Mohamed A Abdelgawad,1 Arafa Musa,2 Atiah H Almalki,3,4 Sami I Alzarea,5 Ehab M Mostafa,2 Mostafa M Hegazy,6 Gomaa Mostafa-Hedeab,7 Mohammed M Ghoneim,6,8 Della GT Parambi,1 Rania B Bakr,1 Nayef S Al-Muaikel,9 Abdullah S Alanazi,10,11 Metab Alharbi,12 Waqas Ahmad,13 Syed NA Bukhari,1 Mohammad M Al-Sanea1 1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 2Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia; 3Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 4Addiction and Neuroscience Research Unit, Taif University, Taif, 21944, Saudi Arabia; 5Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 6Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo, 11371, Egypt; 7Department of Pharmacology, Medical College, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 8Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia; 9Department of Chemistry, College of Science, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 10Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia; 11Health Sciences Research Unit, Jouf University, Sakaka, Aljouf, Saudi Arabia; 12Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 13Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Mohamed A AbdelgawadDepartment of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Kingdom of Saudi ArabiaTel +966 595435214Email mohamedabdelwahab976@yahoo.comArafa MusaDepartment of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Kingdom of Saudi ArabiaTel +966 558775403Email akmusa@ju.edu.saIntroduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.Methods: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 μM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 μM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 μM and 2.8 μM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.Keywords: kinase inhibitors, anti-inflammatory, multitarget agents, BRAF, anticancer