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

• Published in: Archiv der Pharmazie (Weinheim) Vol. 351; no. 6; pp. e1800030 - n/a
• Main Authors: Nandha, B., Ramareddy, Sureshbabu A., Kuntal, Hazra
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.06.2018; Wiley Subscription Services, Inc
• Subjects: 5‐lipoxygenase; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; anti‐inflammatory activity; Arachidonate 5-Lipoxygenase - drug effects; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Carrageenan; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Edema - drug therapy; Edema - enzymology; Epoxide Hydrolases - antagonists & inhibitors; Female; fluorobenzimidazole; Humans; Ibuprofen - pharmacology; Inflammation - drug therapy; Inflammation - enzymology; Inhibitory Concentration 50; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Male; Pharmacology & Pharmacy; Physical Sciences; rat paw edema; Rats; Rats, Wistar; Science & Technology; soluble epoxide hydrolase; Structure-Activity Relationship; DESIGN; fluorobenzimidazole; BENZIMIDAZOLE DERIVATIVES; CYCLOOXYGENASE-2; soluble epoxide hydrolase; anti-inflammatory activity; MURINE; MULTIPLE LIGANDS; MODELS; INFLAMMATION; IN-VIVO; BIOLOGICAL EVALUATION; DUAL INHIBITORS; 5-lipoxygenase; rat paw edema
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201800030

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 IC50 values of less than 1 μM (0.9 μM) against 5‐LOX, while compound 4k displayed promising activity against sEH with IC50 ≤ 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. 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. Compounds 4f, 4g, 4k, 4n, and 8e showed potent anti‐inflammatory activity and significant inhibition of edema comparable to the standard drug ibuprofen.