- Synthesis, characterization, antiparasitic and cytotoxic evaluation of thioureas conjugated to polyamine scaffolds
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A series of mono- and multimeric 4-amino-7-chloroquinoline and ferrocenyl thioureas have been prepared by the reaction of a 7-chloroquinoline methyl ester and a ferrocenylimine methyl ester with various amines. These compounds were characterized using standard spectroscopic and analytical techniques. The compounds were evaluated against the NF54 (CQ-sensitive) and Dd2 (CQ-resistant) strains of Plasmodiumfalciparum. The quinoline compounds show enhanced activity compared to the ferrocene compounds against this parasite. Compound 5 displays the most promising activity against the NF54 strain. Compounds 5 and 6 are effective at inhibiting β-hematin formation perhaps due to an increased number of quinoline moieties. The trimeric (12) and tetrameric (13) ferrocenyl compounds also inhibit β-hematin formation, albeit to a lesser degree compared to the quinoline thioureas. The compounds were also screened against the G3 strain of Trichomonasvaginalis and here the ferrocene-containing compounds show a slightly higher parasite growth inhibition compared to the quinoline thioureas. The quinoline compounds were also found to be more cytotoxic compared to the ferrocenyl compounds. Compound 6 displays good cytotoxicity against WHCO1 oesophageal cancer cells.
- Stringer, Tameryn,Taylor, Dale,De Kock, Carmen,Guzgay, Hajira,Au, Aaron,An, Seung Hwan,Sanchez, Benjamin,O'Connor, Raquel,Patel, Neal,Land, Kirkwood M.,Smith, Peter J.,Hendricks, Denver T.,Egan, Timothy J.,Smith, Gregory S.
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- Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues
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The design, synthesis, and antimalarial activity of chimeras of thiosemicarbazones (TSC) and ferroquine (FQ) is reported. Key structural elements derived from FQ were coupled to fragments capable of coordinating metal ions. Biological evaluation was conducted against four strains of the malaria parasite Plasmodium falciparum and against the parasitic cysteine protease falcipain-2. To establish the role of the ferrocenyl moiety in the antiplasmodial activity of this series, purely organic parent compounds were also synthesized and tested. The presence of the aminoquinoline structure, allowing transport of the compounds to the food vacuole of the parasite, seems to be the major contributor to antimalarial activity.
- Biot, Christophe,Pradines, Bruno,Sergeant, Marie-Helene,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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- Coordinated dissociative proton transfers of external proton and thiocarbamide hydrogen: MS experimental and theoretical studies on the fragmentation of protonated S-methyl benzenylmethylenehydrazine dithiocarboxylate in gas phase
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The dissociation chemistry of the protonated S-methyl benzenylmethylenehydrazine dithiocarboxylate, PhCH{double bond, long}N{single bond}NHC({double bond, long}S)SCH3, has been investigated by collision-induced dissociation (CID) mass spectrometry experiments in combination with density functional theory (DFT) calculations. Eliminations of H2S, CH3SH and (NSC)SCH3 were the three fragmentation reactions observed in the tandem mass spectra, witnessed by the MS/MS analysis of native 34S-isotopic ion and the D-labeling CID-MS experiment. Of the three fragmentations, both the added proton and the internal thiocarbamide hydrogen shift to the fragment ion (m/z 106) in the dissociation of losing (NSC)SCH3, while both of them shift to the neutral fragment H2S to generate the minor product ion at m/z 177. In the case of the feasible fragmentation process of CH3SH elimination, one of the proton/the thiocarbamide hydrogen migrates to the fragment ion at m/z 163, and the other migrates to the neutral specie. Calculated results show that thiocarbamide sulfur (S5) is the most thermodynamically favored position for protonation. The mechanisms of these reactions were postulated according to the theoretical results, and the reaction energy profiles were also constructed. These results indicated that fragmentation of the protonated molecule was viewed as a result of the coordinated migration of both the external proton and the thiocarbamide hydrogen.
- Jiang, Kezhi,Bian, Gaofeng,Hu, Nan,Pan, Yuanjiang,Lai, Guoqiao
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- Nickel(II) and palladium(II) chelates of dehydroacetic acid Schiff bases derived from thiosemicarbazide and hydrazinecarbodithioate
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Dehydroacetic acid Schiff bases DAE (1) and DATS (2) were isolated from the reaction of dehydroacetic acid (2-acetyl-5-hydroxy-3-oxo-4-hexenoic acid-δ-lactone) with hydrazine-S-methylcarbodithioate and the corresponding acid amide, thiosemicarbazide, respectively. Reaction of such Schiff bases with nickel(II) and palladium(II) ions afforded the dimeric monoligand chelates [M(DAE-2H)]2 and [M(DATS-2H)]2; M = Ni(II) or Pd(II). In the presence of monodentate Lewis bases, B, square-planar chelates [M(DAE-2H)B] and [M(DATS-2H)B], in which B = pyridine or triphenylphosphine, were isolated. The stoichiometry and structure of the isolated organic ligands and their chelates were confirmed through elemental analyses, molecular weight determination, and infrared, ultraviolet-visible, and 1H and 13C nuclear magnetic resonance spectroscopy.
- Kubaisi,Ismail
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- Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells
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Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas. Shimada et al. report that the compound NSC319726 arrests glioblastoma-patient-derived cells at picomolar concentrations. The compound binds to copper, generates ROS using ambient oxygen, and depletes nucleotide pools. This represents a new strategy for potently blocking the growth of glioblastoma.
- Shimada, Kenichi,Reznik, Eduard,Stokes, Michael E.,Krishnamoorthy, Lakshmi,Bos, Pieter H.,Song, Yuyu,Quartararo, Christine E.,Pagano, Nen C.,Carpizo, Darren R.,deCarvalho, Ana C.,Lo, Donald C.,Stockwell, Brent R.
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- Synthesis, crystal structure, and herbicidal activities of 2-cyanoacrylates containing 1,3,4-thiadiazole moieties
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Three series of novel 2-cyanoacrylates 7a-7f, 9a-9f, 10a-10f containing 1,3,4-thiadiazole ring moieties were synthesized as herbicidal inhibitors of photosystem II (PS II) electron transportation. Their structures were clearly verified by 1H NMR, 13C NMR, elemental analysis (or HRMS analysis) and single-crystal X-ray diffraction analysis. Bioassay showed that a suitable group at the 3-position of acrylates was essential for high herbicidal activity. In particular, compound 7e showed the best herbicidal activities and gave 100% inhibitory activity against rape and amaranth pigweed at a dose of 1.5 kg/ha. Introduction of substituent with higher polarity such as sulfinyl or sulfonyl to the 5-position of 1,3,4-thiadiazole decreased herbicidal activities.
- Wang, Tingting,Miao, Wenke,Wu, Shanshan,Bing, Guifang,Zhang, Xin,Qin, Zhenfang,Yu, Haibo,Qin, Xue,Fang, Jianxin
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- Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53
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We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.
- Gilleran, John A.,Yu, Xin,Blayney, Alan J.,Bencivenga, Anthony F.,Na, Bing,Augeri, David J.,Blanden, Adam R.,Kimball, S. David,Loh, Stewart N.,Roberge, Jacques Y.,Carpizo, Darren R.
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p. 2024 - 2045
(2021/02/16)
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- Synthetic method 2 -methylsulfonyl -5 - trifluoromethyl -1 , 3, 4 - thiadiazole
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The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method 2 -methylsulfonyl -5 - trifluoromethyl -1 , 3, 4 - thiadiazole. To the invention, hydrazine hydrate and carbon disulfide are subjected to addition reaction, and then under basic conditions, dimethyl sulfate is replaced to obtain the intermediate material A, and the intermediate material A is obtained. The intermediate material B is obtained by reacting the intermediate material B with hydrogen peroxide to obtain 2 - methylsulfonyl -5 - trifluoromethyl -1 , 3, 4 - thiadiazole, the operation is simple, the operation is easy, and the yield is high.
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Paragraph 0011
(2021/10/20)
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- PHARMACEUTICAL COMPOUNDS AND THERAPEUTIC METHODS
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The invention provides a complex comprising Zn2+ and a compound of formula (I): or a deuterated analog thereof, or an ion or poly-ion thereof, or a salt thereof that is useful for treating cancer, as well as compositions and kits comprising such complexes.
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Page/Page column 9-10
(2020/11/03)
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- Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans
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Abstract: Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals. Graphic abstract: [Figure not available: see fulltext.]
- Franz, Katherine J.,Hunsaker, Elizabeth W.,McAuliffe, Katherine J.
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- The role of methyl and benzyl substituted dithiocarbazate of 2-acetyl pyridine for the formation of bridged dimeric and unbridged monomeric copper(II) complexes and catecholase mimetic activity of the complexes
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Monomeric [Cu(L1)Cl] (1) and dimeric [Cu(L2)Cl]2 (2) copper(II) complexes, where HL1 = methyl-2-(1-(pyridine-2-yl)ethylidene)-hydrazine-1-carbodithioate and HL2 = benzyl-2-(1-(pyridine-2-yl)ethylidene)hydrazine-1-carbodithioate, have been synthesized and characterized by X-ray crystallography, TGA and spectral methods. Complex 1 crystallizes in a space group P21/n and adopts a square planar environment surrounding the Cu ion, and complex 2 is a triclinic crystal system with space group Pī. Complex 2 is a centrosymmetric dimer where each copper atom forms two chloro bridges and completes five coordination with the tridentate NNS donor. Density functional calculations demonstrate that chloro-unbridged structure of 1 is favored by London dispersion between its layers. It is noticed that the layers are usually packed closely in the solid phase, such attractive interactions are sterically hindered between the layers of 2. Due to the presence of large phenyl group that extend from one layer to the other, the layers cannot slide on top of each other. This leads to the chloro-bridged structure of 2 stabilized by electrostatic interactions between Cu and Cl atoms located at different layers. Both complexes exhibit prominent catecholase activity in methanol following the oxidation of 3,5-di-tert-butyl catechol (DTBC) to the corresponding quinone. Based on the observed turn over frequency of 1 (25.19 h?1) and 2 (10.76 h?1), the monomeric complex demonstrates more catechol mimetic oxidation than the dimer. A plausible mechanism of catecholase activity has been discussed.
- Santra, Ananyakumari,Brandao, Paula,Mondal, Gopinath,Bera, Pradip,Jana, Abhimanyu,Bhattacharyya, Indranil,Pramanik, Chandana,Bera, Pulakesh
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- CHEMICAL ACTIVATORS OF NICOTINAMIDE MONONUCLEOTIDE ADENLYLY TRANSFERASE 2 (NMNAT2) AND USES THEREOF
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The present application relates to novel semicarbazones and thiosemicarbazones, to processes for preparing them, to pharmaceutical preparations comprising them, to the use of the novel semicarbazones and thiosemicarbazones for treatment and/or prophylaxis of diseases and to the use thereof for production of a medicament for treatment and/or prophylaxis of diseases, especially of neurodegeneration and age-associated diseases or conditions associated with NAD loss. The present application also provides a method for high throughput screening of NMNAT2 activators.
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Page/Page column 23; 34-35
(2020/06/22)
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- A class of nitrogen-containing sulfur substituents of the naphthalimide compound, preparation method and application thereof
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The present invention discloses a class of nitrogen-containing sulfur substituent naphthalimide compound, a preparation method and applications thereof, wherein the compound has a structure represented by a general formula Y, R is one selected from a six-membered ring containing hetero atom, the following structures defined in the specification, -NHCH2CH2OH, -NHCH2CH2N(CH3) and -NHCH2CH2CH2CH3, the hetero atom is at least one selected from N, O and S, the six-membered ring containing the hetero atom at least has a N atom, and R is bound with the mother nucleus in the general formula T through the N atom. According to the present invention, the methyldithiocarbazate is bounded into the active site of the naphthalimide to prepare the compound of the present invention, and the class of the compounds provide growth inhibition activities on breast cancer cells, cervical cancer cells and a variety of tumor cells with different tissue origins while provide low inhibition activities on human body normal cells, and have wide prospects in the tumor cell growth inhibition drug preparation. The general formula Y is defined in the specification.
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Paragraph 0027; 0032; 0033; 0034
(2019/04/15)
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- PROCESS FOR THE PREPARATION OF THIADIAZOLE DERIVATIVES
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A process is described for the preparation of thiadiazole derivatives and more specifically a new synthetic process of compounds having general formula (I) and intermediate compounds having general formula (XVI).
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Page/Page column 20-21
(2019/12/28)
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- Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities
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A novel series of spirobenzo[h]chromene and spirochromane derivatives was designed, synthesized and evaluated as potential anticancer agents against MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (human lung carcinoma) cell lines using MTT assay. Eight compounds 7, 8e, 13a-e and 16 showed a better anticancer activity than that of sorafenib, the multi-kinase inhibitor with IC50 values between 1.78 and 5.47 μM or erlotinib with IC50 values over 20 μM. Representative compounds 8e, 13c and 16 were selected for further mechanistic investigation via EGFR, B-RAF and tubulin polymerization assays. Compound 16 was the most potent EGFR inhibitor (IC50 = 1.2 μM), yet compounds 8e, 13c and 16 displayed moderate tubulin polymerization inhibition effects. Molecular docking studies of those compounds revealed their possible binding modes into the active sites of both EGFR and B-RAF kinases. The newly developed compounds represent a therapeutically promising approach for the treatment of different types of cancer.
- Abdelatef, Shaimaa A.,El-Saadi, Mohammed T.,Amin, Noha H.,Abdelazeem, Ahmed H.,Omar, Hany A.,Abdellatif, Khaled R.A.
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p. 567 - 578
(2018/03/21)
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- Synthesis and pesticidal activities of novel anthranilic diamides containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs
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A series of novel anthranilic diamide derivatives containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs were synthesized via multi-step reactions. The structures of seven title compounds (methyl 2-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3- methylbenzylidene)hydrazinecarbodithioate 7 and 3-bromo-N-(2-((2-substitutedcarbamothioylhydrazono)methyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 8a-8f) were confirmed by melting points, IR, 1H NMR, 13C NMR, and HRMS. The bioassays showed that some of the compounds exhibited modest insecticidal activities against oriental armyworm (Mythimna separata Walker), particularly, compound 8b (3-bromo-N-(4-chloro-2-methyl-6-((2-(methylcarbamothioyl)hydrazono)methyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide) held 100% and 30% larvicidal activity at the concentration of 25 mg/L and 10 mg/L, respectively. In addition, several compounds displayed favorable fungicidal activities against Alternaria solani Sorauer and Physalospora piricola at 50 μg/mL, and were comparable with the controls Chlorothalonil and Triadimefon. The results in this paper will provide important information for further research and development of sulfur-containing heterocyclic agrochemicals.
- Liu, Qiao-Xia,Wang, Bao-Lei,Mao, Ming-Zhen,Xiong, Li-Xia,Li, Zheng-Ming
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p. 593 - 599
(2018/09/25)
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- N-methyl ciprofloxacin aldehyde thiosemicarbazone derivatives as well as preparation method and application thereof
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The invention discloses N-methyl ciprofloxacin aldehyde thiosemicarbazone derivatives as well as a preparation method and application thereof. The chemical structure general formula of the derivatives is described in the description, wherein R is a hydrogen atom, or an alkyl or a cyclopropyl which has 1 to 5 carbon atoms. The N-methyl ciprofloxacin aldehyde thiosemicarbazone derivatives realize the splicing of three dominant pharmacophores, i.e. fluoroquinolone skeleton, Schiff base imine and thiourea, thus improving the antitumor activity of a new compound and reducing the toxic and side effects for normal cells; therefore, the N-methyl ciprofloxacin aldehyde thiosemicarbazone derivatives can be taken as anti-tumor active substances for developing anti-tumor drugs with brand-new structures.
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Paragraph 0033-0034
(2017/07/19)
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- N-methyl gatifloxacin aldehyde thiosemicarbazone derivative and preparation method and application thereof
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The invention discloses N-methyl gatifloxacin aldehyde thiosemicarbazone derivative and a preparation method and application thereof. The N-methyl gatifloxacin aldehyde thiosemicarbazone derivative has a chemical structural formula as a following formula I. In the formula I, substituent R is an H atom or alkyl or cyclopropyl with 1 to 5 carbon atoms. According to the N-methyl gatifloxacin aldehyde thiosemicarbazone derivative disclosed by the invention, combination of three kinds of advantage pharmacophore of a fluoroquinolone framework, imine Schiff base, thiourea and the like is achieved; thus, antineoplastic activity of novel compound is improved, a toxic and side effect of normal cells is reduced, and the N-methyl gatifloxacin aldehyde thiosemicarbazone derivative can serve as antineoplastic activity substance to develop antineoplastic drug with a novel structure.
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Paragraph 0014
(2017/07/22)
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- New insight into the structural, electrochemical and biological aspects of macroacyclic Cu(II) complexes derived from S-substituted dithiocarbazate schiff bases
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Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7.
- Low, May Lee,Maigre, Laure,Tahir, Mohamed Ibrahim M.,Tiekink, Edward R.T.,Dorlet, Pierre,Guillot, Régis,Ravoof, Thahira Begum,Rosli, Rozita,Pagès, Jean-Marie,Policar, Clotilde,Delsuc, Nicolas,Crouse, Karen A.
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- Synthesis of 5-acetyl-2-arylamino-4-methylthiazole thiosemicarbazones under microwave irradiation and their in vitro anticancer activity
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A series of 21 new tri- and tetra-cyclic thiosemicarbazone derivatives were prepared via the condensation of morpholine, piperazine or N-(4-methoxyphenyl)piperazine with seven methyl hydrazine-carbodithioate derivatives of 5-acetyl-2-arylamino-4-methylthiazoles under microwave irradiation. All compounds were tested for their cytotoxic activity in vitro against human gastric, lung and breast cancer cell lines. The results showed that some of the compounds displayed moderate anticancer activity. The most potent compound, a morpholinosubstituted analogue, exhibited significant activity against human breast cancer cells.
- Shi, Hai-Bo,Hu, Wei-Xiao,Zhang, Wei-Mao,Wu, Yan-Fei
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- Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: Synthesis, cytotoxic and antimalarial evaluation
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A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.
- Kumar, Kewal,Schniper, Sarah,González-Sarrías, Antonio,Holder, Alvin A.,Sanders, Natalie,Sullivan, David,Jarrett, William L.,Davis, Krystyn,Bai, Fengwei,Seeram, Navindra P.,Kumar, Vipan
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- Conjugation of a new series of dithiocarbazate schiff base copper(II) complexes with vectors selected to enhance antibacterial activity
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A new series of six Schiff bases derived from S-methyldithiocarbazate (SMDTC) and S-benzyldithiocarbazate (SBDTC) with methyl levulinate (SMML, SBML), levulinic acid (SMLA, SBLA), and 4-carboxybenzaldehyde (SM4CB, SB4CB) were reacted with copper(II), producing complexes of general formula ML2 (M = Cu(II), L = ligand). All compounds were characterized using established physicochemical and spectroscopic methods. Crystal structures were determined for three Schiff bases (SMML, SBML, SBLA) and two Cu(II) complexes (Cu(SMML)2 and Cu(SMLA)2). In order to provide more insight into the behavior of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. The parent ligands and their respective copper(II) complexes exhibited moderate antibacterial activity against both Gram-negative and Gram-positive bacteria. The most active ligand (SB4CB) and its analogous S-methyl derivative (SM4CB) were conjugated with various vector moieties: polyarginines (R1, R4, R9, and RW9), oligoethylene glycol (OEG), and an efflux pump blocker, phenylalanine-arginine-β-naphthylamide (PAβN). Nonaarginine (R9) derivatives showed the most encouraging synergistic e ffects upon conjugation and complexation with copper ion including enhanced water solubility, bacteria cell membrane permeability, and bioactivity. These Cu(II)-R9 derivatives display remarkable antibacterial activity against a wide spectrum of bacteria and, in particular, are highly efficacious against Staphylococcus aureus with minimum inhibitory concentration (MIC) values of 0.5-1 μM. This pioneer study clearly indicates that the conjugation of cell-penetrating peptides (CPPs) to dithiocarbazate compounds greatly enhances their therapeutic potential.
- Low, May Lee,Maigre, Laure,Dorlet, Pierre,Guillot, Rgis,Pags, Jean-Marie,Crouse, Karen A.,Policar, Clotilde,Delsuc, Nicolas
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p. 2269 - 2284
(2015/02/19)
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- Synthesis and biological evaluation of novel thiosemicarbazone-triazole hybrid compounds as antimalarial agents
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Anovel series of thiosemicarbazone-triazole hybrids were efficiently synthesized and evaluated for their activity against the 3D7 strain of the malaria parasite, Plasmodium falciparum. Although the hybrids were found not to be as potent as the standard chloroquine, they have shown activities interesting enough to warrant future structure activity relationship (SAR) studies.
- Kinfe, Henok H.,Belay, Yonas H.
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p. 130 - 135
(2013/07/26)
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- Methyl-2-arylidene hydrazinecarbodithioates: Synthesis and biological activity
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Methyl-2-arylidene hydrazine-carbodithioate has not been of particular interest to researchers even though its metal complexes are extensively reported on due to their biological activity. This study examined the cytostatic and antiviral activity of twelve methyl-2-arylidene hydrazinecarbodithioates reported by many researchers as intermediates for the synthesis of thiosemicarbazides and the preparation of their metal complexes. Compounds IIc, IIi, and IIl with tridentate ligand features were found to have the lowest IC50 value (6.5 μM, ≈ 1 μM, and 0.8 μM, respectively) against HL60 human promyelocytic leukemia cells. They were also most inhibitory to human embryonic lung (HEL) fibroblast proliferation (5.3 μM, 17 μM, and 2.6 μM). Compound IIc and IIl show antiviral activity against wild-type herpes simplex virus (HSV), varicella zoster virus (VZV), and acyclovirresistant HSV; however, these activities were observed at concentrations at which the compounds also markedly inhibit HL60 and HEL cell proliferation.
- Mahapatra, Manojkumar,Kulandaivelu, Umasankar,Saiko, Philipp,Graser, Geraldine,Szekeres, Thomas,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,Jayaprakash, Venkatesan
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p. 650 - 656
(2013/07/26)
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- Synthesis antimicrobial and anticancer activity of N′- arylmethylidene-piperazine-1-carbothiohydrazide
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Ten newly synthesized thiosemicarbazones of piperazine (3a-3j) were evaluated for their antibacterial and antifungal activity against non-pathogenic strains of Escherichia coli (NCIM 2068), Klebsiella pneumonia (NCIM 2957), Staphylococcus aureus (NCIM 2079), and Bacillus subtilis (NCIM 2921); pathogenic strains of Vibrio cholerae, protease, Candida albicans and Aspergillus niger. All the 10 compounds (3a-3j) were found to be better than Ciprofloxacin against B. subtilis and four molecules (3c, 3d, 3e, and 3h) against S. aureus. Compound 3j, a derivative of benzophenone, has been identified as a potent and promising candidate against C. albicans. The compounds were also evaluated for their anticancer activity against HBL-100 and HL60 cell lines. Compound 3a, a p-hydroxy benzaldehyde derivative, has been identified as a potent and promising candidate.
- Kulandaivelu, Umasankar,Shireesha, Boyapati,Mahesh, Chidara,Vidyasagar, Jannu Vincent,Rao, Tadikonda Rama,Jayaveera,Saiko, Philipp,Graser, Geraldine,Szekeres, Thomas,Jayaprakash, Venkatesan
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p. 2802 - 2808
(2013/07/26)
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- Synthesis and antiproliferative evaluation of piperazine-1- carbothiohydrazide derivatives of indolin-2-one
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By varying the substituents (R1) at the indolin-2-one scaffold, a series of indolin-2-one derivatives bearing 4-phenylpiperazine-1- carbothiohydrazide moiety at the C3-position were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines. We further selected the 5-chloroindolin-2-one moiety for the extension to another series of compounds by varying the substituents (R2) at the phenyl group connected with the piperazine ring. Among all the compounds synthesized, 6d and 6l were most potent with IC50 values of 3.59 and 5.58 μM, respectively against A549 lung cancer cells, while 5f and 6l possessed IC 50 values of 3.49 and 4.57 μM, respectively against HCT-116 colon cancer cells which were comparable to that of Sunitinib, an indolin-2-one derivative in cancer therapy.
- Lin, Hui-Hui,Wu, Wei-Yao,Cao, Sheng-Li,Liao, Ji,Ma, Li,Gao, Man,Li, Zhong-Feng,Xu, Xingzhi
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p. 3304 - 3307
(2013/06/27)
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- Evaluation of the Influence of thiosemicarbazone-triazole hybrids on genes implicated in lipid oxidation and accumulation as potential anti-obesity agents
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A series of thiosemicarbazone-triazole hybrids 1a-h are efficiently synthesised and evaluated for their influence on the expression of genes, cpt-1, acc-1 and pgc-1, which are essential in lipid metabolism. The test results show that hybrids 1c and 1g exhibited relatively high influence on the expression of cpt-1 and pgc-1 and suppression of acc-1 as desired.
- Kinfe, Henok H.,Belay, Yonas H.,Joseph, Jitcy S.,Mukwevho, Emmanuel
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p. 5275 - 5278
(2013/09/23)
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- Effect of substitution at N″-position of N′-hydroxy-N-amino guanidines on tumor cell growth
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Structural modification of one of our earlier reported lead molecule (ABNM13) has been carried out to study the effect of different substituents at the N″-position of N-hydroxy-N′-amino guanidines (HAGs) on their anticancer activity. Compounds with electron donating substituents were found to be less active. In contrast, those with electron withdrawing groups were found favorable for anticancer activity. The obtained results provide significant SAR information that may be useful for further drug designing with HAGs.
- Basu, Arijit,Sinha, Barij Nayan,Saiko, Philipp,Szekeres, Thomas
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experimental part
p. 4934 - 4938
(2012/08/28)
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- TUMOUR TREATMENT AGENTS AND METHOD
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N1-(3-Methoxypropyl)-2-(pyridylmethylidene)-hydrazine-1-carbothioamide (I) and its Cu2+, Pd2+ and Pt2+ complexes are effective anti-tumor agents. Also disclosed are compositions comprising (I) and its Cu2+, Pd2+ and Pt2+ complexes, and the use of the compositions in the treatment of malignant tumors.
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Page/Page column 11
(2011/07/07)
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- A crystallographic study of S-methyl 2-(5-chloro-2-oxoindolin-3-ylidene) hydrazinecarbodithioate
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S-methyl 2-(5-chloro-2-oxoindolin-3-ylidene)hydrazinecarbodithioate (SM5ClISA) has been prepared from S-methyldithiocarbazate and 5-chloroisatin. The compound crystallized in monoclinic crystal system with space group P 2 1/n, Z = 4, V = 1201.85(7) A3 and unit cell parameters a = 6.5466(2) A, b = 7.5056(3) A, c = 24.6509(8) A, α = γ = 90° and β = 97.1434(18)°. The crystal structure reveals that the compound exists in the thione form with the chlorine occupies the fifth position in the isatin ring with the bond length of 1.739(2) A. The 5-chloroisatin moiety is trans with respect to the C3-N2 and C3-S4 bonds whereas the methyl group of the dithiocarbazate moiety is cis with respect to the C3-N2 and C3-S5 bonds.
- Manan, Mohd Abdul Fatah Abdul,Tahir, M. Ibrahim M.,Crouse, Karen A.,Watkin, David J.
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scheme or table
p. 230 - 235
(2011/09/30)
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- Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors
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A series of isatin-β-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-β-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.
- Kang, Iou-Jiun,Wang, Li-Wen,Hsu, Tsu-An,Yueh, Andrew,Lee, Chung-Chi,Lee, Yen-Chun,Lee, Ching-Yin,Chao, Yu-Sheng,Shih, Shin-Ru,Chern, Jyh-Haur
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scheme or table
p. 1948 - 1952
(2011/05/04)
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- Synthesis, antimicrobial and anticancer activity of new thiosemicarbazone derivatives
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Thiosemicarbazones of p-aminobenzoic acid (PABA) were synthesized and tested for their antimicrobial and anticancer activity. Hydroxamate derivatives 4a-4l were found to have better antimicrobial and anticancer activity than their acid counterpart. Compound 4d was found to have good antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis with IC50 value of about 1 aμM. Compound 4f showed potent antifungal activity against Candida albicans (IC50a=a1.29 aμM) and compound 4h showed potent anticancer activity (IC50a=a0.07 aμM). Hydroxamate derivatives 4a-4l were found to show better antimicrobial and anticancer activity in compariosn with their acid counterparts 3a-3l. Copyright
- Kulandaivelu, Umasankar,Padmini, Valisakka Gari,Suneetha, Kyatham,Shireesha, Boyapati,Vidyasagar, Jannu Vincent,Rao, Tadikonda Rama,Jayaveera,Basu, Arijit,Jayaprakash, Venkatesan
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experimental part
p. 84 - 90
(2011/09/21)
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- Substituted hydrazinecarbothioamide as potent antitubercular agents: Synthesis and quantitative structure-activity relationship (QSAR)
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A series of novel substituted hydrazinecarbothioamides was synthesized and evaluated for anti-TB activity. Three most active compounds viz. 1, 6 and 12 were found to exhibit minimum inhibitory concentration (MIC) of 0.4 μg/mL, whereas four compounds viz. 3, 5, 10 and 11 showed comparatively lesser activity with MIC value of 0.8 μg/mL against Mycobacterium tuberculosis strain. A highly significant QSAR equation explaining 81.8% variance is described.
- Singh, Supriya,Mandal, Pintu K.,Singh, Nagendra,Misra, Anup K.,Singh, Shubhra,Chaturvedi, Vinita,Sinha, Sudhir,Saxena, Anil K.
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experimental part
p. 2597 - 2600
(2010/07/13)
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- Design, synthesis and anticancer activity of piperazine hydroxamates and their histone deacetylase (HDAC) inhibitory activity
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Six compounds were synthesized with piperazine in linker region and hydroxamate as Zinc Binding Group (ZBG). They were screened against three cancer cell-lines (NCIH460; HCT116; U251). Compounds 5c and 5f with GI50 value of 9.33 ± 1.3 μM and 12.03 ± 4 μM, respectively, were tested for their inhibitory potential on hHDAC8. Compound 5c had IC50 of 33.67 μM. Compounds were also screened for their anticancer activity against HL60 human promyelocytic leukemia cell line due to the presence of pharmacophoric features of RR inhibitors in them. Compound 5c had IC 50 of 0.6 μM at 48 h.
- Chetan, Bhadaliya,Bunha, Mahesh,Jagrat, Monika,Sinha, Barij Nayan,Saiko, Philipp,Graser, Geraldine,Szekeres, Thomas,Raman, Ganapathy,Rajendran, Praveen,Moorthy, Dhatchana,Basu, Arijit,Jayaprakash, Venkatesan
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supporting information; experimental part
p. 3906 - 3910
(2010/09/03)
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- Synthesis and antitumoractivity of liquiritigenin thiosemicarbazone derivatives
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In an attempt to develop potent and selective antitumor agents,a series of liquiritigenin thio-semicarbazone derivatives were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against K562,DU-145,SGC-7901,HCT-116 and Hela cell lines. The pharmacological results showed that most of the prepared compounds displayed excellent selective cytotoxicity toward K562 and DU-145 cells. From the structureeactivity relationships we may conclude that the introduction of a thiosemicarbazone functional group at the 4-position in the skeleton of liquiritigenin is associated with an increase in cytotoxicity.
- Hu, Kun,Yang, Ze-Hua,Pan, Sha-Sha,Xu, Hua-Jin,Ren, Jie
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scheme or table
p. 3453 - 3458
(2010/08/13)
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- Synthesis and characterization of oxothiomolybdenum(VI) complexes of some ONS chelating ligands by in situ oxo removal and sulphido insertion in the corresponding dioxomolybdenum(VI) complexes
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This work reports the synthesis, characterization and electrochemical studies of several [MoVIOS]2+ complexes of some tridentate ONS donor ligands obtained by the condensation of salicylaldehyde/2- hydroxyacetophenone with S-benzyl and S-methyl dithiocarbazates. In this work PPh3 and PPh3S mixture is used as the synthetic reagent. The general strategy of synthesizing the complexes of the [MoOSL] type with the [MoOS]2+ core from corresponding complexes with the [MoO 2]2+ core by in situ oxoremoval-sulphide addition process. Presence of the oxothio core in all the [MoOSL] complexes is established by their reaction with KCN resulting in the formation of the CNS- species. All the complexes are characterized by various spectroscopic (NMR, IR, UV-Vis) techniques and also by cyclic voltammetry. All the complexes exhibit an irreversible overall 2 electron reductive response probably by proton assisted loss of the sulphide group leading to the formation of the corresponding [MoOL] complex.
- Pramanik, Nikhil Ranjan,Ghosh, Saktiprosad,Raychaudhuri, Tapas Kumar,Mandal, Sudhanshu Sekhar
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experimental part
p. 564 - 569
(2010/06/19)
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- Synthesis and Ribonucleotide reductase inhibitory activity of thiosemicarbazones
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Ribonucleotide reductase (RR) is an important therapeutic target for anticancer drugs. The structure of human RR features a 1:1 complex of two homodimeric subunits, hRRM1 and hRRM2. Prokaryotically expressed and highly purified recombinant human RR subunits, hRRM1 and hRRM2, were used for holoenzyme-based [3H]CDP reduction in vitro assay. Ten new thiosemicarbazones (7-16) were synthesized and screened for their RR inhibitory activity. Two thiosemicarbazones derived from p-hydroxy benzaldehyde (9 and 10) were found to be active but less potent than the standard, Hydroxyurea (HU). Guided by the activity of compounds 9 and 10, 11 new thiosemicarbazones (17-27) derived from p-hydroxy benzaldehyde were prepared and screened for their RR inhibitory activity. All the 11 compounds were more potent than HU.
- Krishnan, Kesavan,Prathiba, Kumari,Jayaprakash, Venkatesan,Basu, Arijit,Mishra, Nibha,Zhou, Bingsen,Hu, Shuya,Yen, Yun
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supporting information; experimental part
p. 6248 - 6250
(2009/08/07)
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- Synthesis and anticancer activity of thiosemicarbazones
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Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC 50 of compound III-16 against SGC-7901 reaches to 0.032 μM.
- Hu, Wei-Xiao,Zhou, Wei,Xia, Chun-Nian,Wen, Xi
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p. 2213 - 2218
(2007/10/03)
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- ANTI-PARASITIC COMPOUNDS AND METHODS OF THEIR USE
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The present invention provides a novel class of compounds that disrupt the parasitic infectious life cycle and serve as promising agents for anti-parasitic therapy.
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Page/Page column 29-30
(2008/06/13)
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- Synthesis of 2-aminoaryl-5-substituted-1,3,4-thiadiazoles in a thermal 1,3-dipolar cycloaddition reaction
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The preparation of a series of new 2-aminoaryl-1,3,4-thiadiazoles substituted with methylsulfanyl, methansulfinyl, or amine in the 5-position is described in this article. The compounds were obtained from N-hydroxyimidoyl chlorides and methyl dithiocarbazinate or 4-substituted thiosemicarbazides in a thermal 1,3-dipolar cycloaddition reaction. The new derivatives were tested for their activity against Mycobacterium tuberculosis. Copyright Taylor & Francis Inc.
- Gobis, Katarzyna,Foks, Henryk,Zwolska, Zofia,Augustynowicz-Kopec, Ewa
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p. 2653 - 2666
(2007/10/03)
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- Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi
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We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds that were effective against the enzymes and the parasites but also some compounds that were parasiticidal despite a lack of activity against the proteases. Several compounds were effective in killing all tested parasites. These promising lead compounds were tested for general toxicity in mice, and only one produced observable toxicity after 62 h. Our results suggest that thiosemicarbazones represent validated drug leads that kill several species of protozoan parasites through the inhibition of cysteine proteases as well as other novel targets.
- Greenbaum, Doron C.,Mackey, Zachary,Hansell, Elizabeth,Doyle, Patricia,Gut, Jiri,Caffrey, Conor R.,Lehrman, Julia,Rosenthal, Philip J.,McKerrow, James H.,Chibale, Kelly
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p. 3212 - 3219
(2007/10/03)
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- A Pummerer-Type Novel Ring Fission of 2-Methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazine Derivatives: A Homologation of Aldehydes and Ketones
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Aldehydes and ketones were converted into 2-methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazines via the formation and base-induced ring-closure of N-alkylidene-N′-bis(alkylthio)methylenehydrazines followed by mCPBA oxidation. The subsequent Pummerer-type ring fission of the rings was performed by treating with trifluoroacetic anhydride or trifluoromethanesulfonic anhydride at -78°C to give α,β-unsaturated esters and ketones in modest yields. Thus, this reaction sequence was regarded as being a new method for the two-carbon homologation of aldehydes and ketones.
- Shimada, Kazuaki,Otaki, Akihiro,Yanakawa, Masaki,Mabuchi, Shosuke,Yamakado, Naoya,Shimoguchi, Takeshi,Inoue, Kazuya,Kagawa, Takashi,Shoji, Kazutoshi,Takikawa, Yuji
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p. 1043 - 1054
(2007/10/03)
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- Insecticidal 6-aryl-pyridine thiosemicarbazones
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This invention relates to novel insecticidal 6-aryl-pyridine-thiosemicarbazones, compositions containing those compounds, methods of using said compounds and compositions.
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- 2-Acetylpyridine thiosemicarbazones. 1. A new class of potential antimalarial agents
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Based on the antimalarial properties observed for 2-acetylpyridine 4-phenyl-3-thiosemicarbazone (1), an extensive series of related thiosemicarbazones was prepared and tested against Plasmodium berghei in mice. Screening results indicated that the presence of the 2-pyridylethylidene group was critical and that certain phenyl, benzyl, phenethyl, or cycloalkyl groups at N4 of the thiosemicarbazone moiety also contribute to antimalarial activity.
- Klayman,Bartosevich,Griffin,Mason,Scovill
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p. 855 - 862
(2007/10/04)
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- Novel benzylideneaminoguanidines
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This disclosure describes novel substituted benzylideneaminoguanidines useful as anti-hypertensive agents and as diuretics.
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