Efficient synthesis of novel colchicine-magnolol hybrids and evaluation of their inhibitory activity on key proteases of 2019-nCoV replication and acute lung injury

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), is a life-threatening infectious condition. Acute lung injury is a common complication in patients with COVID-19. 3-chymotrypsin-like protease (3CL^pro) of 2019-nCoV and neutrophil elastase are critical targets of COVID-19 and acute lung injury, respectively. Colchicine and magnolol are reported to exert inhibitory effects on inflammatory response, the severe comorbidity in both COVID-19 and acute lung injury. We thus designed and synthesized a series of novel colchicine-magnolol hybrids based on a two-step synthetic sequence. It was found that these novel hybrids provided unexpected inhibition on 3CL^pro and neutrophil elastase, a bioactivity that colchicine and magnolol did not possess. These findings not only provide perquisites for further in vitro and in vivo investigation to confirm the therapeutic potentiality of novel colchicine-magnolol hybrids, but also suggest that the concurrent inhibition of 3CL^pro and neutrophil elastase may enable novel colchicine-magnolol hybrids as effective multi-target drug compounds.

Graphical Abstract

Keywords:

• COVID-19
• colchicine
• magnolol
• hybrid
• 3-chymotrypsin-like protease
• neutrophil elastase

Disclosure statement

The authors confirm that this article content has no conflicts of interest.

Additional information

Funding

The authors acknowledge the research grants from Shenzhen Science and Technology Innovation Commission (JSGG20210901145539016, JCYJ20190812171005713, JCYJ20210324121611032, JCYJ20180227175929767, ZDSYS20190902093401689), Shenzhen Baoan Chinese Medicine Development Foundation (2020KJCX-KTYJ-215), Shenzhen excellent scientific and technological innovation talents training project—PhD Initiation Program (RCBS20210706092212002), GuangDong Basic and Applied Basic Research Foundation (2020A1515011427, 2022A1515011777, 2021A1515012474), Guangdong TCM Strong Provincial science and technology special key project (No. 20215002), and the National Natural Science Foundation of China (81804145).