5397-03-5Relevant articles and documents
Synthesis, characterization, antiparasitic and cytotoxic evaluation of thioureas conjugated to polyamine scaffolds
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.
, p. 90 - 98 (2013)
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.
Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues
Biot, Christophe,Pradines, Bruno,Sergeant, Marie-Helene,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
, p. 6434 - 6438 (2007)
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.
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
Jiang, Kezhi,Bian, Gaofeng,Hu, Nan,Pan, Yuanjiang,Lai, Guoqiao
, p. 17 - 23 (2010)
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.
Nickel(II) and palladium(II) chelates of dehydroacetic acid Schiff bases derived from thiosemicarbazide and hydrazinecarbodithioate
Kubaisi,Ismail
, p. 1785 - 1788 (1994)
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.
Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells
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.
, p. 585 - 7,594 (2018)
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.
Synthesis, crystal structure, and herbicidal activities of 2-cyanoacrylates containing 1,3,4-thiadiazole moieties
Wang, Tingting,Miao, Wenke,Wu, Shanshan,Bing, Guifang,Zhang, Xin,Qin, Zhenfang,Yu, Haibo,Qin, Xue,Fang, Jianxin
, p. 959 - 967 (2011)
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.
Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53
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.
, p. 2024 - 2045 (2021/02/16)
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.
Synthetic method 2 -methylsulfonyl -5 - trifluoromethyl -1 , 3, 4 - thiadiazole
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Paragraph 0011, (2021/10/20)
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.
PHARMACEUTICAL COMPOUNDS AND THERAPEUTIC METHODS
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Page/Page column 9-10, (2020/11/03)
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.
Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans
Franz, Katherine J.,Hunsaker, Elizabeth W.,McAuliffe, Katherine J.
, (2020/06/26)
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.]
