RESUMO
New imidazole derived thiosemicarbazones and hydrazones were prepared by condensation of 4(5)-imidazole carboxaldehyde, 4-(1H-imidazole-1-yl)benzaldehyde and 4-(1H-imidazole-1-yl)acetophenone with a thiosemicarbazide or hydrazide. All compounds were characterized by quantitative elemental analysis, IR and NMR techniques. Eight structures were determined by single crystal X-ray diffraction. The antifungal activities of the compounds were evaluated. None of the compounds exhibited significant activity against Aspergillus flavus and Candida albicans, while 4(5)-imidazolecarboxaldehyde thiosemicarbazone (ImT) and 4-(1H-imidazole-1-yl)benzaldehyde thiosemicabazone (4ImBzT) were highly and selectively active against Cladosporium cladosporioides. 4(5)-Imidazolecarboxaldehyde benzoyl hydrazone (4(5)ImPh), 4(5)-imidazolecarboxaldehyde-para-chlorobenzoyl hydrazone (4(5)ImpClPh), 4(5)-imidazolecarboxaldehyde-para-nitrobenzoyl hydrazone (4(5)ImpNO2Ph), 4-(imidazole-1-yl)acetophenone-para-chloro-benzoyl hydrazone (4ImAcpClPh) and 4-(imidazole-1-yl)acetophenone-para-nitro-benzoylhydrazone (4ImAcpNO2Ph) were highly active against Candida glabrata. 4(5)ImpClPh and 4(5)ImpNO2Ph were very effective against C. cladosporioides. In many cases, activity was superior to that of the reference compound nystatin.
Assuntos
Antifúngicos/farmacologia , Hidrazonas/farmacologia , Imidazóis/química , Tiossemicarbazonas/farmacologia , Antifúngicos/química , Aspergillus flavus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cladosporium/efeitos dos fármacos , Produtos Agrícolas , Hidrazonas/química , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Nistatina/farmacologia , Doenças das Plantas/microbiologia , Tiossemicarbazonas/química , Difração de Raios XRESUMO
Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Gálio/química , Tiossemicarbazonas/química , Tubulina (Proteína)/química , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cristalografia por Raios X , Eritrócitos/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Cinética , Células MCF-7 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Multimerização Proteica/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Piridinas/química , Staphylococcus aureus/efeitos dos fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Complexes [Sb(HAcPh)Cl(2)] (1), [Sb(HAcpClPh)Cl(2)] (2), [Sb(HAcpNO(2)Ph)Cl(2)] (3) and [Bi(HAcPh)Cl(2)] (4), [Bi(HAcpClPh)Cl(2)] (5), [Bi(HAcpNO(2)Ph)Cl(2)] (6) were obtained with 2,6-diacetylpyridine bis(benzoylhydrazone) (H(2)AcPh), 2,6-diacetylpyridine bis(para-chlorobenzoylhydrazone) (H(2)AcpClPh), and 2,6-diacetylpyridine bis(para-nitrobenzoylhydrazone) (H(2)AcpNO(2)Ph). The bis(benzoylhydrazones) were inactive as antimicrobial agents against gram-positive and gram-negative bacteria and against Candida albicans but upon coordination to antimony(III) and bismuth(III) antimicrobial activity was demonstrated. The studied compounds were tested for their cytotoxic activities against Jurkat and HL60 (leukemia), MCF-7 (breast tumor), HCT-116 (colorectal carcinoma) and peripheral blood mononuclear (PBMC) cells. All bis(benzoylhydrazones) proved to be poorly cytotoxic. Upon coordination of the bis(benzoylhydrazones) to antimony(III) and bismuth(III) cytotoxicity significantly improved. Complex (5) presented high therapeutic indexes (TI = 11-508) against all cell lineages.
Assuntos
Antimônio/química , Bismuto/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Piridinas/química , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Testes de Sensibilidade Microbiana , Compostos Organometálicos/síntese químicaRESUMO
Complexes [Au(H2Ac4DH)Cl]âMeOH (1) [Au(H(2)2Ac4Me)Cl]Cl (2) [Au(H(2)2Ac4Ph)Cl]Clâ2H(2)O (3) and [Au(H(2)2Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes (2) and (4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex (2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ouro , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Auranofina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Fragmentação do DNA , DNA Super-Helicoidal/química , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/químicaRESUMO
2-acetylpyridine N(4)-phenyl thiosemicarbazone (H2Ac4Ph), and its N(4)-ortho-tolyl (H2Ac4oT), N(4)-meta-tolyl (H2Ac4mT), N(4)-para-tolyl (H2Ac4pT), N(4)-ortho-chlorophenyl (H2Ac4oClPh), N(4)-meta-chlorophenyl (H2Ac4mClPh) and N(4)-para-chlorophenyl (H2Ac4pClPh) derivatives were assayed for their cytotoxicity against RT2 (expressing p53 protein) and against T98 (expressing mutant p53 protein) glioma cells. The compounds were highly cytotoxic against RT2 (IC50=24-1.4 nM) and T98 cells (IC50=50-1.0 nM). IC50 for cisplatin=5 (RT2) and 17 µM (T98). The thiosemicarbazones presented haemolytic activity with IC50>10(-3)M, indicating a very good therapeutic index. SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.
Assuntos
Apoptose/efeitos dos fármacos , Glioma/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glioma/patologia , Modelos Moleculares , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Células Tumorais CultivadasRESUMO
The palladium(II) complexes [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] were prepared with N(4)-ortho- (H2Bz4oT) N(4)-meta- (H2Bz4mT) and N(4)-para- (H2Bz4pT) tolyl-thiosemicarbazones derived from 2-benzoylpyridine. The free thiosemicarbazones proved to be highly cytotoxic against Jurkat, HL60 and the resistant HL60.Bcl-X(L) leukemia cell lines at nanomolar concentrations, but were much less cytotoxic to HepG2human hepatoma cells. Upon coordination to palladium(II) the cytotoxic activity against all studied cell lines decreases. However, the high cytotoxicity of the free thiosemicarbazones against leukemia, together with their hepatotoxic profile similar to that of cisplatin suggest that N(4)-tolyl thiosemicarbazones have potential as chemotherapeutic drug candidates.
Assuntos
Antineoplásicos/farmacologia , Leucemia/patologia , Paládio/química , Tiossemicarbazonas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Tiossemicarbazonas/químicaRESUMO
The gallium(III) complexes [Ga(2Am4DH)(2)]NO(3) (1), [Ga(2Am4Me)(2)]NO(3) (2) and [Ga(2Am4Et)(2)]NO(3) (3) were prepared with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives. The thiosemicarbazones were cytotoxic against malignant RT2 glioblastoma cells (expressing p53 protein) with IC(50) values in the 7.3-360 microM range, and against malignant T98 glioblastoma cells (expressing mutant p53 protein) with IC(50) values in the 3.6-143 microM range. Coordination to gallium strongly increased the cytotoxic potential in complexes 2 and 3, which showed IC(50) values in the 0.81-9.57 microM range against RT2 cells and in the 3.6-11.30 microM range against T98 cells, and were 20-fold more potent than cisplatin. All thiosemicarbazones and gallium complexes were able to induce cell death by apoptosis.
Assuntos
Antineoplásicos/química , Gálio , Glioblastoma/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Tiossemicarbazonas/químicaRESUMO
[RuCl(L)(PPh(3))(2)] complexes with 2-benzoylpyridine- and 2-pyridineformamide-derived thiosemicarbazones (HL) were obtained and fully characterized. The complexes form cis-trans isomers. The cis isomer is disfavored by the sterical effect of two bulky groups close to each other whereas the trans isomer is disfavored by the electronic effect of competition of two phosphorous for pi-bonding d orbitals of the metal. Our results suggest that, although both factors may be operating simultaneously, in CH(2)Cl(2) solution the balance of these counterpoising effects favors the formation of the trans isomer.
Assuntos
Eletroquímica/métodos , Formamidas/química , Compostos Organometálicos/química , Fosfinas/química , Piridinas/química , Rutênio/química , Tiossemicarbazonas/química , Isomerismo , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
Reaction of n-butyltin trichloride [(n-Bu)SnCl(3)] with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives gave [(n-Bu)Sn(2Am4DH)Cl(2)] (1), [(n-Bu)Sn(2Am4Me)Cl(2)] (2), and [(n-Bu)Sn(2Am4Et)Cl(2)] (3). Thiosemicarbazones as well as their tin complexes are active as antimicrobials against the growth of Candida albicans and Salmonella typhimurium and were highly active against malignant glioblastoma. The cytotoxic activity of complexes 1-3 is similar. Among the studied compounds [(n-Bu)Sn(2Am4DH)Cl(2)] (1) was the most active as antiproliferative (cytostatic) agent. Thiosemicarbazones and their tin(IV) complexes proved to be more potent as cytotoxic agents than cisplatin. All the compounds were able to induce apoptosis.