- Synthesis of some novel N5-sulfonylated and N1-alkyated pyrazole derivatives and their antimicrobial activity in conjunction with molecular docking study
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Some novel N5-sulfonylated 4 were synthesized via sulfonylation of 5-amino-1H-pyrazole derivative 1 with arylsulfonyl chlorides. On the other hand, N1-alkylated pyrazoles 7 and 10 were synthesized through alkylation of compound 1 with each of chloroacetamides and ethylchloroacetate under different conditions. Condensation of compounds 4 and 7 with different aromatic aldehydes furnished the corresponding arylidene derivatives. In spite of, condensation of 10 with aromatic aldehydes afforded the 2-(5-amino-2-aryl-1H-pyrazol-1-yl)acetic acid. The structure of the newly synthesized compounds was elucidated by elemental analyses and spectral data. Also, the suggested mechanisms for their formation were studied. Additionally, some selected new compounds were screened against antimicrobial activity. Compound 7c exhibited a higher activity against Candida albicans (inhibition zone diameter [IZD] = 31.3 ± 0.6 mm) than the standard antibiotic Nystatin (IZD = 21 ± 0.5 mm). Also, compound 7c showed minimum inhibitory concentration = 125 and 250 μg/mL against Klebsiella pneumonia and Staphylococcus aureus, respectively. Molecular docking study also was carried out for compound 7c.
- Metwally, Nadia H.,Mohamed, Mona S.,Ragab, Eman A.
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- Reaction of 5-Amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with Hydroxycyclohexanones
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The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-5-hydroxy-5- methyl-2,4-di(ethoxycarbonyl)cyclohexanones in acetic acid furnished previously unknown 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazoline derivatives.
- Semenova,Oganesyan,Dotsenko,Chigorina,Aksenov,Aksenova,Netrebae
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- Design, synthesis, anticancer evaluation, molecular docking and cell cycle analysis of 3-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine derivatives as potent histone lysine demethylases (KDM) inhibitors and apoptosis inducers
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A novel series of pyrazolo[1,5-a]pyrimidines were synthesized and proved by their spectral and elemental analysis, some elected of the newly synthesized compounds were examined for their cytotoxic activity employing MTT assay on two cancer cell lines (Breast and Hela cancers). Compounds 5, 7e and 7i showed the higher cytotoxicity against two cancer cell lines with (IC50 = 13.91 ± 1.4 and 22.37 ± 1.8 μM/L), (IC50 = 6.56 ± 0.5 and 8.72 ± 0.9 μM/L) and (IC50 = 4.17 ± 0.2 and 5.57 ± 0.4 μM/L) for two cancer cell lines breast and hela respectively, using doxorubicin as a reference drug. The most potent cytotoxic active compounds 5, 7e and 7i presented inhibitory activity against KDM (histone lysine demethylases) with IC50 = 4.05, 1.91 and 2.31 μM, respectively. The most potent KDM inhibitor 7e (IC50 = 1.91 μM) showed to cause cell cycle arrest at G2/M phase by 4 folds than control and induce total apoptotic effect by 10 folds more than control. In silico studies performed on the more potent cytotoxic active compounds 5, 7e and 7i included lipinisk's rule of five. Moreover, molecular docking study was utilized to explore the binding mode of the most active compounds to the target enzyme (PDB-ID: 5IVE). Also, some bioinformatics studies were carried out for compounds 7e and 7i using Swiss ADME (Swiss Institute of bioinformatics 2018).
- Metwally, Nadia Hanafy,Mohamed, Mona Said,Ragb, Eman Ali
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- Synthesis of some novel pyrazolo[1,5-a]quinazolines and their fused derivatives
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New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid. Condensation of compounds 4a,b with various aromatic aldehydes furnished the corresponding arylidene derivatives 6a–j. On the other hand, condensation of 4a,b with o-hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a–h. Coupling of compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono derivatives 12a–h. Also, reaction of compounds 4a,b with phenyl isothiocyanate, followed by addition of ethyl chloroacetate and chloroacetonitrile, afforded the polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of hydrazine hydrate and guanidine hydrochloride afforded pyrazolo[4″,3″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and pyrimido[5″,4″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b, respectively. The structures of all the newly synthesized compounds were elucidated by elemental analyses and spectral data. The plausible mechanisms have been postulated to account for their formation.
- Ragab, Eman Ali,Metwally, Nadia Hanafy,Mohamed, Mona Said
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- Pyrazolo-oxo-diaza compound as BTK inhibitor
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The invention provides a pyrazolo-oxo-diaza compound with a remarkable inhibition effect on Bruton's tyrosine protein kinase (BTK) or a hydrate, a solvate, a prodrug, a stereoisomer or a tautomer of pharmaceutically acceptable salt of the pyrazolo-oxo-diaza compound. The invention also provides a process for preparing the compound of the invention and an intermediate compound which can be used inthe process. The compound provided by the invention can be used for preparing medicines for treating diseases related to disorder or imbalance of activity of Bruton's tyrosine kinase (BTK).
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Paragraph 0117-0120
(2021/03/24)
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- Pyrazolo [1, 2] diaza compound
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The invention provides a pyrazolo [1, 2] diaza compound as well as a preparation method and application thereof. The compound provided by the invention has a remarkable selective BTK kinase inhibition effect, effectively improves the off-target effect phenomenon of the existing BTK inhibitor, and can improve the drug targeting property, so that the toxic and side effects are reduced.
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Paragraph 0032; 0115-0116
(2021/07/21)
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- Synthesis, anticancer evaluation, CDK2 inhibition, and apoptotic activity assessment with molecular docking modeling of new class of pyrazolo[1,5-a]pyrimidines
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2-Cyanopyrazolo[1,5-a]pyrimidine derivative 3 reacted with some aromatic aldehydes, arenediazonium salts, hydrazine hydrate, and guanidine hydrochloride to create a series of novel pyrazolo[1,5-a]pyrimidine derivatives. Spectroscopic data confirmed the structure of the newly synthesized compounds. Some target compounds were tested in vitro for anticancer efficacy against three cancer cell lines: HepG-2, MCF-7, and Hela. On the most efficient anticancer compounds 6b,c, 6f, and 6h,i, the CDK-2 enzyme was evaluated. Using the HepG-2 cancer cell line, compounds 6b and 6i demonstrated the most effective inhibitory activity against CDK-2, with IC50 values of 0.199 ± 0.005?μg/ml and IC50 = 0.206 ± 0.007?μg/ml, respectively, compared to Dinaciclib and Roscovitine, which had IC50 values of 0.021 ± 0.002 and 0.230 ± 0.007?μg/ml, respectively. In cell cycle assay, compounds 6b, 6f and 6i arrest cell cycle at G2/M, G1/S and G2/M phases, respectively. Compound 6f has a stronger apoptosis induction effect (27.82%) than compounds 6b (7.92%) and 6i (19.21%). Also, silico studies (Molecular docking and Lipinski’s rules) for compounds 6b, 6f and 6i were carried out. Graphic abstract: [Figure not available: see fulltext.]
- Metwally, Nadia Hanafy,Mohamed, Mona Said,Deeb, Emad Abdullah
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p. 5027 - 5060
(2021/08/31)
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- Novel quinazoline-containing compound, and intermediate and application thereof
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The present invention discloses a quinazoline-containing compound having the formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt or a prodrug molecule thereof. The compound is suitable for use as an Aurora kinase inhibitor and is thus suitable for the treatment of Aurora-mediated diseases characterized by excessive or abnormal cell proliferation, for example, cancer.
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Paragraph 0142; 0144; 0146
(2021/06/12)
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- As inhibitors of Aurora kinases substituted pyrimidine derivatives
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The present invention relates to a substituted and aurora kinase-inhibiting pyrimidine derivative as represented by formula (I) or (Ia), tautomer, hydrate, solvate, ester or pharmaceutically acceptable salt thereof, and pharmaceutical composition comprising the compounds as active ingredients, as well as uses of the compounds and the pharmaceutical composition thereof in the preparation of drugs for protecting against, treating, curing or alleviating proliferative diseases of a patient.
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Paragraph 0365-0369
(2016/10/09)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention comprises inter alia compounds as shown in formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 124
(2010/12/29)
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- AURORA KINASE INHIBITORS
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Disclosed herein are Aurora kinase Inhibitors represented by Structural Formula (I): Values for the variables in Structural Formula (I) are defined herein.
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Page/Page column 49-50
(2009/10/22)
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- PHOSPHONOOXY QUINAZOLINE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a nitrogen atom and one or two further nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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