Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

Abstract

Because of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, nonsteroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure-activity relationship (SAR) of various novel {2-[(2-, 3-and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5-or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings.

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction

“…Reacting the synthesised amidoximes 2a-f with the carboxylic acid group of chalcone 3 and 5 using carbonyldiimidazole (CDI) in acetonitrile gave the chalcone/aryl carboximidamides 4a-f and 6a-f, respectively, in good yield. The structure of the newly synthesised chalcone/aryl carboximidamides 4a-f and 6a-f was characterised by IR, 1 H NMR, 13 aromatic protons appeared in their expected chemical shifts. In addition, a characteristic doublet signal at d 7.67-7.71 ppm assigned to be one of olefin hydrogen with coupling constant 15.4 Hz, which confirm the E configuration.…”

“…Notably, prolonged use of traditional non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin, indomethacin and ibuprofen promoted the appearance of several undesired side effects such as gastrointestinal irritation, ulceration and bleeding due to their inhibitory action on the gastroprotective prostanoids formed by COX-1 enzymes in the gastrointestinal tract 3 , 12 that highlighted the significance of the innovation of new potent and selective COX-2 inhibitors with less gastro-intestinal side effects and with more safety profile such as celecoxib and its analogues 13 , 14 . Nevertheless, prolonged administration of selective COX-2 for inhibition of prostaglandins production stimulated the metabolism of arachidonic acid pathway to LOX enzyme leading to increased availability of substrate which consequently resulted in increased leukotriene production by lipoxygenase pathway that intensifies airway inflammation and exaggerates bronchoconstriction 12 .…”

Vaptans or voluntary increased hydration to protect the kidney: how do they compare?

“…Inhibitors of prostaglandin synthesis have been used for elucidating their influence on kidney function. They include non-steroidal anti-inflammatory drugs (NSAID) indomethacin, meclofenamate, aspirin (acetyl salicylic acid), and more recently, selective inhibitors of either COX-1 or COX-2 [79] or selective antagonists of the different receptors [80,81].…”

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases

“…However, the knowledge of the anti-oncogenic mechanism remains uncompleted and the involvement of LOX and COX-independent pathways were also highlighted [195]. NSAIDs could be used to prevent and to participate in tumor decrease in several cancers [202][203][204] The COX-2 overexpression in colorectal cancer reaches 80% [180]. Several clinical studies revealed that NSAIDS could be used for the prevention (long-term use of aspirin [157]) and treatment of colon cancer (SC-58125 [157], celecoxib and rofecoxib [205]).…”