Bioorganic Chemistry 134 (2023) 106444 Available online 25 February 2023 0045-2068/© 2023 Elsevier Inc. All rights reserved. Design, synthesis, cytotoxic activities, and molecular docking of chalcone hybrids bearing 8-hydroxyquinoline moiety with dual tubulin/EGFR kinase inhibition Mohammed M. Amin a , Gamal El-Din A. Abuo-Rahma b, c, * , Montaser Sh. A. Shaykoon a , Adel A. Marzouk a, d , Mohammed A.S. Abourehab e , Roshdy E. Saraya f , Mohamed Badr g , Ahmed M. Sayed h , Eman A.M. Beshr b, * a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt b Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia 61519, Egypt d National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA e Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia f Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42515, Egypt g Department of Biochemistry, Faculty of Pharmacy, Menoufa University, Menoufa, Egypt h Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, 62513 Beni-Suef, Egypt A R T I C L E INFO Keywords: 8-Hydroxyquinoline Chalcone Antiproliferative Tubulin Polymerization inhibition EGFR kinase inhibitors Dual acting antiproliferative ABSTRACT The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids 3a–m of hopeful anticancer activity. According to NCI screening and MTT assay results, compounds 3d- 3f, 3i, 3k, and 3l displayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these com- pounds, 3e and 3f showed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that 3e, 3d, and 3i had good tubulin polymerization inhibition (IC 50 = 5.3, 8.6, and 8.05 µM, respectively) compared to the reference Combretastatin A4 (IC 50 = 2.15 µM). Moreover, 3e, 3l, and 3f exhibited EGFR inhibition (IC 50 = 0.097, 0.154, and 0.334 µM, respectively) compared to Erlotinib (IC 50 = 0.056 µM). Compounds 3e and 3f were investigated for their effects on the cell cycle, apoptosis induction, and wnt1/β-catenin gene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and β-actin were detected by Western blot. In-silico molecular docking, physicochemical, and pharmacokinetic studies were implemented for the validation of dual mechanisms and other bioavailability standards. Hence, Compounds 3e and 3f are promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition. 1. Introduction World health organization (WHO) statistics reported approximately ten million deaths, or about one in six deaths, related to cancers in 2020, making it the highest cause of death worldwide. Breast, colon, rectum, lung, and prostate cancers are the top widespread kinds of cancer [1]. About 43 % of all malignancies diagnosed in males in 2020 are colo- rectal, lung, and prostate cancers. Breast, lung, and colorectal are the three predominant malignancies in women, and in 2020, they account for 50 % of newly diagnosed cancers in female patients [2]. Multi-drug resistance and some dangerous side-effects acquired by the human body to usual anticancer drugs are challenging a critical requirement for the promotion of novel and well-effective molecules with improved activity approaches and good toxicological profles [3]. 8-Hydroxyquinoline (8HQ) is a well-established heterocyclic scaffold that was incorporated in several clinically used chemotherapeutics. For example, the anticancer, antimalarial, antifungal, and antiprotozoal compound Clioquinol (I); and the antibacterial and anticancer com- pound Nitroxoline (II). Due to the drawbacks of the former compounds as toxicity, lower selectivity, and developed resistance, there is a vital need to introduce new entities to overcome the reported disadvantages. Several strategies, including molecular functionalization, structural * Corresponding authors at: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt (G.A.). E-mail addresses: gamal.aborahama@mu.edu.eg (G.E.-D.A. Abuo-Rahma), eman_beshr@mu.edu.eg (E.A.M. Beshr). Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg https://doi.org/10.1016/j.bioorg.2023.106444 Received 13 November 2022; Received in revised form 18 February 2023; Accepted 21 February 2023