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 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced 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 / Cerqua, Ida; Musella, Simona; Peltner, Lukas Klaus; D'Avino, Danilo; Di Sarno, Veronica; Granato, Elisabetta; Vestuto, Vincenzo; Di Matteo, Rita; Pace, Simona; Ciaglia, Tania; Bilancia, Rossella; Smaldone, Gerardina; Di Matteo, Francesca; Di Micco, Simone; Bifulco, Giuseppe; Pepe, Giacomo; Basilicata, Manuela Giovanna; Rodriquez, Manuela; Gomez-Monterrey, Isabel M; Campiglia, Pietro; Ostacolo, Carmine; Roviezzo, Fiorentina; Werz, Oliver; Rossi, Antonietta; Bertamino, Alessia. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:21(2022), pp. 14456-14480. [10.1021/acs.jmedchem.2c00817]

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

Cerqua, Ida;Musella, Simona;D'Avino, Danilo;Granato, Elisabetta;Di Matteo, Rita;Bilancia, Rossella;Rodriquez, Manuela;Gomez-Monterrey, Isabel M;Ostacolo, Carmine;Roviezzo, Fiorentina;Rossi, Antonietta;
2022

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 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced 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.
2022
Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization / Cerqua, Ida; Musella, Simona; Peltner, Lukas Klaus; D'Avino, Danilo; Di Sarno, Veronica; Granato, Elisabetta; Vestuto, Vincenzo; Di Matteo, Rita; Pace, Simona; Ciaglia, Tania; Bilancia, Rossella; Smaldone, Gerardina; Di Matteo, Francesca; Di Micco, Simone; Bifulco, Giuseppe; Pepe, Giacomo; Basilicata, Manuela Giovanna; Rodriquez, Manuela; Gomez-Monterrey, Isabel M; Campiglia, Pietro; Ostacolo, Carmine; Roviezzo, Fiorentina; Werz, Oliver; Rossi, Antonietta; Bertamino, Alessia. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:21(2022), pp. 14456-14480. [10.1021/acs.jmedchem.2c00817]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/899232
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