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Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1β in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, [4-(N-substituted sulfamoyl)phenyl]carbonohydrazonoy dicyanides 3a-c were synthesized and condensed with various hydrazine hydrate derivatives to produce the corresponding 3,5-diaminopyrazole derivatives 4-9, respectively. Furthermore, condensation of 3b with ax-naphthol, urea and thiourea yielded the pyrimidine derivatives 10 and 11a,b, respectively. Also, condensation of 3b with hydroxylamine hydrochloride produced the isoxazole derivative 12. Treatment of 3b with different secondary amines afforded the piperidine and piperazine derivatives 13a-c, respectively, while its condensation with diamines yielded the corresponding diazepine, benzodiazepine and benzooxazepine derivatives 14-16. Reaction of 3b with malononitrile or diazonium salt 2b with MND followed by treatment with malononitrile afforded the pyrido-pyridazine derivative 18. Anti-inflammatory and analgesic evaluation of some of the synthesized compounds as representative examples exhibited equipotent activity to that of the reference drug celecoxib. The ulcerogenic potential of the tested derivatives showed a complete safety profile on G.I.T. system. Molecular docking studies showed that the tested compounds induced good fitting and forming different hydrogen bonds with the amino acid residues at the active sites of COX-2 enzyme.

A series of 2-substituted phenyl derivatives of nicotinic acid 4a-l were synthesized and evaluated for their analgesic and anti-inflammatory activities. Compounds including 2-bromophenyl substituent, 4a, c, and d, proved to display distinctive analgesic and anti-inflammatory activities in comparison to mefenamic acid as a reference drug. Compound 4c could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic profile. Effect of the compounds 4a-l on the serum level of certain inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 was also determined.

A series of nicotinic acid derivatives structurally related to niflumic acid and certain pyridazine-containing compounds have been synthesized and characterized by analytical and spectral data. All compounds were screened for their potential analgesic and anti-inflammatory activities. The compounds which displayed analgesic and anti-inflammatory activities were tested for ulcerogenicity and screened for in vivo inhibition of certain inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Compounds 1c, 2a, 2b, and 5a have shown potent analgesic and anti-inflammatory activities.

A 48-year-old white female who was suffering from dermatomyositis and Chlamydia pneumoniae infection, developed acute rapidly fatal thrombotic thrombocytopenic purpura (TTP) following treatment with steroids and doxycycline. As a relationship between TTP and the inflammatory myopathies is now probably well established, it is very likely that our patient's TTP became manifest in association with dermatomyositis. Nevertheless, C. pneumoniae infection and doxycycline therapy cannot be excluded entirely as cofactors responsible for triggering her thrombotic microangiopathy.