Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities.
A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC50s of 0.75-70.50μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Heba S
HS
Abd-Ellah
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Mohamed
M
Abdel-Aziz
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: Shoman_mai@yahoo.com.
Mai E
ME
Shoman
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Eman A M
EA
Beshr
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Tamer S
TS
Kaoud
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Al-Shaimaa F F
AF
Ahmed
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006099:Granuloma / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014456:Ulcer / Q000139:chemically induced / Q000188:drug therapy
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010069:Oxadiazoles; D010091:Oximes; C583463:1,3,4-oxadiazole; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
1,3,4-Oxadiazole; Analgesic; Anti-inflammatory; COX inhibitors; Ibuprofen; NSAIDs; Nitric oxide