El-Sayed N.A.Nour M.S.Salem M.A.Arafa R.K.Department of Pharmaceutical ChemistryFaculty of PharmacyCairo UniversityKasr El-Aini StreetCairo11562Egypt; Department of Pharmaceutical ChemistryFaculty of PharmacyOctober University of Modern Sciences and Arts (MSA)6thof October CityGizaEgypt; Biomedical Sciences ProgramZewail City of Science and TechnologyUniversity of Science and TechnologyOctober Gardens6thof October CityGiza12578Egypt; Drug Design and Discovery LaboratoryHelmy Institute of Science and TechnologyZewail City of Science and TechnologyCairo12578Egypt2020-01-092020-01-0920192235234https://doi.org/10.1016/j.ejmech.2019.111693PubMed ID 31539778https://t.ly/JXvBlScopusNovel 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 SASEnglishAnticancerCyclooxygenasesEGFRIn silico ADMEMolecular dockingMolecular dynamicsOxadiazolesantineoplastic agentcelecoxibcyclooxygenase 1cyclooxygenase 2cyclooxygenase 2 inhibitorcytotoxic agentdiclofenacdoxorubicinepidermal growth factor receptor kinase inhibitorerlotinibindometacinoxadiazole derivativeantineoplastic agentcyclooxygenase 2cyclooxygenase 2 inhibitorEGFR protein, humanepidermal growth factor receptoroxadiazole derivativeprotein kinase inhibitorantineoplastic activityArticlecomputer modelcontrolled studydrug cytotoxicitydrug designdrug potencydrug screeningdrug synthesisenzyme inhibitionin vitro studymalignant neoplasmmolecular dockingmolecular dynamicsMTT assayUO-31 cell linecell proliferationcell survivalchemical structurechemistrydose responsedrug designdrug effecthumanmetabolismmolecular modelstructure activity relationsynthesistumor cell cultureAntineoplastic AgentsCell ProliferationCell SurvivalCyclooxygenase 2Cyclooxygenase 2 InhibitorsDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorErbB ReceptorsHumansModels, MolecularMolecular StructureOxadiazolesProtein Kinase InhibitorsStructure-Activity RelationshipTumor Cells, CulturedArticlehttps://doi.org/10.1016/j.ejmech.2019.111693PubMed ID 31539778