New oxadiazoles with selective-COX-2 and EGFR dual inhibitory activity: Design, synthesis, cytotoxicity evaluation and in silico studies

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dc.AffiliationOctober University for modern sciences and Arts (MSA)
dc.contributor.authorEl-Sayed N.A.
dc.contributor.authorNour M.S.
dc.contributor.authorSalem M.A.
dc.contributor.authorArafa R.K.
dc.contributor.otherDepartment of Pharmaceutical Chemistry
dc.contributor.otherFaculty of Pharmacy
dc.contributor.otherCairo University
dc.contributor.otherKasr El-Aini Street
dc.contributor.otherCairo
dc.contributor.other11562
dc.contributor.otherEgypt; Department of Pharmaceutical Chemistry
dc.contributor.otherFaculty of Pharmacy
dc.contributor.otherOctober University of Modern Sciences and Arts (MSA)
dc.contributor.other6th
dc.contributor.otherof October City
dc.contributor.otherGiza
dc.contributor.otherEgypt; Biomedical Sciences Program
dc.contributor.otherZewail City of Science and Technology
dc.contributor.otherUniversity of Science and Technology
dc.contributor.otherOctober Gardens
dc.contributor.other6th
dc.contributor.otherof October City
dc.contributor.otherGiza
dc.contributor.other12578
dc.contributor.otherEgypt; Drug Design and Discovery Laboratory
dc.contributor.otherHelmy Institute of Science and Technology
dc.contributor.otherZewail City of Science and Technology
dc.contributor.otherCairo
dc.contributor.other12578
dc.contributor.otherEgypt
dc.date.accessioned2020-01-09T20:40:30Z
dc.date.available2020-01-09T20:40:30Z
dc.date.issued2019
dc.descriptionScopus
dc.description.abstractNovel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents. � 2019 Elsevier Masson SASen_US
dc.description.urihttps://www.scimagojr.com/journalsearch.php?q=17464&tip=sid&clean=0
dc.identifier.doihttps://doi.org/10.1016/j.ejmech.2019.111693
dc.identifier.doiPubMed ID 31539778
dc.identifier.issn2235234
dc.identifier.otherhttps://doi.org/10.1016/j.ejmech.2019.111693
dc.identifier.otherPubMed ID 31539778
dc.identifier.urihttps://t.ly/JXvBl
dc.language.isoEnglishen_US
dc.publisherElsevier Masson SASen_US
dc.relation.ispartofseriesEuropean Journal of Medicinal Chemistry
dc.relation.ispartofseries183
dc.subjectAnticanceren_US
dc.subjectCyclooxygenasesen_US
dc.subjectEGFRen_US
dc.subjectIn silico ADMEen_US
dc.subjectMolecular dockingen_US
dc.subjectMolecular dynamicsen_US
dc.subjectOxadiazolesen_US
dc.subjectantineoplastic agenten_US
dc.subjectcelecoxiben_US
dc.subjectcyclooxygenase 1en_US
dc.subjectcyclooxygenase 2en_US
dc.subjectcyclooxygenase 2 inhibitoren_US
dc.subjectcytotoxic agenten_US
dc.subjectdiclofenacen_US
dc.subjectdoxorubicinen_US
dc.subjectepidermal growth factor receptor kinase inhibitoren_US
dc.subjecterlotiniben_US
dc.subjectindometacinen_US
dc.subjectoxadiazole derivativeen_US
dc.subjectantineoplastic agenten_US
dc.subjectcyclooxygenase 2en_US
dc.subjectcyclooxygenase 2 inhibitoren_US
dc.subjectEGFR protein, humanen_US
dc.subjectepidermal growth factor receptoren_US
dc.subjectoxadiazole derivativeen_US
dc.subjectprotein kinase inhibitoren_US
dc.subjectantineoplastic activityen_US
dc.subjectArticleen_US
dc.subjectcomputer modelen_US
dc.subjectcontrolled studyen_US
dc.subjectdrug cytotoxicityen_US
dc.subjectdrug designen_US
dc.subjectdrug potencyen_US
dc.subjectdrug screeningen_US
dc.subjectdrug synthesisen_US
dc.subjectenzyme inhibitionen_US
dc.subjectin vitro studyen_US
dc.subjectmalignant neoplasmen_US
dc.subjectmolecular dockingen_US
dc.subjectmolecular dynamicsen_US
dc.subjectMTT assayen_US
dc.subjectUO-31 cell lineen_US
dc.subjectcell proliferationen_US
dc.subjectcell survivalen_US
dc.subjectchemical structureen_US
dc.subjectchemistryen_US
dc.subjectdose responseen_US
dc.subjectdrug designen_US
dc.subjectdrug effecten_US
dc.subjecthumanen_US
dc.subjectmetabolismen_US
dc.subjectmolecular modelen_US
dc.subjectstructure activity relationen_US
dc.subjectsynthesisen_US
dc.subjecttumor cell cultureen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectCell Proliferationen_US
dc.subjectCell Survivalen_US
dc.subjectCyclooxygenase 2en_US
dc.subjectCyclooxygenase 2 Inhibitorsen_US
dc.subjectDose-Response Relationship, Drugen_US
dc.subjectDrug Designen_US
dc.subjectDrug Screening Assays, Antitumoren_US
dc.subjectErbB Receptorsen_US
dc.subjectHumansen_US
dc.subjectModels, Molecularen_US
dc.subjectMolecular Structureen_US
dc.subjectOxadiazolesen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectTumor Cells, Cultureden_US
dc.titleNew oxadiazoles with selective-COX-2 and EGFR dual inhibitory activity: Design, synthesis, cytotoxicity evaluation and in silico studiesen_US
dc.typeArticleen_US
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