Synthesis of cannabidiol-based compounds as ACE2 inhibitors with potential application in the treatment of COVID-19

Gabriel Vitor de Lima Marques; Daisymara Priscila de Almeida Marques; Felipe Alves Clarindo; Jesus Alberto Avendaño-Villarreal; Fabiana Sélos Guerra; Patrícia Dias Fernandes; Eduardo Nicolau Dos Santos; Elena Vitalievna Gusevskaya; Markus Kohlhoff; Fabrício de Araújo Moreira; Luis Adan Flores Andrade; Flávio Guimarães da Fonseca; Jordana Grazziela Alves Coelho Dos-Reis; Renata Barbosa de Oliveira

doi:10.1016/j.ejmech.2023.115760

Synthesis of cannabidiol-based compounds as ACE2 inhibitors with potential application in the treatment of COVID-19

Eur J Med Chem. 2023 Nov 15:260:115760. doi: 10.1016/j.ejmech.2023.115760. Epub 2023 Aug 28.

Authors

Gabriel Vitor de Lima Marques¹, Daisymara Priscila de Almeida Marques², Felipe Alves Clarindo², Jesus Alberto Avendaño-Villarreal³, Fabiana Sélos Guerra⁴, Patrícia Dias Fernandes⁴, Eduardo Nicolau Dos Santos³, Elena Vitalievna Gusevskaya³, Markus Kohlhoff⁵, Fabrício de Araújo Moreira⁶, Luis Adan Flores Andrade⁷, Flávio Guimarães da Fonseca⁷, Jordana Grazziela Alves Coelho Dos-Reis², Renata Barbosa de Oliveira⁸

Affiliations

¹ Universidade Federal de Minas Gerais, Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Belo Horizonte, Brazil.
² Universidade Federal de Minas Gerais, Departamento de Microbiologia, Instituto de Ciências Biológicas, Belo Horizonte, Brazil.
³ Universidade Federal de Minas Gerais, Departamento de Química, Instituto de Ciências Exatas, Belo Horizonte, Brazil.
⁴ Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Programa de Pesquisa em Descoberta de Fármacos, Laboratório de Farmacologia da Dor e da Inflamação, Rio de Janeiro, Brazil.
⁵ Instituto René Rachou (IRR) - FIOCRUZ Minas, Química de Produtos Naturais Bioativos (QPNB), Belo Horizonte, Brazil.
⁶ Universidade Federal de Minas Gerais, Departamento de Farmacologia, Instituto de Ciências Biológicas, Belo Horizonte, Brazil.
⁷ Universidade Federal de Minas Gerais, Departamento de Microbiologia, Instituto de Ciências Biológicas, Belo Horizonte, Brazil; Universidade Federal de Minas Gerais, Centro de Tecnologia de Vacinas - CT Vacinas, Belo Horizonte, Brazil.
⁸ Universidade Federal de Minas Gerais, Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Belo Horizonte, Brazil. Electronic address: [email protected].

PMID: 37657273
DOI: 10.1016/j.ejmech.2023.115760

Abstract

Cannabis is a general name for plants of the genus Cannabis. Used as fiber, medicine, drug, for religious, therapeutic, and hedonistic purposes along the millenia, it is mostly known for its psychoactive properties. One of its major constituents, cannabidiol (CBD), a non-psychoactive substance, among many other biological activities, has shown potential as an anti-SARS-CoV-2 drug. In this work, three derivatives and an analogue of CBD were synthesized, and cell viability and antiviral activities were evaluated. None of the compounds showed cytotoxicity up to a maximum concentration of 100 μM and, in contrast, displayed a significant antiviral activity, superior to remdesivir and nafamostat mesylate, with IC₅₀ values ranging from 9.4 to 1.9 μM. In order to search for a possible molecular target, the inhibitory activity of the compounds against ACE2 was investigated, with expressive results (IC₅₀ ranging from 3.96 μM to 0.01 μM).

Keywords: ACE2 inhibitors; COVID-19; Cannabidiol derivatives; SARS-CoV-2.

MeSH terms

Angiotensin-Converting Enzyme 2
Antiviral Agents / pharmacology
COVID-19*
Cannabidiol* / pharmacology
Humans
SARS-CoV-2

Substances

Cannabidiol
Angiotensin-Converting Enzyme 2
Antiviral Agents