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 (IC(50)s of 0.41 +/- 0.01 and 0.43 +/- 0.10 microM 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.
Cerqua I, Musella S, Peltner LK, D'Avino D, Di Sarno V, Granato E, Vestuto V, Di Matteo R, Pace S, Ciaglia T, Bilancia R, Smaldone G, Di Matteo F, Di Micco S, Bifulco G, Pepe G, Basilicata MG, Rodriquez M, Gomez-Monterrey IM, Campiglia P, Ostacolo C, Roviezzo F, Werz O, Rossi A, Bertamino A (2022) Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization Journal of Medicinal Chemistry
Cerqua I, Musella S, Peltner LK, D'Avino D, Di Sarno V, Granato E, Vestuto V, Di Matteo R, Pace S, Ciaglia T, Bilancia R, Smaldone G, Di Matteo F, Di Micco S, Bifulco G, Pepe G, Basilicata MG, Rodriquez M, Gomez-Monterrey IM, Campiglia P, Ostacolo C, Roviezzo F, Werz O, Rossi A, Bertamino A (2022) Journal of Medicinal Chemistry
