Naphthoquinone derivatives as potential immunomodulators: prospective for COVID-19 treatment

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Moraes, Vitor Tassara ; Caires, Franco Jazon ; da Silva-Neto, Pedro V. ; Mendonca, Jacqueline Nakau ; Fraga-Silva, Thais F. C. ; Fontanezi, Bianca Bueno ; Marcato, Priscyla Daniely ; Deperon Bonato, Vania Luiza ; Sorgi, Carlos Arterio ; Beraldo Moraes, Luiz Alberto ; Clososki, Giuliano Cesar

• Document type: Journal article
• Source: RSC ADVANCES; v. 14, n. 10, p. 10-pg., 2024-02-21.

Abstract

Inflammation plays a crucial role in COVID-19, and when it becomes dysregulated, it can lead to severe outcomes, including death. Naphthoquinones, a class of cyclic organic compounds widely distributed in nature, have attracted significant interest due to their potential biological benefits. One such naphthoquinone is 3,5,8-trihydroxy-6-methoxy-2-(5-oxohexa-1,3-dienyl)-naphthanthene-1,4-dione (3,5,8-TMON), a compound produced by fungi. Despite its structural similarity to shikonin, limited research has been conducted to investigate its biological properties. Therefore, the objective of this study was to evaluate the effects of 3,5,8-TMON and its synthetic derivatives in the context of inflammation induced by lipopolysaccharide (LPS) and SARS-CoV-2 infection in vitro using cell cultures. 3,5,8-TMON was obtained by acid treatment of crude extracts of fermentation medium from Cordyceps sp., and two derivatives were accessed by reaction with phenylhydrazine under different conditions. The results revealed that the crude extract of the fungi (C. Ex) inhibited the activity of transcription factor NF-kB, as well as the production of nitric oxide (NO) and interleukin-6 (IL-6) when LPS induced it in RAW 264.7 cells. This inhibitory effect was observed at effective concentrations of 12.5 and 3.12 mu g mL-1. In parallel, 3,5,8-TMON and the new derivatives 3 and 4 demonstrated the ability to decrease IL-6 production while increasing TNF, with a specific effect depending on the concentration. These concentration-dependent agonist and antagonist effects were observed in THP-1 cells. Furthermore, 3,5,8-TMON inhibited IL-6 production at concentrations of 12.5 and 3.12 mu g mL-1 in Calu-3 cells during SARS-CoV-2 viral infection. These findings present promising opportunities for further research into the therapeutic potential of this class of naphthoquinone in the management of inflammation and viral infections. The microbial naphthoquinone 3,5,8-TMON and its derivatives showed great anti-inflammatory activity, regulating cytokines and with promising activity mitigating COVID-19 inflammatory impacts. (AU)

• FAPESP's process: 22/05327-7 - Exploring the medicinal chemical space of aromatics with highly selective synthetic tools
• Grantee: Giuliano Cesar Clososki
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/16916-3 - Development of an electrophilic amination methodology for aromatic indolizines
• Grantee: Vitor Tassara de Moraes
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/50928-2 - INCT 2014: Pharmaceutical Nanotechnology: a transdisciplinary approach
• Grantee: Maria Vitória Lopes Badra Bentley
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/13532-7 - Tandem mass spectrometry applied in the development of analytical methods in identification of polar microbial metabolites
• Grantee: Luiz Alberto Beraldo de Moraes
• Support Opportunities: Regular Research Grants