COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human Coronavirus (hCoV) that spreads among humans and animals. Great efforts have been made to develop therapeutic agents to treat COVID-19 and, among the available viral molecular targets, the cysteine protease SARS-CoV-2 Mpro is considered the most appealing one due to its essential role for viral replication. However, the inhibition of Mpro activity is, an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael's acceptor cinnamic ester was employed as an electrophilic warhead for covalent inhibition of Mpro by endowing some peptidomimetic derivatives with such functionality. Among the synthesized compounds, the indole-based inhibitors 17 and 18 efficiently impaired the in vitro replication of the beta hCoV-OC-43, in the low micromolar range (EC50 = 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative 12 showed an antiviral activity of note (EC50 = 5.27 μM) against another hCoV, namely the hCoV-229E, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results sustain the feasibility of considering the cinnamic framework for the development of new Mpro inhibitors endowed with antiviral activity against human coronaviruses.

Synthesis of SARS-CoV-2 Mpro Inhibitors bearing a Cinnamic Ester Warhead with In Vitro Activity against Human Coronaviruses / A. Citarella, D. Moi, M. Pedrini, H. Pérez-Peña, S. Pieraccini, A. Dimasi, C. Stagno, N. Micale, T. Schirmeister, G. Sibille, G. Gribaudo, A. Silvani, C. Giannini, D. Passarella. - In: ORGANIC & BIOMOLECULAR CHEMISTRY. - ISSN 1477-0520. - 18:21(2023 May 14), pp. 18.3811-18.3824. [10.1039/D3OB00381G]

Synthesis of SARS-CoV-2 Mpro Inhibitors bearing a Cinnamic Ester Warhead with In Vitro Activity against Human Coronaviruses

A. Citarella
Primo
;
M. Pedrini;S. Pieraccini;A. Silvani;C. Giannini
Penultimo
;
D. Passarella
Ultimo
2023

Abstract

COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human Coronavirus (hCoV) that spreads among humans and animals. Great efforts have been made to develop therapeutic agents to treat COVID-19 and, among the available viral molecular targets, the cysteine protease SARS-CoV-2 Mpro is considered the most appealing one due to its essential role for viral replication. However, the inhibition of Mpro activity is, an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael's acceptor cinnamic ester was employed as an electrophilic warhead for covalent inhibition of Mpro by endowing some peptidomimetic derivatives with such functionality. Among the synthesized compounds, the indole-based inhibitors 17 and 18 efficiently impaired the in vitro replication of the beta hCoV-OC-43, in the low micromolar range (EC50 = 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative 12 showed an antiviral activity of note (EC50 = 5.27 μM) against another hCoV, namely the hCoV-229E, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results sustain the feasibility of considering the cinnamic framework for the development of new Mpro inhibitors endowed with antiviral activity against human coronaviruses.
Settore CHIM/06 - Chimica Organica
14-mag-2023
13-apr-2023
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/965776
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