ABSTRACT
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.
Subject(s)
Antifungal Agents/pharmacology , Hydrazones/pharmacology , Imidazoles/chemistry , Thiosemicarbazones/pharmacology , Antifungal Agents/chemistry , Aspergillus flavus/drug effects , Candida albicans/drug effects , Cladosporium/drug effects , Crops, Agricultural , Hydrazones/chemistry , Hydrogen Bonding , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Nystatin/pharmacology , Plant Diseases/microbiology , Thiosemicarbazones/chemistry , X-Ray DiffractionABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gallium/chemistry , Thiosemicarbazones/chemistry , Tubulin/chemistry , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Cell Cycle Checkpoints/drug effects , Cell Shape/drug effects , Coordination Complexes/chemistry , Crystallography, X-Ray , Erythrocytes/drug effects , HeLa Cells , Humans , Inhibitory Concentration 50 , Kinetics , MCF-7 Cells , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Protein Multimerization/drug effects , Pseudomonas aeruginosa/drug effects , Pyridines/chemistry , Staphylococcus aureus/drug effects , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/pathology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Female , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Humans , Inhibitory Concentration 50 , Microtubules/drug effects , Molecular Structure , Structure-Activity Relationship , Tubulin/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
Subject(s)
Antimony/chemistry , Bismuth/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Pyridines/chemistry , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bacteria/drug effects , Candida albicans/drug effects , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Organometallic Compounds/chemical synthesisABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Auranofin/pharmacology , Cell Line, Tumor , Cell Survival , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , DNA Fragmentation , DNA, Superhelical/chemistry , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/drug effects , Models, Molecular , Molecular Conformation , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/chemistryABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Glioma/drug therapy , Thiosemicarbazones/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Glioma/pathology , Models, Molecular , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Thiosemicarbazones/chemistry , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Leukemia/pathology , Palladium/chemistry , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Thiosemicarbazones/chemistryABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Gallium , Glioblastoma/drug therapy , Thiosemicarbazones/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Glioblastoma/pathology , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Thiosemicarbazones/chemistryABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Formamides/chemistry , Organotin Compounds/chemistry , Pyridines/chemistry , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , X-Ray DiffractionABSTRACT
[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.
