Synthesis, characterization and antiamoebic activity of new indole-3-carboxaldehyde thiosemicarbazones and their Pd(II) complexes

In continuation of our research on thiosemicarbazones and their metal complexes as antiamoebic agents, a new series of indole-3-carboxaldehyde thiosemicarbazones (TSC) 1-7 were prepared by condensing indole-3-carboxaldehyde with cycloalkylaminothiocarbonyl hydrazines. Their palladium(II) complexes of the [Pd(TSC)Cl2] type, were synthesized upon coordination with [Pd(DMSO)2Cl2]. The chemical structures of all the compounds were established by elemental analyses, electronic, IR, (1)H NMR and (13)C NMR spectral data. The structure of the complexes was further established by thermogravimetric analysis and FAB MS. Spectroscopic data revealed that thiosemicarbazones act as bidentate ligands, making use of thione sulphur and azomethine nitrogen atom for coordination to the Pd(II) ion. Among all the compounds evaluated for antiamoebic activity using HM1:IMSS strain of Entamoeba histolytica, all palladium complexes were found to be more active than their respective ligands. Moreover, ligand 5 and complexes 1a-3a, 5a and 7a showed antiamoebic activity, at lower IC(50) doses when compared to the reference drug metronidazole with IC(50)=1.81 microM.     

Copper(II) complexes with substituted thiosemicarbazones of thiophene-2-carboxaldehyde: synthesis, characterization and antiamoebic activity against E. histolytica

In an effort to develop potent antiamoebic agents, a series of thiosemicarbazone (TSC) ligands 1-5 derived from thiophene-2-carboxaldehyde and N4-substituted thiosemicarbazides has been prepared and characterized using various spectroscopic techniques. Treatment of the ligands with cupric chloride produced the copper(II) complexes [Cu(TSC)2Cl2] 1a-5a where ligand bind through thionic sulfur and the azomethine nitrogen. The possible geometries of the complexes were assigned on the basis of magnetic moment, electronic and thermal patterns as well as infrared spectral studies. The thiosemicarbazones and their copper complexes were tested for their in vitro antiamoebic activity against HK-9 strain of Entamoeba histolytica and showed significant growth inhibition. The results revealed that these complexes are effective chemicals in inhibiting amoebal growth, with compound 5 (having -N(CH3)(C6H5) substituent at N4) and complexes 1a-5a being more effective than the commercial antiamoebic drug, metronidazole, based on IC50 values. These data also indicated that the compounds 3a and 5a are most effective among the complexes studied (IC50=0.26 microM of 3a and IC50=0.21 microM of 5a versus IC50=1.81 microM of metronidazole).     

Cyclooctadiene Ru(II) complexes of thiophene-2-carboxaldehyde-derived thiosemicarbazones: synthesis, characterization and antiamoebic activity

Thiosemicarbazones (TSC) 1-10 were synthesized by condensing substituted thiosemicarbazide with thiophene-2-carboxaldehyde. These thiosemicarbazones were further reacted with [Ru(eta4-C8H12)(CH3CN)2Cl2] to form complexes of the type [Ru(eta4-C8H12)(TSC)Cl2] 1a-10a. Thiosemicarbazones exhibited antiamoebic activity in the range IC50=1.09-5.42 microM. In vitro assessment of antiamoebic activity indicated that the thiosemicarbazones 3, IC50=1.67 microM, 4, IC50=1.11 microM and 6, IC50=1.09 microM showed substantially less IC50 value than metronidazole (IC50=1.87 microM), a commonly used drug against amoebiasis. Cyclooctadiene Ru(II) complexes of thiosemicarbazones showed significant improvement in antiamoebic activity (IC50=0.30-1.39 microM). All the complexes possess noteworthy potencies and showed less IC50 values than metronidazole against HK-9 strain of Entamoeba histolytica. Among all the complexes, the most promising antiamoebic activities was shown by the complexes 4a and 6a (IC50=0.31 microM of 4a and IC50=0.30 microM of 6a versus metronidazole).     

Novel bidentate complexes of Cu(II) derived from 5-nitrofuran-2-carboxaldehyde thiosemicarbazones with antiamoebic activity against E. histolytica

The novel analogues of 5-nitrofuran-2-carboxaldehyde thiosemicarbazones 1-10 were synthesized and their copper(II) complexes 1a-10a were obtained by means of coordination with cupric chloride. All these compounds have been characterized by elemental analysis, IR, electronic spectra and thermogravimetric patterns while ligands have also been characterized by 1H NMR spectral studies. These copper complexes are bidentate and possess octahedral geometry around Cu(II) ion. Their antiamoebic activities were carried out to ascertain their effectiveness in comparison to their corresponding thiosemicarbazones. A number of these complexes possess noteworthy potencies towards HK-9 strain of Entamoeba histolytica in vitro. The complexes 2a-7a, 9a and 10a showed less IC50 value than metronidazole, the drug of choice for amoebiasis. Moreover, complexes 2a and 9a have shown the most promising antiamoebic activities (IC50 = 0.38 microM of 2a and IC50 = 0.34 microM of 9a versus IC50 = 1.81 microM of metronidazole). These results indicate that the metallated thiosemicarbazone may be lead molecule to inhibit growth of E. histolytica.     

4-nitroacetophenone-derived thiosemicarbazones and their copper(II) complexes with significant in vitro anti-trypanosomal activity

N(4)-methyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4M, 1), N(4),N(4)-dimethyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4DM, 2) and N(4)-piperidyl-4-nitroacetophenone thiosemicarbazone (H4NO(2)Ac4Pip, 3) and their copper(II) complexes [Cu(4NO(2)Ac4M)(2)] (4), [Cu(4NO(2)Ac4DM)(2)] (5) and [Cu(4NO(2)Ac4Pip)(2)] (6) were tested for their in vitro ability to inhibit the growth of Trypanosoma cruzi epimastigote forms. H4NO(2)Ac4DM (2), [Cu(4NO(2)Ac4M)(2)] (4) and [Cu(4NO(2)Ac4DM)(2)] (5) proved to be as active as the clinical reference drugs nifurtimox and benznidazol. Taking into consideration the serious side effects and the poor efficacy of the reference drugs, as well as the appearance of resistance during treatment, the studied compounds could constitute a new class of anti-trypanosomal drug candidates.     

Syntheses, characterization and in vitro antiamoebic activity of new Pd(II) complexes with 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives

Reaction of neutral NS bidentate ligands, 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazolines, isolated by cyclization of chalcone with N-4-substituted thiosemicarbazide of aromatic amines (1-8), with [Pd(DMSO)(2)Cl(2)] (DMSO=dimethylsulfoxide) leads to the formation of new complexes of the type [Pd(L)Cl(2)] (1a-8a). The structures of the compounds were elucidated by UV, IR, (1)H NMR, (13)C NMR and ESI-MS spectral data and thermogravimetric analysis and their purities were confirmed by elemental analyses. The antiamoebic activity of these complexes was evaluated by microdilution method against HM1:IMSS strain of Entameoba histolytica and the results were compared with the standard drug, metronidazole. Generally palladium complexes showed better activity than their corresponding ligands. Compound 3a showed better IC(50)=0.05 microM as compared to metronidazole IC(50)=1.82 microM.     

Palladium(II) complexes of NS donor ligandsderived from S-methyl-dithiocarbazate, S-benzyldithiocarbazateand thiosemicarbazide as antiamoebic agents

Synthesis of palladium(II) complexes of the type [PdLCl(2)] (where L = Schiff bases derived from 2-acetylpyridine and S-methyldithiocarbazate, S-benzyldithiocarbazate or thiosemicarbazide) have been isolated by the reaction of [Pd(DMSO)(2)C1(2)] and respective ligands. The complexes have been characterized by elemental analyses, IR, 1H-NMR, electronic spectra and thermogravimetric analysis. It is concluded that the thionic sulphur and the azomethine nitrogen atoms of the ligands are bonded to the metal ion. Assessment of antiamoebic activity against Entamoeba histolytica (strain HK-9) was done by using a microdilution method. [Pd(2-Acpy-SMDT)C1(2)] and Pd(2-Acpy-SBDT)C1(2)] have shown greater activity, whereas [Pd(2-Acpy-TSC)C1(2)] showed similar activity as metronidazole in vitro.     

Synthesis and antiamoebic activity of new 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives and their Pd(II) complexes

Some 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives (L), 1-8 were synthesized by a base-catalyzed Claisen-Schmidt condensation of benzaldehyde with acetophenone followed by cyclization with various N-4 substituted thiosemicarbazides. The palladium(II) complexes [PdLCl2], 1a-8a of these ligands were obtained by reacting them with [Pd(DMSO)2Cl2]. All compounds have been characterized by means of elemental analyses, electronic, IR, 1H NMR and mass spectroscopic data, while the complexes have additionally been characterized by thermogravimetric patterns. The in vitro antiamoebic activity was evaluated against the HM1:IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. The preliminary test results showed that the complexes had better antiamoebic activity than their respective ligands. Moreover, the complexes showed better inhibition of the test organism. The results suggest that the ligands 4, 7 and the complexes 2a-4a, 6a-8a were found with IC50 lower than that of the standard drug metronidazole and thus are better inhibitor of growth of E. histolytica.     

Novel platinum(II) and palladium(II) complexes of thiosemicarbazones derived from 5-substitutedthiophene-2-carboxaldehydes and their antiviral and cytotoxic activities

A series of thiosemicarbazones and their platinum(II) and palladium(II) complexes have been synthesized. The chemical structures of ligands and their complexes were characterized by UV–Vis, IR, ¹H NMR, ¹³C NMR, MS spectra, elemental analysis and TGA. The antiviral and cytotoxic activities of all compounds have been tested. Results of broad antiviral evaluation showed that none of the compounds evaluated endowed with anti-DNA or -RNA virus activity at subtoxic concentrations except for the palladium complex 1b. This compound exhibited slightly selective inhibition against cytomegalovirus. The platinum complex 4a exhibited the best cytostatic activities against human cervix carcinoma. Ligands 2, 4 and 5 showed cytostatic potential. The palladium complexes were in general less cytostatic than the corresponding platinum complexes or unliganded congeners.     

In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents

Reactions of thiosemicarbazones of 2-formyl and 2-acetyl pyridine and containing an azepane ring (hexamethyleneiminyl ring) incorporated at N(4)-position, HL(1) (1) and HL(2) (2) with platinum(II) afforded the complexes, [Pt(L(1))Cl] (3) and [Pt(L(2))Cl] (4). Characterization of the compounds was accomplished by means of elemental analysis and spectroscopic techniques NMR, UV-vis and IR spectroscopy. The single-crystal X-ray structure of complex [Pt(L(2))Cl] (4) shows that the ligand monoanion coordinates in a planar conformation to the metal via the pyridyl N atom, the imine-N atom, and thiolato S-atom. Compounds 1-4 have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). Ligand 2 exhibited high activity as anticancer agent against all four cancer cell lines, while ligand 1 exhibited selectivity against MCF-7, L-929 cell lines and complex 4 against A-549, T-24 cancer cell lines. Also, the acute toxicity and antitumor activity were evaluated on leukemia P388-bearing mice. Complex 3 afforded five to six cures against leukemia P388. The in vivo results of the antitumor activity show the two platinum complexes as very effective chemotherapeutic antileukemic agents.     

New Pd(II) complexes of the synthesized 1-N-substituted thiosemicarbazones of 3-indole carboxaldehyde: characterization and antiamoebic assessment against E. histolytica

Reaction of 3-indole carboxaldehyde with aminothiocarbonyl hydrazines resulted in the formation of 3-indole carboxaldehyde thiosemicarbazones (TSCs) 1-13. The synthesized thiosemicarbazones were used as ligands in the formation of [Pd(TSC)Cl2] complexes with palladium(II) metal ion precursor, [Pd(DMSO)2Cl2]. The chemical structures of all the compounds were established by electronic, IR, 1H NMR and 13C NMR spectral data. The structure of the complexes was further established by FABMS and DTA. It is concluded that the thione sulphur and the azomethine nitrogen atom of the ligands are bonded to the metal ion. The testing of the antiamoebic activity of these compounds against the protozoan parasite Entamoeba histolytica suggests that compounds 5, 3a, 5a and 8a-13a might be endowed with important antiamoebic properties since they showed less IC50 values than metronidazole. Moreover, compound 12a displays remarkable antiamoebic activity than metronidazole (IC50 values of 0.29 vs 1.81 microM, respectively). MTT assay showed that the compounds are non-toxic to human kidney epithelial cell line.     

Novel Pd(II) complexes of 1-N-substituted 3-phenyl-2-pyrazoline derivatives and evaluation of antiamoebic activity

Cyclization of Mannich base with N(4)-substituted thiosemicarbazides by different aliphatic, aromatic and cyclic amines afforded a series of new 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones (PYZ-TSC) 1-10. Reaction of [Pd(DMSO)(2)Cl(2)] with pyrazoline derivatives led to new palladium(II) complexes [Pd(PYZ-TSC)Cl(2)] 1a-10a. The structures of all the compounds were characterized by spectroscopic methods. It was concluded that the pyrazoline thiosemicarbazone derivatives have two chelating arms, one attached at the 2-position of the pyrazole ring (that is, N donor) and other (S donor) linked to the thiosemicarbazone branch. The determination of antiamoebic activity of all the compounds was done using HM1:IMSS strain of Entamoeba histolytica, among all the complexes, 8a showed the most promising IC(50)=0.37 microM vs. IC(50)=1.81 microM of metronidazole, the reference drug. MTT assay showed that the compounds are non-toxic to human kidney epithelial cell line.     

Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure-activity relationships

Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.     

Pyridine-derived thiosemicarbazones and their tin(IV) complexes with antifungal activity against Candida spp

[(n-Bu)Sn(2Ac4oClPh)Cl₂] (1), [(n-Bu)Sn(2Ac4oFPh)Cl₂] (2), [(n-Bu)Sn(2Ac4oNO₂Ph)Cl₂] (3), [(n-Bu)Sn(2Bz4oClPh)Cl₂] (4), [(n-Bu)Sn(2Bz4oFPh)Cl₂] (5) and [(n-Bu)Sn(2Bz4oNO₂Ph)Cl₂] (6) were obtained by reacting [(n-Bu)SnCl₃] with 2-acetylpyridine-N(4)-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N(4)-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N(4)-orthonitrophenyl thiosemicarbazone (H2Ac4oNO₂Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO₂Ph). The antifungal activity of the studied compounds was evaluated against several Candida species.Upon coordination of H2Bz4oNO₂Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO₂Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.     

Synthesis, characterization, antiamoebic activity and cytotoxicity of novel 2-(quinolin-8-yloxy) acetohydrazones and their cyclized products (1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives)

A series of 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives were synthesized by the cyclization of novel 2-(quinolin-8-yloxy) acetohydrazones. In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica. The results showed that all the 2-(quinolin-8-yloxy) acetohydrazones were more active than their cyclized products (1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives). SAR showed that the compounds having quinoline ring and hydrazone linkage with free N-H group are responsible for higher antiamoebic activity. The cytotoxic studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were nontoxic at the concentration range of 1.56-50?μM.     

Stereospecific ligands and their complexes. Part VII. Synthesis, characterization and in vitro antitumoral activity of platinum(II) complexes with O,O'-dialkyl esters of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid

Platinum(II) complexes (1-4) with bidentate N,N'-ligands, O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid were synthesized and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. DFT calculations were performed for the complexes and it was found that only one diastereoisomer could be formed. Cytotoxic activity of complexes 1-4 was determined against chronic lymphocytic leukemia cells (CLL) and compared to the activity of ligand precursors L1 · 2HCl-L4·2HCl and corresponding palladium(II) complexes, [PdCl(2)L] (L = L1-L4). The complexes were found to exhibit significantly higher antitumor activities than cisplatin on CLL cells. Cytotoxic effect of platinum(II) complexes on CLL cells was higher compared to corresponding palladium(II) complexes. In addition the mode of cell death induced by platinum(II) complexes was determined.     

Bis-pyrazolines: synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica

The cyclization of chalcone with N-4 substituted thiosemicarbazides under basic condition led to the formation of new compounds, thiocarbamoyl bis-pyrazoline derivatives. The structure of the compounds were elucidated by UV, IR, (1)H NMR, (13)C NMR and ESI-MS spectral data and thermogravimetric analysis, and their purities were confirmed by elemental analyses. The antiamoebic activity of these complexes was evaluated by microdilution method against HM1:IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. Structure-activity relationship shows that the compound with aromatic substituents at the thiocarbamoyl group was more active than those with the cyclic groups. However, it was clear from the IC(50) values that the compounds 15 and 20 are more active and both showed a structural resemblance having an electron withdrawing groups attached to the phenyl ring. MTT assay showed that all the compounds are non-toxic to human kidney epithelial cell line.     

Synthesis, characterization and antimicrobial activity of Co(II), Zn(II) and Cd(II) complexes with N-benzyloxycarbonyl-S-phenylalanine

In this paper the first complexes of M(2+) ions (M(2+) = Zn(2+), Cd(2+) and Co(2+)) with N-benzyloxycarbonyl-S-phenylalaninato ligand (1-3) are described. The new complexes were characterized by means of elemental analysis, IR and UV-vis spectroscopy, molar conductivity measurements and (1)H, (13)C and (15)N NMR spectroscopy (1D and 2D). The Co(II) complex adopts an octahedral geometry, and the Zn(II) and Cd(II) complexes adopt a tetrahedral one. For the first time, the antimicrobial activity of N-benzyloxycarbonyl-S-phenylalaninato ligand (N-Boc-S-phe) and the complexes 1-3 was investigated against gram-positive: Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Bacillus subtilis and gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and two strains of the yeast Candida albicans. It was shown that the complexes were effective against most strains. The best activity was detected against the yeast C. albicans.     

Synthesis, characterization and biological activity of Pt(II) and Pt(IV) complexes with 5-methyl-5(4-pyridyl)-2,4-imidazolidenedione

New platinum(II) and platinum(IV) complexes with 5-methyl-5(4-pyridyl)-2,4-imidazolidenedione and various halogen ions with general formula [PtL(2)X(2)] and [PtL(2)Cl(4)], where L is the organic ligand and X is Cl(-), Br(-), J(-), were synthesized. The molecular formulae of all the complexes were confirmed by elemental analysis, IR, (1)H, (13)C NMR spectral analyses and molar conductivity. The cytotoxic effects of these complexes were examined on some human tumor cell lines. The newly synthesized cis-[PtL(2)Cl(2)] exerted cytotoxic activity against SKW-3, MCF-7, EJ, U-266 tumor cell lines, while cis-[PtL(2)Br(2)], trans-[PtL(2)I(2)] were less active. The higher oxidation state complex cis-[PtL(2)Cl(4)] was inactive in all cell lines but in SKW-3 some augmentation of the cytotoxicity was seen after co-administration of ascorbic acid but not when treated in combination with reduced glutathione or N-acetylcysteine. A DNA-fragmentation analysis revealed that the cytotoxicity of the dichloro analogue, characterized with superior activity compared to the other complexes, is mediated by induction of apoptotic cell death.     

Synthesis, characterization and antitumor activity of new type binuclear platinum(II) complexes

Five new type binuclear platinum(II) complexes (a-e) have been synthesized and characterized by elemental analysis, conductivity, thermal analysis, IR, UV, (1)H NMR and mass spectral techniques. The cytotoxicity of the complexes was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulforhodamine B (SRB) assays. The acute toxicity and antitumor activity of complex ein vivo were also studied. The results indicate that complexes a-d have no activity against HL-60, MCF-7, BGC-823, EJ and HCT-8 cell lines, with a higher IC(50) value (>50 microM). Complex e confers substantially greater cytotoxicity against HL-60, MCF-7, BGC-823, EJ and HCT-8 cell lines with an IC(50) value of 0.02+/-0.009, 1.70+/-0.21, 4.00+/-0.35, 0.98+/-0.02 and 1.02+/-0.21 microM, respectively. LD(50) of complex e is 815.3mg/kg, it was significantly higher than that of cisplatin and carboplatin. Complex e at dose of 4, 12 and 20mg/kg has no activity against mouse hepatocarcinoma H22 and Lewis lung carcinoma in mice, but displays significant activity against human ovarian carcinoma A2780 and human colon carcinoma HCT-116 in nude mice at dose of 12 mg/kg, and activity is similar to that of cisplatin at dose of 4 mg/kg. Complex e at dose of 20mg/kg has no activity against human lung adenocarcinoma A549 in nude mice (P>0.05). The results suggest that the species of amine for the new type binuclear platinum complexes have important effect on their cytotoxicity, and they may be a new class platinum anticancer drugs.