Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3-carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation.

Abstract

The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway.

• Authors: Ferdinando Bruno, Suann Errico, Simona Pace, Maxim B Nawrozkij, Arthur S Mkrtchyan, Francesca Guida, Rosa Maisto, Abdurrahman Olgaç, Michele D'Amico, Sabatino Maione, Mario De Rosa, Erden Banoglu, Oliver Werz, Antonio Fiorentino, Rosanna Filosa
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 155 Pg. 946-960 (Jul 15 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 30015253 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Indoles
• Lipoxygenase Inhibitors
• Carrageenan
• Arachidonate 5-Lipoxygenase
• Prostaglandin-E Synthases

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Arachidonate 5-Lipoxygenase (metabolism)
• Carrageenan (administration & dosage)
• Dose-Response Relationship, Drug
• Edema (chemically induced, drug therapy, metabolism)
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Inflammation (drug therapy, metabolism)
• Lipoxygenase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Molecular Structure
• Neutrophils (drug effects, metabolism)
• Prostaglandin-E Synthases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship