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

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.

SUBMITTER: Cerqua I

PROVIDER: S-EPMC9661480 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Cerqua Ida I Musella Simona S Peltner Lukas Klaus LK D'Avino Danilo D Di Sarno Veronica V Granato Elisabetta E Vestuto Vincenzo V Di Matteo Rita R Pace Simona S Ciaglia Tania T Bilancia Rossella R Smaldone Gerardina G Di Matteo Francesca F Di Micco Simone S Bifulco Giuseppe G Pepe Giacomo G Basilicata Manuela Giovanna MG Rodriquez Manuela M Gomez-Monterrey Isabel M IM Campiglia Pietro P Ostacolo Carmine C Roviezzo Fiorentina F Werz Oliver O Rossi Antonietta A Bertamino Alessia A

Journal of medicinal chemistry 20221101 21

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 ...[more]

PMID: 36318728

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Project description:BackgroundNon-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 selective inhibitors, have been explored for prevention and treatment of several inflammatory chronic conditions including arthritis, and cancer. However, the long-term use of these drugs is associated with gastrointestinal, renal, and cardiovascular side effects. Later, COX/5-lipoxygenase (5-LOX) dual inhibitors (eg, licofelone) have been developed but did not enter into the market from the clinical trails due to COX-1/2 inhibition-associated side effects. Hence, targeting microsomal prostaglandin E synthase-1 (mPGES-1) and 5-LOX can be an ideal approach while sparing COX-1/2 activities for development of the next generation of anti-inflammatory drugs with better efficacy and safety.Materials and methodsIn silico (molecular modelling) studies were used to design a mPGES-1/5-LOX dual inhibitory and COX-1/2 sparing lead molecule licofelone analogue-9 (LFA-9) by modifying the pharmacophore of licofelone. In vitro cell-free enzymatic (mPGES-1, 5-LOX, COX-1/2) assays using fluorometric/colorimetric methods and cell-based assays (LPS-induced PGE2, LTB4, and PGI2 productions from macrophages) using ELISA technique, isothermal calorimetry, and circular dichroism techniques were performed to determine the mPGES-1/5-LOX inhibitory efficacy and selectivity. Anti-inflammatory efficacy of LFA-9 was evaluated using a carrageenan (inflammogen)-induced rat paw edema model. Infiltration/expression of CD68 immune cells and TNF-α in paw tissues were evaluated using confocal microscope and immunoblot analysis. Anti-cancer effect of LFA-9 was evaluated using colon spheroids in vitro.ResultsLFA-9 inhibited mPGES-1/5-LOX and their products PGE2 and LTB4, spared COX-1/2 and its product PGI2. LFA-9 bound strongly with human mPGES-1/5-LOX enzymes and induced changes in their secondary structure, thereby inhibited their enzymatic activities. LFA-9 inhibited carrageenan-induced inflammation (70.4%) in rats and suppressed CD68 immune cell infiltration (P ≤ 0.0001) and TNF-α expression. LFA-9 suppressed colon tumor stemness (60.2%) in vitro through inhibition of PGE2 (82%) levels.ConclusionOverall study results suggest that LFA-9 is a mPGES-1/5-LOX dual inhibitor and showed anti-inflammatory and colorectal cancer preventive activities, and warranted detailed studies.

Dataset Information

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

Publications

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

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