Synthesis of substituted fluorobenzimidazoles as inhibitors of 5‐lipoxygenase and soluble epoxide hydrolase for anti‐inflammatory activity

Abstract

A new series of 4-((5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)methyl)-benzoic acids 4a-o and 2-(5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)-2-methylpropanoic acids 8a-e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX) were investigated. These molecules were designed based on the combination of 5-LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5-LOX inhibitory activity. Compound 4g showed remarkable activity with IC values of less than 1 μM (0.9 μM) against 5-LOX, while compound 4k displayed promising activity against sEH with IC ≤ 1 μM (0.7 μM). These compounds were evaluated for their in vivo potential using the carrageenan-induced rat paw edema assay. Based on the obtained results, the structure-activity relationship was established and a correlation between the activities was observed. Compounds 4f, 4g, 4k, 4n, and 8e showed potent anti-inflammatory activity and significant inhibition of edema (64.13, 67.39, 66.30, 65.21, and 58.69%, respectively) at a dose of 100 mg/kg, comparable to the standard drug ibuprofen (70.65%) at 3 h.

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

“…Nandha et al designed and developed a potential sEH/5-LOX dual inhibitor (FFBMB, 71 ) based on the structure of the 5-LOX inhibitor RWJ-63556 (Figure ), a benzimidazole analog, and the sEH inhibitor t -TUCB. The in vivo study confirmed that FFBMB ( 71 ) possessed significant inhibition of carrageenan-induced rat paw edema …”

“…The in vivo study confirmed that FFBMB (71) possessed significant inhibition of carrageenan-induced rat paw edema. 120 2.2.3. sEH/FLAP Dual Inhibitors. FLAP is a nuclear membrane-anchored protein responsible for transferring AA to 5-LOX that produces proinflammatory LTs.…”

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

“…Other strategies in this regard include benzimidazole derivatives as dual sEH/5-Lipoxygenase inhibitors using virtual screening [ 139 ]. Substituted fluorobenzimidazoles derivatives have been reported as dual inhibitors of 5-lipoxygenase and sEH [ 140 ]. A hybrid imidazo-[1,2a]-pyridine-based dual inhibitor of sEH and 5-lipoxygenase exhibits high potency in vitro [ 141 ].…”

Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity

“…4). Nandha et al further optimized this initial hit compound by incorporating several known pharmacophores of both 5-LOX and sEH [55]. Based on this structure-activity relationship (SAR) study, several potent 5-LOX/sEH dual inhibitors ranging from low micromolar to high nanomolar potencies against both targets have been obtained.…”