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Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Process for the preparation of zonisamide

The present invention provides an improved process for the preparation of zonisamide or a derivative thereof comprising (a) reacting 1,2-benzisoxazole-3-methane-sulfonic acid with a halogenating agent in a first organic solvent to provide benzisoxazole methane sulfonyl halide; and, (b) reacting benzisoxazole methane sulfonyl halide with an amine in a second organic solvent to form zonisamide or a derivative thereof.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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METHODS FOR HAIR FOLLICLE STEM CELL PROLIFERATION

The present invention relates to compositions of Sonic Hedgehog (Shh) pathway activators and Wnt agonists and methods of using them to induce self-renewal of hair follicle stem cells, including inducing the hair follicle stem cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into hair follicle epithelial cells.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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1,2-Benzisoxazole-3-acetamide derivatives as dual agents for DPP-IV inhibition and anticancer activity

Herein, we have designed various benzisoxazole acetamide derivatives with and without glycine spacer as DPP-IV inhibitors. Compounds 9a?d and 11a?e were synthesized and screened for their in vitro DPP-IV inhibition. Compounds 11a and 11c showed moderate activity for DPP-IV inhibition, whereas other remained inactive at 25?200 muM concentrations. DPP-IV inhibition can be a good strategy for modulating diabetes and cancer; hence, we have screened compounds 9a?d and 11a?e for their anticancer activity using MTT assay against A549 and MCF7 cell lines. Compounds 9a?d without glycine spacer have shown good anticancer activity compared to compounds 11a?e with glycine spacer. Compound 9b has shown moderate activity with IC50 values 4.72 ¡À 0.72 and 4.39 ¡À 0.809 muM against A549 and MCF7 cell lines, respectively. Interestingly, compound 9c with cyano group has shown very good anticancer activity with IC50 2.36 ¡À 0.34 muM against MCF7 cell line as compared to fluorouracil with IC50 45.04 ¡À 1.02 muM.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Synthesis and antimicrobial studies of novel methylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazole derivatives

Novel methylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazoles (3a-f) were synthesized from benzisoxazolyl-3-acetic acid and thiosemicarbazide. Reaction of 3 with bromine in glacial acetic acid in the presence of anhydrous sodium acetate yielded the corresponding 5-bromo derivatives (4a-f). While compound 3 furnished the 5-nitroso derivatives (5a-f) on refluxing with sodium nitrite solution. Thiocyanato derivatives (6a-f) were obtained by treating the imidazothiadiazole 3 with bromine and potassium thiocyanate in glacial acetic acid at room temperature. The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analysis. All the compounds were screened for their antibacterial and antifungal activities. Some of the compounds displayed very good antibacterial and antifungal activity.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Conventional & non conventional synthesis of biologically active novel pyrimidine and its moleculer descriptor study

3-Formylchromones 1 when treated with 2-(benzo[cf]isoxazol-3-yl) acetic acid 2 under microwave irradiation afforded 3-((E)-2-benzo[c/] isoxazol-3-yl) vinyl)-4H-chromen- 4-ones (3). Compounds 3 on treatment with thiourea gave the compound 5-(2- (benzo[d]isoxazol-3-yl) vinyl)-4(-2-hydroxypenyl) pyrimidine-2(1H)- Thiones 4. Compounds 3 on treatment with guanidine gave the compound 2-(5-(2- (benzol[dJisoxazol-3-yl)vinyl)-l,2-dihydro-2-iminopyrimidin-4- yl) phenols 5. Moleculer descriptor properties were analyzed by using simple moleculer descriptor used by “Lipinski’s rule of 5”. The structures of compounds were established on the basis of spectral data. Synthesized compounds were screened for their antimicrobial activities.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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IDO inhibitors

Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunosuppression associated with an infectious disease, e.g., HIV-I infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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1H-PYRROLE-2,5-DIONE COMPOUNDS AND METHODS OF USING THEM TO INDUCE SELF-RENEWAL OF STEM/PROGENITOR SUPPORTING CELLS

The present invention relates to 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells, including inducing the stem/progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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AUXIN-LIKE ACTIVITY OF 1,2-BENZISOXAZOLE-3-ALKANOIC ACIDS

A series of benzisoxazole-alkanoic acids, differing in the length of the side-chain, have been synthesized and their activity tested on pea stem elongation, flax root growth and shoot regeneration from tomato cotyledon explants.All compounds had little or no effect on cell elongation or root growth, but a stimulating effect on shoot induction in vitro, thus showing that their activity, like that of 1,2-benzisoxazole acetic acid. is partly independent of the side-chain and is linked to the structure of the benzisoxazole ring. – Key words: 1,2-Benzisoxazole-3-alkanoic acids; auxin-like activity; pea stem elongation; flax root growth; in vitro shoot generation.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics