Design,synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAFV600E inhibitors |
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| Affiliation: | 1. Department of Pharmacy, Faculty of Chemistry, National University of Mexico, Mexico, D.F., Mexico;2. Institute of Chemistry, National University of Mexico, Mexico, D.F., Mexico;3. Department of Biological Systems and Agricultural and Animal Production, Metropolitan University-Xochimilco, Mexico, D.F., Mexico;4. Department of Pathology, General Hospital, Mexico, D.F., Mexico;1. Medicinal Chemistry and Pharmacology, Hyderabad 500007, India;2. Centre for Chemical Biology, CSIR—Indian Institute of Chemical Technology, Hyderabad 500007, India;1. Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad de México 04510, México;2. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, México;3. Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México 06720, México;4. Instituto Nacional de Enfermedades Respiratorias, Ciudad de México 14080, México;5. Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla Estado de México 54090, México;1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;2. School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China;3. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China;2. Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China |
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| Abstract: | A series of novel 5-phenyl-1H-pyrazole derivatives (5a–5u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAFV600E inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 μM for BRAFV600E. Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAFV600E active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives. |
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| Keywords: | Pyrazole Niacinamide Molecular docking 3D-QSAR |
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