1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines: synthesis and in vitro antiamoebic activities

The title compounds were prepared by reaction of Mannich bases with various N-4 substituted thiosemicarbazides. The chemical structures of the compounds were proved by means of their UV, IR, 1H NMR, 13C NMR spectroscopic data and elemental analyses. The in vitro antiamoebic activities of these compounds were evaluated by microdilution method against HM1:IMSS strain of Entamoeba histolytica and compared with the standard drug, metronidazole. It was concluded that 3-chloro and 3-bromo substituents on the phenyl ring at position 3 of the pyrazoline ring enhanced the antiamoebic activity. Compounds 9, 17, 18, 20 and 21 showed less IC50 value than metronidazole.     

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 antiamoebic activity of metronidazole thiosemicarbazone analogues

Repeated treatment of Entamoeba histolytica infection with commonly used antiamoebic drugs results in not only increasing the toxicity potential but also leads to the development of clinical resistance. Thus new effective agents with less toxicity against amoebiasis are urgently required. With this view, metronidazole thiosemicarbazone analogues 1-11 were synthesized wherein thioamide moiety was substituted by different cyclic and aromatic amines. These compounds were screened against HM1:IMSS strain of E. histolytica parasite cultured in vitro and the sensitivity of the parasite to the metronidazole thiosemicarbazones was evaluated using the microdilution method. Eight compounds (1-4, 7-9 and 11) were found better inhibitors of E. histolytica growth since IC50 values elicited by these compounds were much lower than metronidazole with compound 4 showing the most promising antiamoebic activity (IC50=0.56 microM). The study suggests the beneficial potential of these leads that need to be further explored in order to discover and develop better and yet safer therapeutic agents for amoebiasis.     

Synthesis of new 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives and evaluation of their antiamoebic activity

In an effort to develop potent antiamoebic agents, we have synthesized chalcones (1-8), amino-5-substituted-(3-phenyl(2-pyrazolinyl))methane-1-thione derivatives (1a-8a) and 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives (1b-8b) and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of E. histolytica. All the compounds were characterized by electronic, IR, (1)H NMR and mass spectroscopic data. It was observed that the antiamoebic activity enhances on modifying the structure of chalcones to the pyrazolines and further to quinoxalines. The MTT assay was performed on human kidney epithelial cell line to check the cytotoxicity of the compounds and the results were compared with metronidazole. Compound 6b showed better antiamoebic activity and less toxicity than metronidazole.     

New derivatives of 3,5-substituted-1,4,2-dioxazoles: synthesis and activity against Entamoeba histolytica

Dioxazole derivatives (1-33) were synthesized in two steps via their corresponding oximes (I-III). All the compounds were characterized using various spectroscopic techniques. A comparative study of in vitro antiamoebic activity of these heterocyclic compounds, viz. 3-o-chloro (1-11), 3-m-chloro (12-22) and 3-p-chloro (23-33) dioxazoles having same substituents at 5-position of dioxazole ring, was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed a regular pattern in the activity and out of 33 compounds assayed 15 compounds showed better antiamoebic activity than metronidazole with IC(50) values in the range 0.41-1.73 microM and 1.80 microM. Dioxazoles having o-chloro, m-chloro, p-chloro, dichloro and pyridine substituents at 5-position were more active than the standard drug metronidazole. The toxicity studies against human kidney epithelial cell line showed that all the compounds were non-toxic. 3,5-Bis-[2-chlorophenyl]-1,4,2-dioxazole (10) was most active and least toxic among all the compounds.     

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.     

Syntheses and evaluation of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b] quinoxaline-2-yl)-2-pyrazoline derivatives

A variety of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b] quinoxaline-2-yl)-2-pyrazoline were obtained by the refluxing of 1-N-thiocarbamoyl 3,5-diphenyl-2-pyrazoline with 2,3-dichloroquinoxaline. The chemical structures of the compounds were elucidated by UV, IR, (1)H NMR, and (13)C NMR spectroscopy. The purity of the compounds was confirmed by their elemental analysis. The antiamoebic activity of these compounds was evaluated by microdilution method against HMI:IMSS strain of Entamoeba histolytica and the IC(50) values were compared with the standard drug metronidazole. Some of the quinoxaline derivatives showed less IC(50) values than metronidazole. To elucidate the toxic effect, MTT assay was performed using kidney epithelial cell line. The results showed that all the compounds are non-toxic.     

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.     

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.     

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.     

Synthesis, characterization and biological evaluation of novel 2,4,6-trisubstituted bis-pyrimidine derivatives

A new series of 2,4,6-trisubstituted bis-pyrimidines were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Out of 16 compounds 8 compounds have shown IC(50) values in the range of 0.10-1.86 μM. Bis-pyrimidine having methyl-, methoxy-, thiomethyl- and dimehyl-phenyl substituents, exhibited higher antiamoebic activity than the reference drug metronidazole (IC(50) = 1.9 μM). The toxicological studies of active compounds on PC12-rat pheochoromocytoma cell line showed that all compounds were non-toxic at a concentration of 100 μM. 4-4'-Benzene-1,3-diylbis[6-(4-methylphenyl-2-(piperidin-1-yl)pyrimidine] (4c) was found most active (IC(50) = 0.10 μM) and least toxic among all the compounds.     

Antiamoebic coumarins from the root bark of Adina cordifolia and their new thiosemicarbazone derivatives

In continuation of our search for potential antiamoebic agents from folklore Indian medicinal plants, we found that the benzene and ethyl acetate extracts from the root bark of Adina cordifolia exhibited strong antiamoebic activity with IC(50) values of 2.92 and 2.50 microg/ml, respectively. Bioassay-guided fractionation of benzene and ethyl acetate extracts led to the isolation of 7-hydroxycoumarin (umbelliferone 1) and 7-beta-D-glucosylcoumarin (skimmin 2), respectively. Umbelliferone 1 was converted into 7-acetoxycoumarin 1a, which on treatment with aluminium chloride afforded 7-hydroxy-8-acetylcoumarin 2a. A new series of thiosemicarbazones 3a-e of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Umbelliferone was also converted into its methoxy derivative (7-methoxycoumarin 4). Subsequently, all the compounds were assessed for antiamoebic activity against HM1:IMMS strain of Entamoeba histolytica. Umbelliferone and skimmin were found to possess a very good activity with IC(50) values of 6.38 and 4.35 microM/ml, respectively. The activity drastically increased on converting compound 2a into its thiosemicarbazone derivatives 3a-e with IC(50) values ranging between 1.06 and 4.46 microM/ml. Compounds 3b,c and e with IC(50) values of 1.49, 1.56 and 1.06 microM/ml, respectively, exhibited even higher antiamoebic activity than the standard drug metronidazole (IC(50)=2.62 microg/ml). The activity of 7-methoxycoumarin (IC(50)=8.92 microM/ml) was less than umbelliferone. Compounds 3b, c and e were tested for toxicity using H9c2 cardiac myoblasts cell line. The compounds exhibit >80% viability at 3.125-200 microg/ml. It is apparent from these results that umbelliferone and skimmin may be a useful lead for the development of new antiamoebic drugs.     

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.     

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.     

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).     

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).     

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.     

synthesis, characterization and in vitro antiamoebic activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones and their Palladium (II) and Ruthenium (II) complexes

Synthesis of new Palladium(II) and Ruthenium(II) complexes of the type, [Pd(L)Cl(2)] and [Ru(eta(4)-C(8)H(12))(L)Cl(2)] [where, L = thiosemicarbazones derived from 5-nitrothiophene-2-carboxaldehyde and cycloalkylaminothiocarbonyl hydrazines] have been isolated by the reaction of [Pd(DMSO)(2)Cl(2)] and [Ru(eta(4)-C(8)H(12))(CH(3)CN)(2)Cl(2)] with 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones. The spectral data revealed that the thiosemicarbazones act as bidentate ligands, making use of thionic sulphur and the azomethine nitrogen atom for coordination to the central metal ion. Microdilution method was used for the assessment of antiamoebic activity of all the compounds against HK-9 strain of Entamoeba histolytica. Among all the thiosemicarbazones, 5-NT-4-BPTSCN (3) showed significant antiamoebic activity (IC(50) - 2.56 microM). Enhancement of antiamoebic activity resulted by introducing palladium and ruthenium metals in the thiosemicarbazone moiety. All the Pd(II) and Ru(II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones were found more active then their respective ligands. The complexes 1a-4a, 1b and 3b showed antiamoebic activity.     

Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines

Ten new 3,5-diphenyl-2-pyrazoline derivatives were synthesised by reacting 1,3-diphenyl-2-propen-1-one with hydrazine hydrate. The chemical structures of the compounds were proved by means of their IR, 1H-NMR spectroscopic data and microanalyses. The antidepressant activities of these compounds were evaluated by the 'Porsolt Behavioural Despair Test' on Swiss-Webster mice. 3-(4-Methoxyphenyl)-5-(3,4-dimethoxyphenyl)-2-pyrazoline, 3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline and 3-(4-chlorophenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline reduced 41.94-48.62% immobility times at 100 mgkg(-1) dose level. In addition, it was found that 4-methoxy and 4-chloro substituents on the phenyl ring at position 3 of the pyrazoline ring increased the antidepressant activity; the replacement of these groups by bromo and methyl substituents decreased activity in mice.     

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.