Abstract
Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects.
Highlights
Based on reactivity of the carboxyl group of IND, new nitric oxide (NO)-IND-OXDs 8a–p were prepared in a few steps (Scheme 1)
It is known that NO is an important endogenous molecule, having a critical role in protecting the GI mucosa while 1,3,4-oxadiazole-2-thiol scaffold is associated with important pharmacological effects, including anti-inflammatory and antioxidant ones
The molecular docking study revealed that 8k, 8l and 8m are COX-2 inhibitors, more selective than celecoxib
Summary
In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was performed. The compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects. The non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed drugs for management of different pathological conditions where inflammation is involved, based on their analgesic, anti-inflammatory and antipyretic effects [1,2].
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