Chikhale, Rupesh ORCID: https://orcid.org/0000-0001-5622-3981
(2018)
Design, synthesis and anticancer studies of novel aminobenzazolyl pyrimidines as tyrosine kinase inhibitors.
Bioorganic Chemistry, 77.
pp. 84-100.
ISSN 0045-2068
Abstract
Abnormal signalling from the Protein tyrosine kinases (PTKs) like receptor tyrosine kinases and intracellular tyrosine kinases can lead to diseases such as cancer especially non-small cell lung cancer, chronic myeloid leukaemia and gastrointestinal stromal tumours. Various Protein tyrosine kinase inhibitors are available but face poor bioavailability, severe toxicities and recent cases of drug-resistant cancers prompts for development of better drug molecules. In this study we report the design and development of a novel Protein Tyrosine Kinase (PTK) inhibitor on the basis of pharmacophore modelling. Compound 2-(benzo[d]oxazol-2-ylamino)-N-(2-chloro-4-fluorophenyl)-4-methyl-6-(3-nitrophenyl) pyrimidine-5-carboxamide 31 was obtained containing essential pharmacophore structural features. This compound exhibited highest activity against leukaemia cell line (RPMI-8226) at 0.7244 µM, renal cancer cell line (A498) at 0.8511 µM and prostate cancer cell line (PC-3) at 0.7932 µM on the NCI five dose assay test. The PTK assay provides promising activity at IC50 of 0.07 µM in the human breast cancer cell line MDA-MB-468. Compound 31 had good intermolecular interaction with PTK in the molecular docking studies, this ligand-enzyme complex was found to stable in the MM-PBSA study over 100 ns. It had 54.22% oral bioavailability with Tmax of 0.60 h which is higher compared to the dasatinib with bioavailability and Tmax of 14–34% and 1–1.42 h respectively. Anticancer action of 31 was found to be impressive in pharmacokinetic studies making it a potential lead molecule.
Item Type: | Article |
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Uncontrolled Keywords: | sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
Faculty \ School: | Faculty of Science > School of Pharmacy |
Related URLs: | |
Depositing User: | LivePure Connector |
Date Deposited: | 17 Aug 2020 23:54 |
Last Modified: | 22 Oct 2022 06:25 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/76461 |
DOI: | 10.1016/j.bioorg.2018.01.008 |
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