Impact of thiosemicarbazones on the accumulation of PpIX and the expression of the associated genes.

Thiosemicarbazone derivatives are known for their broad biological activity including their antitumor potency. The aim of the current study was to examine the effect of a novel series of non-toxic iron chelators on the accumulation of protoporphyrin IX after external 5-aminolevulonic acid administration. From this series we selected one the most promising derivative which causes a pronounced increase in the concentration of protoporphyrin IX. The increase of the photosensitizer concentration is necessary for the trigger the efficient therapeutic effect of the photodynamic reaction. For selected compound 2 we performed an examination of a panel of the genes that are involved in the heme biosynthesis and degradation. Results indicated the crucial roles of ferrochelatase and heme oxygenase in the described processes. Surprisingly, there was a strict dependence on the type of the tested cell line. A decrease in the expression of the two aforementioned enzymes after incubation with compound 2 and 5-aminolevulonic acid is a commonly known fact and we detected this trend for the MCF-7 and HCT 116 cell lines. However, we noticed the upregulation of the tested targets for the Hs683 cells. These unconventional results prompted us to do a more in-depth analysis of the described processes. In conclusion, we found that compound 2 is a novel, highly effective booster of photodynamic therapy that has prospective applications.

Enhancement in anti-tubercular activity of indole based thiosemicarbazones on complexation with copper(I) and silver(I) halides: Structure elucidation, evaluation and molecular modelling.

A series of monomeric tetrahedral complexes of stoichiometry, [MX(HL)(Ph3P)2] (In case of M = Cu, H1L, X = I, 1; Br, 2; Cl, 3; H3L, X = I, 4; Br, 5; Cl, 6; H4L, X = I, 7; Br, 8; Cl, 9 and in case of M = Ag, H1L, X = Cl, 13; Br, 14; H2L, X = Cl, 15, Br 16; H3L, X = Cl, 17, Br, 18) were synthesized by the reaction of copper (I) or silver (I) halides with indole-3-thiosemicarbazone (H1L) or 5-methoxy indole-3-thiosemicarbazone (H2L) or 5-methoxy indole-N1-methyl-3-thiosemicarbazone (H3L), whereas dimers of stoichiometry, [Cu2(µ-X)2(η1-S-H2L)2(Ph3P)2] (X = I, 10; Br, 11; Cl, 12) were obtained by the reaction of copper (I) halides with indole-N1-methyl-3-thiosemicarbazone (HIntsc-N1-Me, H2L). The synthesized complexes were characterized using NMR (1H and 13C) and single crystal X-ray diffraction (H2L, 3, 7, 8, 10, 11 and 13) as well as elemental analysis. Anti- M. tuberculosis activity of ligands (H1L-H4L) and their metal complexes (1-18) were evaluated against M. tuberculosis H37RV strain ATCC 27294. It has been observed that there is unusual enhancement in anti TB activity of these ligands on complexation with copper (I) and silver (I). Molecular modelling studies in the active binding site are also giving complementary theoretical support for the experimental biological data acquired.

Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents.

The cytotoxic activity of thiosemicarbazones (TSC) and thiocarbohydrazones was investigated against the MelRm melanoma cell line. In general, the melanoma line was susceptible to metal coordinating agents, the most useful of which incorporated the dipyridyl ketone hydrazone sub-structure. The impact of copper supplementation on the cytotoxic activity towards the melanoma line (MelRm) of metal coordinating agents when acting as ionophores is less predictable than the general improvement that has been seen in other cancer cells such as breast adenocarcinoma (MCF-7). The bimetallic nature of thiocarbohydrazone complexes with resultant loss of lipophilicity is a limiting factor in usage against MelRm. The cytotoxic activity of TSC against MelRm when used as copper ionophores could be markedly improved through combination with a partner drug capable of disrupting cellular defences to oxidative stress. In the absence of copper supplementation, both TSC and thiocarbohydrazones could be used to initiate cell cycle arrest and this could be employed to improve cytotoxicity profiles of other metallodrugs such as cisplatin.

Chemistry, antiproliferative activity and low nephrotoxicity of 3,5-diacetyl-1,2,4-triazol bis(4N-thiosemicarbazone) ligands and their platinum(II) complexes.

The preparation and characterization of 3,5-diacetyl-1,2,4-triazol bis(4,4-dimethylthiosemicarbazone) ligand, H(3)L(1), and its dinuclear platinum complex [Pt(mu-HL(1))](2) is described. The crystal and molecular structure of the platinum complex has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized together with the analogous monosubstituted ligand 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H(5)L(2)) and its dinuclear platinum(ii) complex [Pt(mu-H(3)L(2))](2) have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H(3)L(1) and [Pt(mu-H(3)L(2))](2) since they not only circumvent cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. Subsequent nephrotoxic study, in LLC-PK1 cells, show that the four compounds investigated exhibit very low nephrotoxicity with respect to cisplatin.

Syntheses and evaluation of glucosyl aryl thiosemicarbazide and glucosyl thiosemicarbazone derivatives as antioxidant and anti-dyslipidemic agents.

A series of N-per-O-acetyl-glucosyl arylthiosemicarbazide and thiosemicarbazone derivatives have been synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Among 16 compounds tested, 3 compounds showed potent anti-dyslipidemic activity and 6 compounds showed potent antioxidant and scavenger of oxygen free radicals activity.

Anticonvulsant and neurotoxicity evaluation of some 6-substituted benzothiazolyl-2-thiosemicarbazones.

Various 6-substituted benzothiazolyl-2-thiosemicarbazones were synthesized and screened for anticonvulsant activity in maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. The 6-methyl benzothiazolyl-2-thiosemicarbazones showed anticonvulsant activity in both mice i.p. and rat oral MES screen. The 6-nitro benzothiazolyl thiosemicarbazone derivative 1a emerged as the most promising one with anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino derivatives had shown better activity when compared to the benzylidene or acetophenone derivatives.

Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain.

While commercial isatins were practically inactive against the target proteases, thiosemicarbazone derivatives were found to be active. The most active compound from the series displayed an inhibitory IC(50) value of 1 microM against rhodesain. One thiosemicarbazone was found to be active against all three proteases with inhibitory IC(50) values of 10 microM or less. A combination of N-benzylation and appropriate substitution on the aromatic portion of the isatin scaffold was generally found to be beneficial especially against cruzain for ketone inhibitors.

Synthesis, spectral studies and screening for amoebicidal activity of new palladium(II) complexes derived from thiophene-2-carboxaldehyde thiosemicarbazones.

In view of the antiamoebic properties observed for many thiophene-2-carboxaldehyde thiosemicarbazones, a series of N(4)-substituted thiosemicarbazones metal complexes derived from thiophene-2-carboxaldehyde was prepared for evaluation against Entamoeba histolytica. Reaction of thiophene-2-carboxaldehyde with cycloalkylaminothiocarbonylhydrazines having different amines gave the corresponding thiosemicarbazones. Reaction of latter with [Pd(DMSO)(2)Cl(2)] gave requisite palladium thiosemicarbazone complexes of the type [Pd(TSC)Cl(2)] (where TSC=thiosemicarbazones). Screening of antiamoebic activity of these compounds was assayed in vitro against (HM-1:1MSS) strain of E. histolytica. Enhancement of antiamoebic resulted from introducing palladium metal in the thiosemicarbazone moiety. Among the studied compounds, [Pd(2-TCA-1,2,3,4-THQTSC)Cl(2)] (2a) showed better activity.

Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones.

Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the rat p.o. MES test at 30 mg kg(-1). Compound 1 [4-(6-chlorobenzothiazol-2-yl)-1-(3-isatinimino)thiosemicarbazone] emerged as the most promising one with an ED(50) of 17.86 and 6.07 mg kg(-1) in mice i.p. and rat p.o., respectively. Compound 1 showed a weak ability to block the expression of fully kindled seizures.

Anticonvulsant evaluation of some 3-oxo and 3-thiosemicarbazono analogues of 1-aryl-1-ethylthio-nonanes and related compounds.

A number of 3-oxo and 3-thiosemicarbazono analogues of 1-aryl-1-ethylthio-nonanes and related compounds were synthesized. Solutions of the thiosemicarbazones in deuterochloroform were shown by PMR spectroscopy to exist principally in the anti configuration at equilibria except when an ortho-methoxy group was present in the aryl ring. In this case intramolecular hydrogen bonding probably accounts principally for the presence of equal amounts of anti and syn isomers. Evaluation of these compounds for anti-convulsant properties revealed that 1-(2-aminoethylthio)-1-(2-chlorophenyl)nonan-3-one hydrochloride (6a) and sodium 2-(N-acetylamino)-3-[1-(2-chlorophenyl)-3-oxononylthio]propionate (6c) were active and thus they could serve as prototype molecules for future development.

2-Acetylpyridine thiosemicarbazones. 12. Derivatives of 3-acetylisoquinoline as potential antimalarial agents.

A series of 3-acetylisoquinoline thiosemicarbazones and their related thiosemicarbazides was prepared for evaluation as potential antimalarial agents. The former were synthesized by the reaction of 3-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(3-isoquinolinyl)ethylidene]hydrazinecarbodithioate, IV. Displacement of the S-methyl group of this intermediate by the requisite amines gave 3-acetylisoquinoline thiosemicarbazones, V. The corresponding thiosemicarbazides, in which the azomethine bond was reduced, were prepared by the reduction of IV with sodium borohydride to give methyl 3-[1-(3-isoquinolinyl)ethyl]hydrazinecarbodithioate, VI. Reaction of this dithioester with amines gave 1-[1-(3-isoquinolinyl)ethyl-3-thiosemicarbazides, VII. The antimalarial properties of series V and VII were evaluated in mice infected with Plasmodium berghei. Significant curative activity could be observed at doses as low as 40 mg/kg for 3 of 10 compounds in series V and at 160 mg/kg for 3 of 11 compounds in series VII.

2-Acetylpyridine thiosemicarbazones. 8. Derivatives of 1-acetylisoquinoline as potential antimalarial agents.

A series of 1-acetylisoquinoline thiosemicarbazones was prepared in order to evaluate their antimalarial properties. This was achieved by the reaction of 1-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(1-isoquinolinyl)ethylidene]hydrazinecarbodithioate (II). Displacement of the S-methyl group from this intermediate by various primary and secondary amines afforded the desired 1-acetylisoquinoline thiosemicarbazones (III). Thiosemicarbazides in which the azomethine moiety of the latter was reduced could be prepared by the reaction of II with NaBH4 to give methyl 3-[1-(1-isoquinolinyl)ethyl]hydrazinecarbodithioate (VIII). Reaction of VII with the appropriate amine gave 1-[1-(1-isoquinolinyl)ethyl]thiosemicarbazides (IX). Evaluation of the antimalarial activity of series III and IX in mice infected with Plasmodium berghei indicated that cures were attainable at dose levels of 40-160 mg/kg.

2-Acetylpyridine thiosemicarbazones. 9. Derivatives of 2-acetylpyridine 1-oxide as potential antimalarial agents.

In view of the antimalarial activity in mice of 2-acetylpyridine thiosemicarbazones, a series of analogous 1-oxides was prepared for evaluation. Their synthesis was achieved by the reaction of 2-acetylpyridine 1-oxide with methyl hydrazinecarbodithioate to give methyl 3-[1-(2-pyridinyl 1-oxide)ethylidene]hydrazinecarbodithioate (II). Reaction of the latter intermediate with secondary amines afforded the desired 2-acetylpyridine 1-oxide thiosemicarbazones (III). Reduction of the azomethine linkage of II with NaBH4 gave methyl 3-[1-(2-pyridinyl 1-oxide)ethyl]-hydrazinecarbodithioate (IV) whose S-methyl group was then displaced by amines to give a 1-[1-(2-pyridinyl 1-oxide)ethyl]thiosemicarbazide, V. Antimalarial activity of III was evaluated against both Plasmodium berghei in the mouse and Plasmodium falciparum in an automated in vitro test system. In both cases, 2-acetylpyridine 1-oxide thiosemicarbazones were found to be less active than the corresponding de-1-oxide analogues. When compounds V were evaluated against Plasmodium berghei in the mouse, a diminution of activity was similarly seen in comparison to the analogues not bearing the 1-oxide moiety.