Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers Hazem A. Mahdy a , Mohammed K. Ibrahim a , Ahmed M. Metwaly b , Amany Belal c,d , Ahmed B.M. Mehany e , Kamal M.A. El-Gamal f , Abdou El-Sharkawy g,h, ⁎ , Mostafa A. Elhendawy i,j , Mohamed M. Radwan i,k , Mahmoud A. Elsohly i,l, ⁎ , Ibrahim H. Eissa a, ⁎ a Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt b Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt c Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt d Pharmaceutical Chemistry Department, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia e Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt f Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt g Department of Anatomy, Faculty of Medicine, Al-Azhar University, Cairo, Egypt h Department of Anatomy, College of Medicine, Jouf University, Saudi Arabia i National Center for Natural Products Research, University of Mississippi, MS 38677, USA j Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt k Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt l Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA ARTICLEINFO Keywords: Anticancer Apoptosis Molecular docking Quinazolin-4(3H)-one VEGFR-2 In vivo studies ABSTRACT Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quina- zoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti- proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26 b , 29 a , 29 b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC 50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC 50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed signifcant tumor growth inhibition efect. Molecular docking studies were also performed and fnally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities. 1. Introduction Cancer is a major cause of mortality all over the world, it approxi- mately causes 13% of all deaths, annually [1]. According to WHO fact sheet published on September 2018, there are 9.6 million deaths oc- curred worldwide. Globally, about 1 in 6 deaths is due to cancer [2]. The most common causes of cancer death are cancers of lung (1.76 million deaths), colorectal (862 000 deaths), stomach (783 000 deaths), liver (782 000 deaths), and breast (627 000 deaths) [2]. It was pre- dicted that global cancer incidence would reach 22 million cases per year by 2030 [3]. The acquired chemotherapeutic resistance of dif- ferent cancer types was increased noticeably in the past few years. [4]. In addition, the poor selectivity of chemotherapeutics causes cytotoxi- city for dividing cells leading to serious side efects, such as im- munosuppression, anemia, diarrhea, nausea, and alopecia [5]. These factors necessitate the discovery of new more active, and more selective https://doi.org/10.1016/j.bioorg.2019.103422 Received 10 July 2019; Received in revised form 3 October 2019; Accepted 3 November 2019 ⁎ Corresponding authors at: Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt (I.H. Eissa). Department of Anatomy, Faculty of Medicine, Al-Azhar University, Cairo, Egypt (A. El-Sharkawy). National Center for Natural Products Research, University of Mississippi, MS 38677, USA (M.A. Elsohly). E-mail addresses: abdouelsharkawy@gmail.com (A. El-Sharkawy), melsohly@olemiss.edu (M.A. Elsohly), Ibrahimeissa@azhar.edu.eg (I.H. Eissa). Bioorganic Chemistry 94 (2020) 103422 Available online 12 November 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved. T