The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 +/- 0.01 and 0.43 +/- 0.10 mu M for 5-LOX and sEH, respectively). When challenged in vivo in zymosaninduced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization

Musella, Simona;Di Sarno, Veronica;Vestuto, Vincenzo;Pace, Simona;Ciaglia, Tania;Smaldone, Gerardina;Di Matteo, Francesca;Di Micco, Simone;Bifulco, Giuseppe;Pepe, Giacomo;Basilicata, Manuela Giovanna;Rodriquez, Manuela;Campiglia, Pietro;Ostacolo, Carmine;Bertamino, Alessia
2022-01-01

Abstract

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 +/- 0.01 and 0.43 +/- 0.10 mu M for 5-LOX and sEH, respectively). When challenged in vivo in zymosaninduced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4809652
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