Design, synthesis and anticancer studies of novel aminobenzazolyl pyrimidines as tyrosine kinase inhibitors

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

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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
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:	https://www.sciencedirect.com/science/ar...
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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