Synthesis, COX-2 inhibition, anti-inflammatory activity, molecular docking, and histopathological studies of new pyridazine derivatives.

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1ß. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity.

This study comprises the design and synthesis of novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against the vascular endothelial growth factor receptor-2 (VEGFR-2). Screening of novel compounds for cytotoxicity was assessed against 60 human cancer cell lines. The two most active compounds, 5b and 5c, and the reference drugs sorafenib and doxorubicin were investigated against HCT-15, PC-3, and CF-295 cancer cell lines. Compound 5c exhibited the highest cytotoxic potential compared to doxorubicin against the HCT-15 and PC-3 tumor cell lines. Moreover, it exhibited higher cytotoxic potential and selectivity toward the HCT-15 cell panel compared with sorafenib. Compound 5c demonstrated promising VEGFR-2 inhibition (concentration needed to inhibit cell viability by 50%, IC50 = 0.068 µM) and superior VEGFR-2 selectivity over the epidermal growth factor receptor and platelet-derived growth factor receptor-ß enzymes. It also reduced the total and phosphorylated VEGFR-2 and induced apoptosis, as evidenced by a 4.3-fold rise in caspase-3 levels. The antioxidant potential of the new compounds was determined via measuring the superoxide dismutase (SOD) levels, among which compound 5c exhibited an SOD level almost comparable to ascorbic acid. These results suggested that compound 5c exhibited dual cytotoxic and antioxidant activities. Docking of 5c into the VEGFR-2 pocket showed a similar binding mode to sorafenib. Moreover, the ADME (absorption, distribution, metabolism, and excretion) profile of 5c outlined drug-likeness. Finally, The density functional theory calculations displayed an increased binding affinity of 5c to the target enzyme.

Pyridazine derivatives as selective COX-2 inhibitors: A review on recent updates.

Selective cyclooxygenase (COX)-2 inhibitors have several advantages over nonselective COX inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]), including the absence of adverse effects (renal and hepatic disorders) associated with the long-term use of standard NSAIDs, as well as an improved gastrointestinal profile. The pyridazine nucleus is regarded as a promising scaffold for the development of powerful COX-2 inhibitors, particularly when selectively functionalized. This article summarizes some methods for the synthesis of pyridazine derivatives. Furthermore, it covers all of the pyridazine derivatives that have appeared as selective COX-2 inhibitors, making it useful as a reference for the rational design of novel selective COX-2 inhibitors.

Anti-inflammatory activity of pyridazinones: A review.

The pyridazinone core has emerged as a leading structure for fighting inflammation, with low ulcerogenic effects. Moreover, easy functionalization of various ring positions of the pyridazinone core structure makes it an attractive synthetic and therapeutic target for the design and synthesis of anti-inflammatory agents. The present review surveys the recent advances of pyridazinone derivatives as potential anti-inflammatory agents to provide insights into the rational design of more effective anti-inflammatory pyridazinones.

New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF-7 breast cancer cell line.

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF-7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20-fold higher anticancer activity than erlotinib, and five of these compounds were up to 11-fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase-9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase-9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre-G1 /G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF-10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF-7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.

Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme.

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-1ß 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.

New pyridazine derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents; design, synthesis and biological evaluation.

New pyridazinone and pyridazinthione derivatives were designed, synthesized and identified through performing 1H NMR, 13C NMR, IR and MS spectroscopic techniques. All the newly synthesized derivatives were evaluated for cyclooxygenase inhibitory activity and COX-2 selectivity using celecoxib and indomethacin, as reference drugs. All compounds showed highly potent COX-2 inhibitory activity with IC50 values in nano-molar range. Moreover, they demonstrated higher selectivity towards COX-2 inhibition compared to indomethacin. Compounds 3d, 3g and 6a exhibited significantly increased potency towards COX-2 enzyme compared to celecoxib with IC50 values of 67.23, 43.84 and 53.01 nM, respectively. They were 1.1-1.7 folds more potent than celecoxib (IC50 = 73.53 nM) and extremely much more potent than indomethacin (IC50 = 739.2 nM). Of particular interest, Compound 3g showed SI of 11.51 which was as high as that of celecoxib (SI 11.78). This compound was further challenged by in vivo anti-inflammatory activity assay and gastric ulcerogenic effect. It showed comparable anti-inflammatory activity to indomethacin as positive control. Moreover, the anti-inflammatory activity of compound 3g was found to be equipotent to celecoxib. Furthermore, the selective COX-2 inhibitor 3g exhibited a superior gastrointestinal safety profile compared to the reference drugs celecoxib and indomethacin with less number of ulcers and milder ulcer score. The molecular docking study of this compound with COX-2 protein revealed more favorable binding mode compared to celecoxib, explaining its remarkable COX-2 inhibitory potency.

Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents.

A series of pyridazinone derivatives, bearing an aryl or pyridyl moiety linked through an ethenyl spacer to position-6 was designed and synthesized. The newly synthesized compounds were screened for preferential inhibition of COX-2 over COX-1 isoforms. Compounds 2c, 2d, 2e, 2f, 3a, 3b, 3c, 3d and 3e are highly potent COX-2 inhibitors with IC50 values in nano-molar range. Moreover, they showed clear preferential COX-2 over COX-1 inhibition with selective indices (SIs) ranging from 4 to 38. Of particular interest, compounds 2d, 2f, 3c and 3d exhibited the most prominent COX-2 inhibitory activity with IC50 values range of 15.56-19.77 nM. They showed SIs of 24, 38, 35 and 24, respectively which were 1.4-2.2 fold higher than celecoxib (SI 17). These four compounds were further investigated in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema method and ulcerogenic liability. Compounds 2f, 3c and 3d demonstrated superior anti-inflammatory activity relative to both indomethacin and celecoxib. None of these compounds showed gastric ulcerogenic effect. On the other hand, compound 2d was found equipotent to celecoxib at the second hour of oral administration. At the fourth hour, it exhibited more potent anti-inflammatory activity than celecoxib, becoming equipotent to indomethacin. It showed mild hyperemia in vivo compared to indomethacin and celecoxib. The molecular docking study of compounds 2d, 2f, 3c and 3d into COX-2 active site revealed a similar binding mode to celecoxib, explaining their remarkable COX-2 inhibitory activity. Taken together, these results indicated that these derivatives are good leads for potential COX-2 inhibitors to be used as potent and safe anti-inflammatory agents.

Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents.

AIMS: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticancer agents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporating cinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffolds with the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterized using both microanalytical and spectral data. METHODS: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancer cells and normal breast cells. RESULTS: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptor tyrosine kinase and topoisomerase I was accomplished. CONCLUSIONS: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds. Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstanding cytotoxic activity against MCF-7 (0.049 µM), tyrosine kinase inhibition (0.22 µM), apoptosis percentage and the highest selectivity index.