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•Synthesis of new pyrazoles substituted with isoxazoles.•Structure elucidation using 2D NMR.•COX-1/COX-2 inhibition assays of all prepared isoxazoles and the furoxan derivative.•In ...vivo anti-inflammatory activity of most COX-2 selective agent.•Ulcer liability and histopathological study of rat stomach samples.
Novel isoxazoles (10, 12a&b, 15a–c) and the furoxan derivative (14) have been prepared as new safe anti-inflammatory agents from the hydroximoyl 9. All compounds were evaluated for COX-1\COX-2 and most of them showed promising selectivity. The furoxan derivative 14 gave 59% inhibitory activity using carrageenan induced paw rat edema model. Ulcer index experiment and histo-pathological study of stomach samples were also included. Also the proposed binding mode of certain newly synthesized compounds with COX-2 isoform was briefly discussed.
Two new series of 1,5-diaryl pyrazoles (5a, 5b, 7a, 7b and 10) and 1,5-diaryl pyrazoline (12a and 12b) were prepared as both Cyclooxygenase-2 and 15-lipoxygenase inhibitors. Carrageenan-induced rat ...paw edema, ulcer index and anti-COX-1/COX-2 and 15-LOX inhibition assays were also included. Cyclization of different pyrazoles was discussed using 2D NMR such as HSQC, HMBC and NOSEY determinations. Compound 5a is more effective with ED50 = 0.98 and 3.98 μM against COX-2 and 15-lipoxygenase respectively, than the references celecoxib (1.54 μM) and meclofenamate sodium (5.64 μM).
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•New thiazolo-celecoxib analogues were designed and synthesized.•Thiazolo-celecoxib drug hybrid showed higher COX-2/15-LOX inhibition properties.•Designed compounds were evaluated as anti-inflammatory activity using Carrageenan-induced rat paw edema and proved activity.•Ulcer liability index of compounds was determined and they showed higher safety profiles.•Most of the compounds were effective as anti-inflammatory and more selective towards COX-2/15-LOX.
Selective inhibition of cyclooxygenase-2 (COX-2) isozyme afforded a useful drug design concept that resulted in the development of effective anti-inflammatory drugs that are devoid of adverse side ...effects, in particular gastrointestinal irritation, ulcerogenicity and renal toxicity attributed to inhibition of the cytoprotective cyclooxygenase-1 (COX-1) isozyme. Unfortunately, some selective COX-2 inhibitory drugs such as rofecoxib and valdecoxib are believed to be responsible for cardiovascular complications. Nitric oxide (NO) is an effective vasodilator that also inhibits platelet aggregation. Therefore hybrid NSAIDs containing NO-donor moieties have been developed to obtain effective treatment of inflammation with reduced GI and cardiovascular side effects. Here we review some of the most promising recent advances in NO-NAISDs donor drug development and summarizes medicinal chemistry efforts in search for new NO-NSAIDs prodrugs in an attempt to pave the way for further development in this promising area of research.
New indomethacin analogs 4a–g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against ...cyclooxygenase 2 (COX‐2; IC50 value range: 0.09–0.4 μМ) as compared with celecoxib (IC50 = 0.89 μМ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX‐2 selectivity index (SI range = 4.07–6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti‐inflammatory activity with edema inhibition (79.36–88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti‐inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX‐2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action.
Eleven indomethacin analogs were synthesized and evaluated for their cyclooxygenase (COX) inhibitory and anti‐inflammatory activities and ulcerogenic liability. All tested compounds showed a higher COX‐2 selectivity index (1.85–5.5‐fold) than indomethacin and most of them were more selective than celecoxib. Compound 5 showed remarkable anti‐inflammatory activity, with a good safety profile. Molecular docking studies were performed to investigate their binding modes in the COX‐2 active site.
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•New thiazolo-celecoxib analogues were designed and synthesized.•Thiazolo-celecoxib drug hybrid showed higher COX-2/15-LOX inhibition properties.•Designed compounds were evaluated as ...anti-inflammatory activity using Carrageenan-induced rat paw edema and proved activity.•Ulcer liability index of compounds was determined to show higher safety profile.•Most active 2b, 3a and 3f were docked in COX-2 and 15-LOX active sites.
Two new series of 1,5-diaryl pyrazoline (3a–f) and 1,5-diaryl pyrazole (5a and 5b) were designed as both COX-2 and 15-LOX inhibitors. All the prepared compounds were fully characterized by all spectral and element analysis. Their anti-inflammatory activity and ulcer index were included. Pyrazoline 3f is the most effective with IC50=1.14 and 4.7μM against COX-2 and 15-LOX respectively, and more potent than celecoxib and meclofenamate references. In addition 3a, 3b, 5a, and 5b were safer with low ulcer index than celecoxib. Docking study was performed for the most active compounds such as 2b, 3a, and 3f on COX-2 and 15-LOX enzymes.
3,6-Dimethyl-1-phenyl-1H-pyrazolo3,4-d1,3oxazin-4-one (3) was prepared by hydrolysis of ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1) to afford the corresponding carboxylic acid 2, ...which was reacted with acetic anhydride to give 3. The pyrazolo3,4-d1,3oxazin-4-one 3 was reacted with hydroxylamine hydrochloride, urea, thiourea, thiosemicarbazide, phenylhydrazine and aromatic amines to afford the corresponding pyrazolo3,4-dpyrimidin-4-ones 4, 5a,b, 6, 7, 8a-e, respectively. Condensation of pyrazoloxazine derivative 3 with 99% hydrazine hydrate afforded the 5-aminopyrazolo3,4-d pyrimidine derivative 9. Coupling of 9 with aromatic aldehydes yielded a series of 3,6-dimethyl-5-(4-substitutedbenzylideneamino)-1-phenyl-1,5-dihydropyrazolo3,4-dpyrimidin- 4-ones 10a-e. The new compounds were tested for their antitumor activity on the MCF-7 human breast adenocarcinoma cell line. Almost all the tested compounds revealed antitumor activity, especially 3,6-dimethyl-5-(4-nitrobenzylideneamino)-1-phenyl-1,5-dihydropyrazolo3,4-dpyrimidin-4-one (10e) which displayed the most potent inhibitory activity with a half maximal inhibitory concentration (IC₅₀) of 11 µM.
Three series of 2-(4-methylsulfonylphenyl) indole derivatives have been designed and synthesized. The synthesized compounds were assessed for their antimicrobial, COX inhibitory and anti-inflammatory ...activities. Compound
7g
was identified to be the most potent antibacterial candidate against strains of
MRSA
,
E. coli, K. pneumoniae, P. aeruginosa,
and
A. baumannii
, respectively, with safe therapeutic dose. Compounds
7a–k, 8a–c,
and
9a–c
showed good anti-inflammatory activity with excessive selectivity towards COX-2 in comparison with reference drugs indomethacin and celecoxib. Compounds
9a–c
were found to release moderate amounts of NO to decrease the side effects associated with selective COX-2 inhibitors. A molecular modeling study for compounds
7b, 7h,
and
7i
into COX-2 active site was correlated with the results of in vitro COX-2 inhibition assays.
New chromene derivatives were synthesized based on 4‐(3,4‐dimethoxy)‐4H‐chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40–141.22 μM). Chromens 5 ...and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c‐Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c‐Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI‐38 cells was confirmed via its IC50 of 115.75 μM comparable with 5‐FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5‐FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29‐fold increase in the total number of apoptotic cells indicating pre‐G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase‐3, caspase‐7, caspase‐9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c‐Src kinase enzyme active site.
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•Novel series of methanesulfonamide containing chalcone, pyrazoline and pyridine derivatives were synthesized with E/Z-stereochemical prediction.•All prepared compounds were screened ...for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity.•Histolopathogical and histochemical studies were assessed to predict the safe effect on gastric mucosa.•Physical features and molecular docking study were predicted.
Novel chalcone 3a-c, pyrazoline 4a-i and pyridine 5a-c, 6a&b derivatives bearing methanesulfonamide moiety were synthesized. Their construction was confirmed using spectral data and elemental analysis. The stereo-chemical configuration for compounds 3a-c was predicted by MM2 property and 1H NMR spectra. All the prepared compounds were screened for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity. The most active anti-inflammatory derivatives, 4f-4i, after 3, 5 & 7 h were further subjected to histopathological and histochemical studies showing safe effect on gastric mucosa, especially 4h derivative. To explore the mechanism of action of COX-2 inhibitory compounds 4f and 6b with the highest S.I. values, they were docked inside COX-2 active site. Physicochemical properties for 4f-i and 6b derivatives were predicted and compared to the reference drug celecoxib. They showed good oral bio-availability specially pyrazoline derivative 4f and pyridine containing compound 6b.
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•Novel sets of 4-aryl-4H-chromene derivatives were synthesized.•Target compounds were screened for their antiproliferative activity against HCT-116, HepG-2 and MCF-7 cell ...lines.•Compounds 4b, 4c and 6d showed superior cytotoxicity against HCT-116, HepG-2 and MCF-7 cell lines.•Compound 4b showed excellent cytotoxic activity against resistant HCT-116 better than doxorubicin.•Potent compounds inhibited both β-tubulin polymerization and c-Src kinase enzymes.•Compound 6d arrested cell cycle at S phase in MCF-7 treated cells and induced both early and late apoptosis.•Potent compounds activated caspase-3, -7, -9 proteins and caused up-regulation of Bax and down-regulation of Bcl-2.•Active compounds showed strong binding pattern inside c-Src kinase enzyme active site.
In this study, three novel sets of 4-aryl-4H-chromene derivatives 4a–c, 6a–d and 7a–c were synthesized and evaluated for anticancer activity. Characterization of new compounds was established on basis of elemental analyses and spectral data. All new compounds were investigated for their antiproliferative activity against HCT-116, HepG-2 and MCF-7 cell lines using vinblastine and staurosporine as positive controls. Compounds 4b, 4c and 6d showed superior cytotoxicity against HCT-116, HepG-2 and MCF-7 cell lines, respectively with IC50 ranged from 3.31 to 4.95 μM. Additionally, compound 4b showed excellent cytotoxic activity (IC50 = 39.83 μM) against resistant HCT-116 better than doxorubicin (IC50 = 164.60 μM), while compounds 4c and 6d exhibited moderate cytotoxic activity against resistant HepG-2 and resistant MCF-7 cell lines. The most potent compounds inhibited both β-tubulin polymerization (IC50 = 8.78 – 16.47 μM) and c-Src kinase (IC50 = 0.07 – 0.18 μM) enzymes. Compounds 4b, 4c and 6d activated caspase-3, caspase-7, and caspase-9 proteins relative to untreated cells, revealing apoptosis induction. Apoptosis was also confirmed through up-regulation of Bax and down-regulation of Bcl-2 protein expression levels. Cell cycle analysis of compound 6d showed accumulation of cells in pre-G1 phase and cell cycle arrest at S phase in MCF-7 treated cells. As well 6d caused 7- and 63- fold increase in apoptotic cell population at early and late apoptosis stages. Finally, molecular modeling study was performed to predict the binding pattern of the target compounds inside c-Src kinase receptor.
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