(a-k), eleven 1-aryl-4-(4,5-dihydro-1H-imidazol-4-yl)-1H-1,2,3-triazoles 2(a-k), and eleven 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-4-yl)-1H-1,2,3-triazoles 3(a-k). In silico studies of physicochemical properties indicated that these compounds obey Lipinski's "rule of 5," suggesting good absorption and cellular permeability, along with tPSA values indicating good oral bioavailability. Fifty-five key intermediates 5(a-k), 6(a-k), 8(a-l), 9(b-h,j-l), 10(b-h,j-l), and 11g were also obtained and characterized by FT-IR, HRMS or GC-MS, and NMR, demonstrating high purity. Regarding biological activity, the derivatives 1(a-g,i-k) showed no cytotoxicity (CC50 > 100 μM), except for 1b CC50= 40,3 ± 12,4 μM). 1(a-c,e,f,h-j) compounds exhibited similar or better activity against the trypomastigote form of T. cruzi than benznidazole (IC50= 19,3 ± 2,8 μM) the reference drug. Analyses involving amastigote form demonstrated that compounds 1f (IC50= 6,6 ± 1,9 μM) and 1i (IC50= 9,4 ± 0,1 μM) were particularly notable, showing an SI > 45 and similar potency to benznidazole (pIC50= 5,52). The treatment of cardiac microtissue with these compounds demonstrated parasitic inhibition comparable to the reference drug, without cardiotoxic effects. Although the molecular docking showed interactions of 1f and 1i with the catalytic domain of cruzipain, these compounds demonstrated only 40% cysteine protease inhibition at 300 μM, indicating that this is not the mechanism of action of these compounds. On the other hand, 2(b-h,j-l) had no cytotoxicity (CC50 > 500 μM) and also no anti-T. cruzi activity against trypomastigote and amastigote forms, except 2b which showed IC50= 2,8 ± 0,2 μM and SI= 179,2, against the trypomastigote form.