key: cord-322354-x61eqaca
authors: Young Lee, Jun; Sup Shin, Young; Lee, Jihye; Kwon, Sunoh; Jin, Young-hee; Seong Jang, Min; Kim, Seungtaek; Hwan Song, Jong; Rae Kim, Hyoung; Min Park, Chul
title: Identification of 4-Anilino-6-aminoquinazoline Derivatives as Potential MERS-CoV Inhibitors
date: 2020-08-08
journal: Bioorg Med Chem Lett
DOI: 10.1016/j.bmcl.2020.127472
sha: 
doc_id: 322354
cord_uid: x61eqaca

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N(4)-(3-Chloro-4-fluorophenyl)-N(6)-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC(50) = 0.157 μM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.

severe respiratory diseases in a broad range of animal species, including humans. [1] [2] [3] In 2003, one of the novel coronaviruses, severe acute respiratory syndrome CoV (SARS-CoV), caused a total of 8,422 cases of SARS with 916 deaths. 4 The other novel coronavirus, Middle East respiratory syndrome CoV (MERS-CoV), has emerged in April 2012 and posed a serious threat to public health. As of 4 April 2020, a total of 2,494 human MERS-CoV infections with 858 deaths had been reported from 27 countries. 5 Although MERS-CoV can cause primary infections from direct contact with animal reservoirs like camels, 6 person-to-person transmission of this virus has mainly occurred in health-care facilities and family clusters. [7] [8] [9] Recently outbreak of COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China and has spread to several other countries.

Drug repositioning for an FDA-approved compound library found that numerous compounds inhibited MERS-CoV infection. However, there are still no approved drugs for coronaviruses. 10 Through high content screening (HCS) platform of Institut Pasteur Korea (IPK) using the Korea Chemical Bank (KCB), 11 we found several novel compounds that can inhibit MERS-CoV infection. 12 We found that N 4 -(3-chloro-4-fluorophenyl)-N 6 -(3methoxybenzyl)quinazoline-4,6-diamine 1 was effective for inhibiting MERS-CoV infection.

Quinazoline derivatives have previously been reported as potent inhibitors of the protein kinase of epidermal growth factor receptor (EGFR). 13 Most of those compounds were approved as anticancer drugs, including Gefitinib, 14 Lapatinib, 15 Erlotinib, 16 and Afatinib 17 . We thought that quinazoline compounds can exhibit good bioavailability and be easily extended to treatment of MERS-CoV infection. Here we report on the synthesis and biological effects of 4-anilino-6-aminoquinazoline derivatives.

The general synthetic route for 4-aminoquinazoline derivatives is described in Scheme 1. Our preliminary structure activity relationship (SAR) studies surrounding 1 were carried out by introducing halide groups on phenyl ring of 4-anilino group (Table 1) . 4-Bromo substituent (6) maintained the potency. 4-Fluoro (7), 3-chloro (8), 4-cyano (9) , and 3-acetyl (10) reduced potency compared to 1. Interestingly, 4-trifluoromethyl (11) can slightly improve the potency.

In the next phase optimization, we observed the effects of the substituents of 6 position of quinazoline ring, having fixed with 3-chloro-4-fluoro and 4-trifluoromethyl substituents on phenyl ring at 4 position ( Table 2 ). Considering activity and cytotoxicity, 20 was thought to be the best compounds for anti-MERS drug and evaluated for its hERG, metabolic stability, cytotoxicity (Table 3) and oral (p.o.) routes at 2 and 5 mg/kg, respectively (Table 4) . 20 showed reasonable oral bioavailability (21 %) 

Summary table of SARS cases by country

Middle East respiratory syndrome coronavirus (MERS-CoV)

The chemical library used in this study was kindly provided by Korea Chemical Bank