Novos candidatos a protótipos de fármacos e metalofármacos antimicrobianos e antineoplásicos biorredutíveis à base de hidrazonas e tiossemicarbazonas funcionalizadas com nitroimidazol e nitrobenzeno

Abstract

2-acetylpyridine-4-nitroimidazolhydrazone (HL1), 2-acetylpyridine-2-nitroimidazolhydrazone (HL2) and 2-benzoylpyridine-4-nitroimidazolhydrazone (HL3) were obtained. The compounds did not show cytotoxic effects against J774.A1 macrophage cells. Only HL1 and HL3 exhibited antileishmanial activity against Leishmania chagasi, while HL2 proved to be inactive, indicating that the presence of the 4-nitro group probably favors the antiparasitic effects. 2-formyl-8-hydroxyquinoline-4-nitroimidazolhydrazone (H2L4), 2-formyl-8-hydroxyquinoline-4-nitrobenzenohydrazone (H2L5), [Sb(HL4)Cl2] (1), [Sb(HL5)Cl2] (2), [Bi(HL4)Cl2] (3) and [Bi(HL5)Cl2] (4) were synthesized. While H2L5 was inactive, H2L4 and complexes (1-4) inhibited the growth of trypomastigotes of Trypanosoma cruzi. All complexes showed activities similar or superior to that of benznidazole used as control. Complexes (2), CE50 = 0.33 µM) and (4) CE50 = 0.06 µM) proved to be the most active against trypomastigotes and as expected, (2) and (4) were also the most effective against the amastigote form, with de EC50 = 3.05 µM (2) and EC50 = 2.31 µM (4). The cytotoxic activities of the compounds were also evaluated against non-infected human hFIB fibroblasts cells and against mouse macrophage cells. In both cases the Bi(III) complexes showed the highest selectivity indexes against trypomastigotes. Investigations on the mode of action of complex (4) on trypomastigotes suggested the occurrence of cell death by necrosis (1-(2-methyl-5-nitroimidazole)propan-2-ylidene)hydrazonecarboxamide (HL6), (1-(2-methyl-5-nitroimidazole)propan-2-ylidene)acetylhydrazone (HL7), (1-(2-methyl-5-nitroimidazole)propan-2-ylidene)benzoylhydrazone (HL8), (1-(2-methyl-5-nitroimidazole)propan-2-ylidene)hydrazinocarbothioamide (HL9), (N-methyl-1-(2-methyl-5-nitroimidazole)propan-2-ylidene)hydrazinocarbothioamide (HL10) and (1-(2-methyl-5-nitroimidazole)propan-2-ylidene)-N-phenyl-hydrazinocarbothioamide (HL11) were obtained as well as [Cu(HL6)2Cl2] (5), [Cu(HL7)Cl2]·½CH3OH (6), [Cu(HL8)2Cl2] (7), [Cu(HL9)Cl2]·½H2O (8), [Cu(HL10)Cl2] (9), [Cu(HL11)Cl2]·½H2O (10), [Ag(HL7)NO3] (11), [Ag(HL8)NO3] (12), [Ag(HL9)NO3] (13), [Ag(HL10)NO3] (14), [Bi(HL9)Cl3] (15), [Bi(HL10)Cl3] (16) and [Bi(HL11)Cl3]·2H2O (17). All compounds revealed to be inactive against several strains of aerobic bacteria. In contrast, the secnidazole-derived ligands showed in vitro antibacterial activity against Gram-positive Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Parabacteroides distasonis and Fusubacterium nucleatum anaerobic bactéria. Upon coordination to Cu(II), Ag(I) and Bi(III), the animicrobial activity significantly increased in several cases suggesting selectivity of the compounds for anaerobic strains. Electrochemical studies on the nitro group reduction generating the nitro anion radical NO_2^(∙-) showed that the compounds have reduction potentials similar to the bio-reducible drugs secnidazole and benznidazole, suggesting that their antibacterial effects might be related to the intracellular reduction of the nitro group. While the secnidazole-derived ligands and the Cu(II) and Bi(III) complexes were devoid of activity, the silver(I) complexes and silver nitrate exhibited antifungal action against Candida albicans, Candida dubliniensis, Candida lusitaniae and Candida glabrata, indicating that the antifungal effects are due to the presence of silver. Complexes (11-17) were evaluated for their antiproliferative activities against HL60 leukemia and HCT-116 (colorectal cancer), PC3 (prostate cance), SNB-19 (glioblastoma) and non-malignant HEK-203 (human embryonic kidney) cells. Complex (13) showed cytotoxic activity against all cell lineages while all other compounds were inactive. The results suggest that further studies on the cytotoxc effects of the compounds on solid tumor cells should be investigated under hypxia conditions. [Au(HL9)P(CH2CH3)3]PF6 (18), [Au(HL10)P(CH2CH3)3]PF6 (19) and [Au(HL11)P(CH2CH3)3]PF6 (20) were obtained and evaluated for their cytotoxicity against HCT-116 colorectal cancer cells under normoxia and hypoxia conditions, as well as against non-malignant HEK-293 human embryonic kidney cell under normoxia. HL9 and HL10 proved to be cytotoxic to both cell lineages under normoxia while HL11 was inactive. Complexes (18-20) and the thriethylphosphinegold(I) precursor showed cytotoxic activity against HCT-116 cells under normoxia and hypoxia conditions as well as against the HEK-293 healthy cells. Complex (19) deserves special interest since it was more active against HCT-116 cells under hypoxia than under normoxia conditions and was more potent against HCT-116 cells under hypoxia that against HEK-293 cells in normoxia, with selectivity index (SI = IC50 HEK-293/ IC50HCT-116 hipoxia) = 3.7, similar to the value obtained for the bioreducible control drug tirapazamine (TPZ, SI = 4). Regarding the reduction of the nitro group, although the compounds presented distinct cytotoxic effects, the electrochemical behaviors of HL9 – HL11 were very similar, as were the electrochemical behaviors of complexes (18-20).