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Various substituted thiazolidin-2-ones were synthesized from the corresponding thiazolidine-2-thiones with bromoethanol in ethanol with sodium ethoxide as a base. The optimal reaction conditions and mechanism were reinvestigated in detail. The bioassay indicated that (S)-4-isobutyl and (S)-4-benzylthiazolidin-2-ones show certain inhibitive activities against Candida albicans and Escherichia coli. Supplemental materials are available for this article. Go to the publisher’s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

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This invention relates to novel compounds of the Formula Ik, Im1, Im2, Im5, In1, In2, In5, Io1, Io2, Io5, Ip1, Ip3, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11beta-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

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The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: where A, B, W1, W2, W3, and R1-R6 are described herein.

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Selected rhodanine-3-carboxylic acids derivatives were synthesized to determine the influence of the structure and the length of the linker between the carboxyl group and the nitrogen atom (N-3) in the 2-thioxo-4-thiazolidinone ring on their activity, monitored via interactions with human serum albumin. Based on fluorescence studies, we concluded that the length of the linker has a limited impact on these interactions. Additionally, we proposed the static mechanism of quenching for all the tested compounds. These derivatives seem to possess an anticancer activity in the nanomolar range with 3 as the most potent compound in both A2780 and A2780cisR cell lines.

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The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy-based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12±0.12) muM. These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 muM. Some of these compounds also showed good activity against dormant Mtb cells. Let sleeping cells lie: Mycobacterium tuberculosis pantothenate synthetase (Mtb PS) has become a target for new therapeutics to treat tuberculosis. Nanomolar thiazolidine inhibitors of Mtb PS were developed by rational inhibitor design involving modelling, in vitro screening and optimisation. Hit expansion of the lead by synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb MIC value of 1.55 muM. Some of these compounds also showed good activity against dormant Mtb cells.

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Described herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula (I) or (I’) structure : or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula (I) or (I’) compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

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Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.

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A fungicidal method which comprises applying to the locus of a plant pathogen a fungicidally effective but non-phytotoxic amount of a compound of the formula (1) STR1 wherein: R1 to R4 are independently H, halo, (C1 -C4) alkyl, branched (C3 -C4) alkyl, halo (C1 -C4) alkyl, (C1 -C4) alkoxy, NO2, or HN2, at least two of R1 to R4 being H, or one of R2 to R4 is –NR7 –Y–Ar or O–Y–Ar and the rest of R1 to R4 are H; W is N, or CR5 ; R5 is H, CH3, Cl, O–Y–Ar, or –NR7 –Y–Ar; R6 is H, CH3, Cl, or Br; A is –O–Alk or –X–Y–Ar; Alk is a C2 -C18 saturated or unsaturated hydrocarbon chain, straight chain or branched, optionally substituted with halo, halo (C1 -C4) alkoxy, (C3 -C8) cycloalkyl, hydroxy, or acetyl; X is O, NR7, or CR8 R9, provided that if one of R2 to R5 is NR7 –Y–Ar or O–Y–Ar, then X–Y–Ar is an identical group; R7 is H, (C1 -C4) alkyl, or acetyl; R8 and R9 are independently H, (C1 -C4) alkyl, halo, or OH, or R8 and R9 combine to form a saturated or unsaturated carbocyclic ring comprising three to seven carbon atoms; Y is an alkylene chain 2 to 8 carbon atoms long that optionally includes an O, S, SO, SO2, or NR7 group, and optionally includes a saturated or unsaturated carbocyclic ring comprising three to seven carbon atoms, and optionally is substituted with (C1 -C3) alkyl, (C1 -C4) alkenyl, phenyl, (C3 -C8) cycloalkyl, hydroxy, halo, or acetyl; and Ar is an aryl group.

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Critically ill patients in the intensive care unit (ICU) present with a variety of different pathologies, and mortality is high despite extensive multi-organ supportive treatment. Reactive oxygen species (ROS) are believed to play a pivotal role in the pathophysiology of organ dysfunction in the ICU. In particular, the role of ROS as a final common pathway of cell damage has been increasingly emphasised in the adult respiratory distress syndrome (ARDS), in central nervous system traumatic and hypoxic states, and as a cause of ischaemic neurological deficits after subarachnoid haemorrhage. Measurement of total antioxidant status (TAS) has shown improved survival of patients with high TAS and poorer outcomes for those with lower values. Attempts to supplement endogenous antioxidant defences have not demonstrated clear benefits in randomised clinical trials, and the use of free radical scavenging agents have had similar mixed results. Considering the wide variation in the nature and severity of illness in the intensive care population, it is not surprising that clear evidence of the efficacy of antioxidant therapies in improving survival has not been clearly demonstrated. However, single component therapies for complex pathophysiological processes are rarely successful, and the role of antioxidants in the critically ill should be thought of as only part of a rational and logical therapeutic approach.

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A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol-substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues. This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.

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