Planejamento, síntese e investigação da potencial atividade antiprotozoária de compostos nitroimidazólicos

Abstract

The class of heterocyclic compounds is the largest and most relevant in organic chemistry, especially azoles, such as imidazole and pyrazole, since they can be found in several bioactive compounds. For instance, nitroimidazole derivatives have shown a wide spectrum of biological activities, including antiparasitic effects. The neglected parasitic diseases trichomoniasis and giardiasis are serious public health problem, affecting 156 and 200 million people worldwide, respectively. In Brazil, it is estimated that trichomoniasis affects 4.3 million people annually, with a general prevalence of 15% and 2.5 to 20% among women. On the other hand, giardiasis has a prevalence of 12.4 to 50% and children are the most infected. Chemotherapy for both diseases consist of using drugs belong to 5-nitroimidazole class, including metronidazole (MTZ), the first-choice drug. However, several side effects have been reported as well as resistance cases related to MTZ. Therefore, there is a need to develop more efficient, less toxic and low-cost drugs. Based on the significant results of the antiprotozoal activities of nitroimidazoles derivatives, in this work it was planned the synthesis of forty compounds, being thirty-seven new, for their trichomonicidal and giardicidal evaluation: two 1-(hydroxyalkyl)-4-nitro-1H-imidazoles 1(a,b), four 2-(4-nitro-1H-imidazol-1-yl)ethyl benzoates 2(a-d), thirty (4-nitro-1H-imidazol-1-yl)alkyl 1-aryl-1H-pyrazole-4-carboxylates 3(a-j), 4(a-j), and 5(a-j), and four (4-nitro-1H-imidazol-1-yl)arylmethanones 6(a-d). The in silico physicochemical properties predictions indicated that all derivatives obey Lipinski’s “rule of five”, suggesting good absorption. In addition, tPSA values ≤ 140 Å2 showed that final compounds may have good oral bioavailability. Regarding the synthesis of all derivatives, thirty-nine key intermediates and twenty-eight final compounds were obtained, completely characterized by FT-IR, HRMS and NMR, and isolated in high purity: 1(a,b), 2(a-d), 3(a-j), 4(c,e), and 5(a-j), besides the unexpected compound 6ax. Furthermore, three byproducts were identified and characterized: 1ax, 14b, and 14c. The remaining derivatives of series 4, 4(a,b,d,f-j), were obtained, but they require purification. Regarding the biological activity, derivatives 3(a-j) and 1a, evaluated so far, showed potent anti-trichomonas effects after 24 h of treatment, highlighting derivatives 3b, 3d, and 3h with IC50 5.3, 5.2, and 4.8 μM, respectively, values quite similar to reference drug MTZ (IC50 = 4.9 μM). All compounds evaluated did not show cytotoxicity (CC50 > 100 μM) against HeLa cells, after 24 h, except 3g, which value was 69.3 μM.