Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: Search for better COX-2 inhibitors

Abstract

. COX-2 inhibitors have been successful in treating inflammatory diseases like acute pain, rheumatoid arthritis and osteoarthritis; a few of them are also being studied for treating different types of cancer and Alzheimer's disease (1). Despite a few recent cautionary reports, the coxib treatment has a high degree of benefit over risk, and strategies for using NSAIDs have been described by Antman et al. (2). A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl--1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti--inflammatory activity by the rat paw edema method. p--Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4--methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L -1 and COX-1 enzyme inhibition of 44% at 88 mmol L -1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L -1 ) and higher COX-1 enzyme inhibition (53% at 88 µmol L -1 ) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg -1 ) vs. celecoxib (48% at 12.5 mg kg -1 ). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

Fenbufen based 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones as safer antiinflammatory and analgesic agents

“…Differently substituted oxadiazole moiety has also been found to have other interesting activities such as analgesic, antibacterial, antifungal, anticonvulsant, anticancer, etc. [16][17][18][19][20].…”

Metal Complexes of New Tetraazamacrocyclic Constrained Oxadiazole Ring as Subunits: Synthesis, DNA Binding and Photonuclease Activity

“…Oxadiazoles are very useful subunits for the development of molecules of pharmaceutical or biological interest. Substituted oxadiazoles derivatives have diverse therapeutic applications as they exhibit antiviral (17), tyrosinase inhibitors (18), antimicrobial (19), cathepsin K inhibitors (20), fungicidal (21), anticancer (22) and antineoplastic properties (23). Moreover, it is considered that the presence of toxophoric -N C-O-linkage (24) is responsible for their potent pharmacological activity.…”

Design, synthesis, and pharmacology of some oxadiazole and hydroxypyrazoline hybrids bearing thiazoyl scaffold: antiproliferative activity, molecular docking and DNA binding studies

“…On the other hand, there are a bunch of reports on 1,3,4-oxadiazoles exhibiting various pharmacological activities, such as anti-diabetic [20], antihypertension [21], analgesic [22], antiviral [23], anticonvulsant [24], antifungal [25] antibacterial [26], anticancer [27], anti-glycation [28], anti-inflammatory [29], antimicrobial [30], and ulcerogenic [31]. Compounds containing oxadiazole units such as Nesapidil, Furamizole, and Zibotentan [32] (Fig.…”