Complexos metálicos de hidrazonas, tiossemicarbazonas e lapachol: atividade farmacológica e avaliação de relações estrutura-atividade

Abstract

The present work comprises the synthesis and characterization of metal compounds with bioactive ligands and the study of their pharmacological profile. Anti-inflammatory, antimicrobial, antiparasitic and antitumor drug candidates were designed. Complex [Zn(LASSBio-466)H2O]2 was synthesized with salicylaldehyde-2-chlorobenzoyl hydrazone (H2LASSBio-466), while [Zn(HLASSBio-1064)Cl]2and [Zn(LASSBio-1064)]2 were obtained with salicylaldehyde-4-chlorobenzoyl hydrazone(H2LASSBio-1064). The compounds were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acidinduced writhing response. Upon coordination, the antinociceptiva activity was favored in thecomplex [Zn(LASSBio-466)H2O]2. H2LASSBio-466 inhibited only the first phase of the formalin test, while [Zn(LASSBio-466)H2O]2 was active in the second phase, indicating its ability to inhibit nociception associated with the inflammatory response. H2LASSBio-1064 inhibited both phases, but this effect was not improved upon coordination. All compoundsshowed levels of inhibition of zymosan-induced peritonitis comparable or higher than indomethacin, indicating an expressive anti-inflammatory profile. Six gallium(III) complexes were obtained with 2-acetylpyridine-phenyl hydrazone (H2AcPh), 2-acetylpyridine-para-chlorophenyl hydrazone (H2AcpClPh),2-acetylpyridine-para-nitrophenyl hydrazone (H2AcpNO2Ph), and the corresponding 2-benzoylpyridine-derived hydrazones (H2BzPh, H2BzpClPh and H2BzpNO2Ph): [Ga(2AcPh)2]NO3·H2O, [Ga(2AcpClPh)2]NO3·H2O, [Ga(2AcpNO2Ph)2]NO3·1,5H2O,[Ga(2BzPh)2]NO3·2H2O, [Ga(2BzpClPh)2]NO3·2H2O e [Ga(2BzpNO2Ph)2]NO3·H2O. The hydrazones and their gallium(III) complexes showed no significant activity against Staphylococcus aureus and Pseudomonas aeruginosa. The antifungal activity of some of thecompounds was similar to that of fluconazole against Candida albicans. Complexation significantly increased the antifungal activity, the best result being observed for [Ga(2AcpClPh)2]NO3·H2O. The studied compounds were also assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioblastoma cells. All compounds showed cytotoxic activity at 1,0 ìmol·L-1. In some cases, coordination to gallium(III) resulted in improved cytotoxic activity against the tested cells. IC50 values wereobtained for the hydrazones, but not for their gallium(III) complexes due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. Unlike H2BzpNO2Ph, all hydrazones were more potent than etoposide. SAR studies suggested thatstereo-electronic properties influence the cytotoxic activity of the hydrazones against the tested glioblastoma cells.Antimalarial activity of the 2-acetylpyridine-derived hydrazones and their gallium(III) complexes was evaluated. Hydrazones were highly active against Plasmodium falciparum and presented low toxicity against human hepatoma cells. Coordination did not improve theantimarial activity and lead to increased cytotoxicity. Complexes [Ga(Lp)]H2O and [Bi(Lp)2]Cl (Lp = lapacholate) were obtained with2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphtoquinone, lapahol. Antiangiogenic activity of compounds was investigated using an animal model of inflammatory angiogenesis induced by a sponge implant. In per os treatment, only the bismuth(III) complex statistically reduced theamount of hemoglobin in the implants at 25 mg/kg/day of lapachol (equivalent doses of other compounds). After ip administration, both lapachol and its bismuth(III) complex reduced neovascularization of the implants. In this case, lapachol- and the bismuth(III) complex- treatedgroups did not present statistical difference between each other. Similarly, the N-acetylglucosaminidase (NAG) activity was reduced only by the bismuth(III) complex in the per os treatment, while i.p. treatment inhibited the angiogenic activity in the treated groups withlapachol and its bismuth(III) complex. These results suggest that the activity of complex [Bi(Lp)2]Cl is attributed to lapachol. Thus, coordination to bismuth was a good strategy to improve the therapeutic effects of lapachol after per os administration. Antimony(III) complexes were obtained with 2-acetyllpyridine-N(4)-orthochlorophenylthiosemicarbazone (H2Ac4oClPh), 2-acetyllpyridine-N(4)-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetyllpyridine-N(4)-orthonitrophenyl thiosemicarbazone (H2Ac4oNO2Ph) and the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2Bz4oFPh and H2Bz4oNO2Ph): [Sb(2Ac4oClPh)Cl2], [Sb(2Ac4oFPh)Cl2], [Sb(2Ac4oNO2Ph)Cl2],[Sb(2Bz4oClPh)Cl2], [Sb(2Bz4oFPh)Cl2] and [Sb(2Bz4oNO2Ph)Cl2]. Anti-Leishmania and anti-Trypanosoma activities of the thiosemicarbazones and their antimony(III) complexes wereevaluated. All compounds showed significant activity antipromastigote against Leishmania major, with IC50 values lower than those glucantime. Coordination resulted in a significant increase ofthe activity only in the case of H2Ac4oFPh (IC50 = 19.4 ìmol·L-1) and its complex [Sb(2Ac4oFPh)Cl2] (IC50 = 8.5 ìmol·L-1). SAR studies showed no correlation between the studied physico-chemical properties and anti-Leishmania activity of the compounds. The studied compounds were also highly active against the epimastigote form of Trypanosoma cruzi, presenting activity higher than that of the reference drug nifurtimox.Complexation of the thiosemicarbazones with antimony(III) resulted in more active compounds in the case of the complexes [Sb(2Ac4oClPh)Cl2] and [Sb(2Bz4oFPh)Cl2]. However, uponcoordination the therapeutic index of the compounds decreased, indicating that the coordination was not a good strategy. H2Ac4oNO2Ph and H2Bz4oClPh showed high therapeutic index, beingconsidered interesting anti-Trypanosoma drug candidates. SAR studies showed no correlation between the studied physico-chemical properties and anti-Trypanosoma activity of the compounds. However, correlations were found between the cytotoxicity of the compounds andtheir physico-chemical properties. Complexes [(n-Bu)Sn(2Ac4oClPh)Cl2], [(n-Bu)Sn(2Ac4oFPh)Cl2], [(n-Bu)Sn(2Ac4oNO2Ph)Cl2], [(n-Bu)Sn(2Bz4oClPh)Cl2], [(n-Bu)Sn(2Bz4oFPh)Cl2] and[(n-Bu)Sn(2Bz4oNO2Ph)Cl2] were obtained with 2-acetylpyridine- and 2-benzoylpyridinederived thiosemicarbazones. The antifungal activity of the thiosemicarbazones and their tin(IV) complexes was evaluated against Candida albicans, Candida krusei, Candida glabrata andCandida parapsilosis. Compounds were highly active against all tested Candida species. In some cases, the antifungal activity was higher or similar than that of fluconazole. In general, 2-acetylpyridine-derived thiosemicarbazones are slightly more active than the corresponding2-benzylpyridine derivatives. H2Ac4oNO2Ph exhibited the highest activity against all tested Candida species. [(n-Bu)SnCl3] proved to be inactive against all species. However, in some cases coordination resulted in increased antifungal activity. The best result was found for[(n-Bu)Sn(2Bz4oNO2Ph)Cl2], whose activity was three times higher against C. albicans and C. krusei and six times higher against C. glabrata and C. parapsilosis than that of the starting thiosemicarbazone. SAR studies showed correlations between the antifungal activity of thecompounds and the studied physico-chemical properties.In the present work, new drug candidates were developed in order to for the treatment of neglected parasitic and microbial diseases, inflammation and degenerative diseases, such as cancer. Thus, this work represents an important contribution to the Medicinal InorganicChemistry