3-Amino-alkylated indoles: unexplored green products acting as anti-inflammatory agents

Sarah Mazzotta; Luca Frattaruolo; Matteo Brindisi; Cristina Ulivieri; Francesca Vanni; Antonella Brizzi; Gabriele Carullo; Anna R Cappello; Francesca Aiello

doi:10.4155/fmc-2019-0234

3-Amino-alkylated indoles: unexplored green products acting as anti-inflammatory agents

Future Med Chem. 2020 Jan;12(1):5-17. doi: 10.4155/fmc-2019-0234. Epub 2019 Nov 11.

Authors

Sarah Mazzotta^{1

2}, Luca Frattaruolo¹, Matteo Brindisi¹, Cristina Ulivieri³, Francesca Vanni³, Antonella Brizzi⁴, Gabriele Carullo¹, Anna R Cappello¹, Francesca Aiello¹

Affiliations

¹ Department of Pharmacy, Health & Nutritional Sciences2, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
² Department of Organic & Medicinal Chemistry, University of Seville, n. 2, 41012 Seville, Spain.
³ Department of Life Sciences, University of Siena, Via Aldo Moro, n. 2, 53100 Siena, Italy.
⁴ Department of Biotechnology, Chemistry & Pharmacy, University of Siena, Via Aldo Moro, n. 2, 53100 Siena, Italy.

PMID: 31710253
DOI: 10.4155/fmc-2019-0234

Abstract

Aim: Over the years, indole has proved to be a versatile scaffold for the design of molecules acting as anti-inflammatory agents. Materials & Methods: A small library of 3-amino-alkylated indoles has been obtained by an optimized Mannich green approach. The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluated in RAW 264.7 macrophages. Results: The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluatedn and, among them, GLYC 4, 5 and 9 displayed the greatest inhibitory effects on nitric oxide production, with IC₅₀ values of 5.41, 4.22 and 6.3 μM, respectively. Conclusion: Our outcomes, overall, highlight the importance of the indole substitution in the anti-inflammatory activity of these compounds, exerted by acting on the interlinked NF-κB/ERK1/2 pathways.

Keywords: ERK1/2 pathway; Mannich reaction; NF-κB pathway; green chemistry; indoles; inflammation; multicomponent reaction.

MeSH terms

Alkylation
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Dose-Response Relationship, Drug
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Macrophages / drug effects
Macrophages / metabolism
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / metabolism
Molecular Structure
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism
Nitric Oxide / antagonists & inhibitors
Nitric Oxide / biosynthesis
RAW 264.7 Cells
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Indoles
Lipopolysaccharides
NF-kappa B
Nitric Oxide
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3