Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Quinazoline-4(3H)-one derivatives as novel and potent inhibitors of soluble epoxide hydrolase: Design, synthesis and biological evaluation Leila Hejazi, Elham Rezaee, Sayyed Abbas Tabatabai ⁎ Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran ARTICLE INFO Keywords: Soluble epoxide hydrolase Quinazoline-4(3H)-one Inhibitor Molecular modeling Biological study ABSTRACT Inhibition of soluble epoxide hydrolase (sEH) is considered as a promising target to reduce blood pressure, improve insulin sensitivity, and decrease infammation. In this study, a series of some novel quinazoline-4(3H)- one derivatives (3a-t) with varying steric and electronic properties was designed, synthesized and evaluated as sEH Inhibitors. Most of the synthesized compounds had similar inhibitory activity to the commercial reference inhibitor, 12-(3-adamantan-1-ylureido)dodecanoic acid, and amongst them, 4-chloro-N-(4-(4-oxo-3,4-dihy- droquinazoline-2-yl)phenyl)benzamide (3g) was identifed as the most active sEH inhibitor (IC 50 = 0.5 nM), about 2-fold more potent compared to the reference inhibitor. The results of molecular modeling followed by biological studies indicate that a quinazolinone ring serves as a suitable scafold to develop novel small molecule candidates to inhibit sEH and the nature of substituent on the amide moiety has a moderate efect on the activity. 1. Introduction The arachidonic acid (AA) cascade comprises of a group of meta- bolic pathways that produce endogenous bioactive lipid mediators, which regulate multiple biological processes such as infammation, hypertension, pain and etc. AA is metabolized by diferent oxygenases including cyclooxygenases, lipoxygenases, and cytochrome P450s. CYP epoxygenase enzymes (including CYP2C, 2 J) transform AA to the anti- infammatory epoxyeicosatrienoic acids (EETs) [1] which are anti-hy- pertensive and anti-infammatory endogens [2,3]. However, EETs are rapidly metabolized to a large extent by soluble epoxide hydrolase (sEH) to the corresponding dihydroxyeicosatrienoic acids (DHETs) with primarily pro-infammatory properties [4,5]. The degradation of EETs to DHETs can be blocked by sEH Inhibitors (sEHIs) that signifcantly increase EET concentrations in plasma and tissues to target hyperten- sion and infammation [6–8]. Stabilization of EETs and blockade of DHETs synthesis, are proposed as a therapeutic approach in several pathological disorders and could lead to novel therapies in various animal models of disease [9]. Thus, there is an increasing interest in the development and preclinical evaluation of novel sEHIs. Although several inhibitors of sEH have been identifed, no sEH inhibitor is available on the market to date. Besides, only a few in- hibitors have reached clinical trials among many candidate chemicals. 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA), AR9281 and GSK2256294 (Fig. 1) have proved their potential to inhibit sEH in a number of in vitro and in vivo studies. A small phase IIa clinical study examined the efect of the well-known sEH inhibitor AUDA; IC 50 = 3.2–100 nM [10], which is commonly used as experimental sEH reference inhibitor, on the vascular tone [11]. After a successful phase I clinical study [12], the sEH inhibitor AR9281; IC 50 = 7 nM failed in a phase IIa study due to lack of efcacy [13]. Two phase I clinical studies with GSK2256294, IC 50 = 27 pM [14] have recently been completed. Many of the sEHIs contain a urea group, such as AUDA and AR9281, or an amide function, such as GSK2256294 as a primary pharmacophore. Quinazolinone scafold had many pharmaceutical properties including antibacterial, cytotoxicity and anti-infammatory activities [15–18]. Based on the suggested pharmacophore models of sEHIs [13,19,20] and in continuance of our previous studies on various heterocyclic com- pounds with sEH inhibitory activity [21,22], some novel quinazoline- 4(3H)-one derivatives were designed and synthesized (Scheme 1, compounds 3a-t) as potent sEHIs. In this series of compounds, the amide group as a primary pharmacophore is placed along a line with a distance of 7 Å in regard to the quinazolinone ring as a secondary pharmacophore (Fig. 2) which is completely compatible with the pro- posed model of Merck scientists for sEH inhibitors [13]. Quinazolinone ring involves crucial structural features to interact with the active site of sEH via hydrogen and hydrophobic bonds and also improves physical properties of amide based sEHIs. In addition, the quinazoline nucleus is used as a basic framework in a number of biologically active com- pounds and FDA approved drug molecules [23]. Therefore, in the https://doi.org/10.1016/j.bioorg.2020.103736 Received 5 October 2019; Received in revised form 3 February 2020; Accepted 7 March 2020 ⁎ Corresponding author. E-mail address: sa_tabatabai@sbmu.ac.ir (S.A. Tabatabai). Bioorganic Chemistry 99 (2020) 103736 Available online 20 March 2020 0045-2068/ © 2020 Elsevier Inc. All rights reserved. T