Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues

Abstract

This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a–5u. Among the series 5a–5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNFα. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 μM and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNFα, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s), which also showed high docking scores of −12.907 and −12.24 compared to celecoxib, with a −9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib.

Hybrid organic molecules as antiinflammatory agents; a review of structural features and biological activity

“…The presence of aryl piperazine attached with the pyridazine ring influences the analgesic and antiinflammatory activities. Compound 33 was the most 31 Hybrid molecules of naproxen and propyphenazone were synthesized via ester or amide linkage in order to minimize gastrointestinal irritation and toxicity. Some potent compounds were produced that showed less GIT toxicity and compound 39 was found to be least toxic.…”

A Methocarbamol Combination to Prevent Toxicity of Non-steroidal Anti Inflammatory Drugs

“…Blue arrow shows mucosal cell get a damage when treated with Ibuprofen. Black arrow represents the mucosal cell get a damage (ulcer) in high resolution (×40) [2]. So, the best way to avoid damage on tissue is using the safe drug.…”

“…In this case, by using 600-MHz which most precise frequency to investigate specific chemical resonance result from metabolic pathway on NMR test, each 600-MHz spectrum represents one time point after dosing for each toxic compound [1]. It can show the toxicity on xenobiotics relatively affect specific regions within the organs (depicted in the figure by shaded boxes): puromycin affects the renal glomeruli; uranyl nitrate affects the lower regions of proximal tubules and others such as result that 2-bromoethanamine affects renal medulla, including loop of Henle and collecting ducts; and hydrazine affects hepatic parenchymal cells [1,2]. Therefore, it's necessary to treat patients based on patient's underlying diseases.…”

One-pot and multi-step syntheses of new 2-(4,5-dihydro-1H-pyrazol-1-yl) thiazole derivatives

“…Among heterocyclic compounds, pyrazole and thiazole scaffolds are very popular because of their versatility in use. The pyrazole derivatives possess an extensive range of biological activities such as anxiolytic 4 , antimicrobial 5 , antihypertensive 6 , antiinflammatory 7 , antipyretic 8 , analgesic 9 , antioxidant 10 , anticancer 11 , sodium channel blocker 12 , antiviral 13 , antidepressant 14 and antidiabetic activity 15 , while the thiazole derivatives which is found in the structure of many compounds naturally found in nature have antiinflammatory 16 , antibacterial 17 , antifungal 18 , antithrombotic 19 , antiHIV 20 , antihypertensive 21 , hypnotic 22 , analgesic 23 , neuroleptic 24 , and antimalarial effects 25 . Also, pyrazole and thiazole compounds having a five atomic ring structure are used in the synthesis of many condensed hetero structures.…”