key: cord-0775724-1ee9aibw
authors: Sup Shin, Young; Young Lee, Jun; Noh, Soojin; Kwak, Yoonna; Jeon, Sangeun; Kwon, Sunoh; Jin, Young-hee; Seong Jang, Min; Kim, Seungtaek; Hwan Song, Jong; Rae Kim, Hyoung; Min Park, Chul
title: Discovery of Cyclic Sulfonamide derivatives as Potent Inhibitors of SARS-CoV-2
date: 2020-11-04
journal: Bioorg Med Chem Lett
DOI: 10.1016/j.bmcl.2020.127667
sha: f8d4a5fe2d95ee44cff2cb40d1c3e4e410896a92
doc_id: 775724
cord_uid: 1ee9aibw

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) continues to spread worldwide, with 25 million confirmed cases and 800 thousand deaths. Effective treatments to target SARS-CoV-2 are urgently needed. In the present study, we have identified a class of cyclic sulfonamide derivatives as novel SARS-CoV-2 inhibitors. Compound 13c of the synthesized compounds exhibited robust inhibitory activity (IC(50) = 0.88 μM) against SARS-CoV-2 without cytotoxicity (CC(50) > 25 μM), with a selectivity index (SI) of 30.7. In addition, compound 13c exhibited high oral bioavailability (77%) and metabolic stability with good safety profiles in hERG and cytotoxicity studies. The present study identified that cyclic sulfonamide derivatives are a promising new template for the development of anti-SARS-CoV-2 agents.

In December 2019, the novel coronavirus was first reported in Wuhan Province, China. 1 The infection has since spread worldwide, with 25 million confirmed cases and 800 thousand deaths as of 31 August 2020. 2 The new virus, derived from zoonotic transmission, was named by the International Committee on Taxonomy of Viruses (ICTV) as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). 3 It is a positive-sense single-stranded RNA virus (ssRNA) that is contagious in humans and other mammals. 3, 4 SARS-CoV-2 shares 82% of its genome with SARS-CoV. 5 Although many studies are ongoing, no effective vaccine or treatment for SARS-CoV-2 infection has yet been developed. 6 The U.S. Food and Drug Administration (FDA) approved emergency use of remdesivir, a nucleotide analogue prodrug, in patients hospitalized with severe disease. 7 However, this intravenous antiviral drug did not improve overall survival rates, but it did decrease recovery time in surviving patients. 6 More effective approaches to treatment are urgently needed.

We attempted to find biologically active compounds in the library 8 

Bank (KCB) using the Institut Pasteur Korea (IPK) high content screening (HCS) platform.

Cyclic sulfonamide compound 1 (Fig. 1 ) was identified as a hit, and exhibited anti-SARS-CoV-2 activity (IC 50 = 15.3 M). Cyclic sulfonamide derivatives are known to have various pharmacological activities such as analgesic 9 , anti-inflammatory 10 Figure 1 . Anti-SARS-CoV-2 compound 1 identified from the KCB library screen.

A series of cyclic sulfonamide derivatives were synthesized as shown in Scheme 1. Saccharin was treated with -bromo ketone and triethylamine to yield the alkylated product 2. A Gabriel-Colman rearrangement of 2 with sodium ethoxide afforded intermediate 3, which was reacted with -chloro amide and -bromo ketone (or benzyl bromide) under basic conditions using sodium hydride to yield 4 and 5, respectively. To synthesize a one-carbon homologation compound, 3 was treated with ClCH 2 CH 2 CONH-p-CF 3 -Ph and sodium hydride. However, elimination of the alkyl chloride substrate yielded an undesired product, CH=CHCONH-p-CF 3 -Ph. Alternatively, we designed to synthesize ,-unsaturated amide 8. Alkenoic acid ester 6 was prepared by reaction of compound 3 and ethyl propiolate with DABCO as a catalyst.

Hydrolysis of 6 with lithium hydroxide afforded carboxylic acid 7. Amide coupling of 7 with 3-(trifluoromethoxy)aniline, EDCI, and DMAP yielded amide 8. To synthesize 7-fluorinated cyclic sulfonamide (Scheme 2), sulfonyl chloride 9 was used as a starting material. Amination of 9 with aqueous ammonium hydroxide yielded sulfonamide 10. Oxidation of 10 with potassium permanganate afforded compound 11. Cyclization of 11 with sulfuric acid yielded fluorinated saccharin 12. Compound 13 was prepared as shown in Scheme 2. 13c was treated with amine groups to yield N-substituted product 14.

Biological activities of the synthesized cyclic sulfonamide derivatives were evaluated in Vero cells to test both anti-SARS-CoV-2 activity and cytotoxicity by cellular phenotypic screening method 13 as shown in Table 1 (Table 1) . Unsubstituent (4a) and 2-chloro (4b) compounds showed no inhibitory effect. 3-Trifluoromethoxy (4c) and 4-trifluoromethyl (4d) at the 2 position improved anti-SARS-CoV-2 activities (IC 50 = 8.90 and 5.30 M, respectively). 4c and 4d exhibited better activity than compound 1 and similar activity to remdesivir and chloroquine (IC 50 = 7.01 and 8.00 M, respectively). Table 1 . Anti-SARS-CoV-2 activity and cytotoxicity of cyclic sulfonamide derivatives We conducted further modifications to increase activity ( Table 2) Compound 13c, found to be a potential anti-SARS-CoV-2 agent, was evaluated for its metabolic stability, human ether a-go-go (hERG) binding, cytotoxicity, and in vivo PK profile ( c Rats (n = 3) were dosed at IV 5 mg/kg and PO 10 mg/kg.

In conclusion, we identified a novel class of cyclic sulfonamide derivatives as SARS-CoV-2 inhibitors using SAR optimization, viral inhibitory assays, cytotoxicity assays, and PK studies. 

World Health Organization (WHO)

COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment

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