Full Paper Design, Synthesis, and Cytotoxic Evaluation of Certain 7-Chloro-4- (piperazin-1-yl)quinoline Derivatives as VEGFR-II Inhibitors Mohamed Nabil Aboul-Enein 1 , Aida M. Abd El-Sattar El-Azzouny 1 , Fatma Abdel-Fattah Ragab 2 , and Mohamed Farouk Hamissa 1 1 Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza, Egypt 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt Signaling pathway inhibition of VEGFR-II is visualized as valuable tool in cancer management. In the current study, the synthesis of novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)- ethanone derivatives (4a–t) was achieved through the amination of 2-chloro-1-(4-(7-chloroquinolin-4- yl)piperazin-1-yl)ethanone (3) with different secondary amines. The structures of the target compounds were confirmed by IR, 1 H-NMR, 13 C-NMR, HRMS, and microanalysis. Compounds 4a–t were subjected to in vitro anticancer screening against human breast cancer (MCF-7) and prostate cancer (PC3) cell lines. The highest cytotoxicty against both cell lines was displayed by 2-(4-(4- bromobenzyl)piperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q), with IC 50 values of 6.502 and 11.751 mM against MCF-7 and PC3 cells, respectively, compared with the standard drug doxorubicin (MCF-7: 6.774 mM, PC3: 7.7316 mM). Due to its notable activity toward MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC 50 of 1.38 mM compared to sorafenib (0.33 mM). The docking study proved that 4q has a binding mode akin to that of VEGFR-II inhibitors. Keywords: Chloro-4-(piperazin-1-yl)quinolines / Cytotoxic evaluation / Human breast cancer cell line (MCF-7) / Human prostate cancer cell line (PC3) / VEGFR-II Received: December 13, 2016; Revised: February 19, 2017; Accepted: February 22, 2017 DOI 10.1002/ardp.201600377 : Additional supporting information may be found in the online version of this article at the publisher’s web-site. Introduction Cancer is one of the major causes of fatality worldwide. It is a cluster of diseases characterized by uninhibited enlarge- ment. The rising frequency of drug tolerance to anticancer chemotherapy constitutes a serious medical problem [1]. Thus, there is an importunate demand to discover and develop novel chemotherapeutic anticancer agents [2]. The angiogenesis has a critical function in cancer cell survival through tumor cell growth [3, 4]. Consequently, the growth factors including: vascular endothelial growth factor (VEGF) [5], epidermal growth factor (EGF) [6], platelet- derived growth factor (PDGF) [7], and basic fibroblast growth factor (bFGF) [8] play an important role in the regulation of angiogenesis. However, the VEGF is considered as the most crucial factor compared to the other growth factors in the angiogenesis process [9]. The family of VEGF consists of six members namely, VEGF-A, B, C, D, E, and placenta growth factor. They bind to VEGF receptors: VEGFR- I, VEGFR-II, and VEGFR-III, which lead to the proliferation and survival of the endothelial cells and consequently tumor formation [10]. Among VEGFRs, the VEGFR-II is the most significant mediating receptor of all the cellular responses to Correspondence: Prof. Mohamed Nabil Aboul-Enein, Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 12622 Dokki, Giza, Egypt. E-mail: mnaboulenein@yahoo.com Fax: þ20-237601877 Arch. Pharm. Chem. Life Sci. 2017, 350, e1600377 Archiv der Pharmazie ARCH RCH P HARM HARM ß 2017 Deutsche Pharmazeutische Gesellschaft www.archpharm.com (1 of 12) e1600377