Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety

Soliman, Wael Mohamed; Abdellatif, Khaled R.A.; Knaus, Edward E.

doi:10.1590/s2175-97902018000417281

Cited by 2 publications

(3 citation statements)

References 36 publications

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“…Scheme 1 illustrated the synthesis of the target thymol–1,5-disubstitutedpyrazole hybrids. The dioxobutanoate derivatives 53 1a–c were cyclised using reaction conditions used in Knorr pyrazole synthesis 54 and celecoxib synthesis 55 by reaction with either hydrazine hydrate or substituted phenylhydrazine hydrochloride in glacial acetic acid. Hydrazine hydrate resulted in both cyclisation and formation of the hydrazide derivatives 2a–c .…”

Section: Resultsmentioning

confidence: 99%

Towards safer anti-inflammatory therapy: synthesis of new thymol–pyrazole hybrids as dual COX-2/5-LOX inhibitors

El-Miligy

Al-Kubeisi²,

Bekhit

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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New thymol − 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 8b , 8g , 8c, and 4a displayed in vitro inhibitory activity against COX-2 (IC 50 = 0.043, 0.045, 0.063, and 0.068 µM ) nearly equal to celecoxib (IC 50 = 0.045 µM ) with high SI (316, 268, 204, and 151, respectively) comparable to celecoxib (327). All target compounds, 4a–c and 8a–i , showed in vitro 5-LOX inhibitory activity higher than reference quercetin. Besides, they possessed in vivo inhibition of formalin-induced paw oedema higher than celecoxib. In addition, compounds 4a, 4b, 8b, and 8g showed superior gastrointestinal safety profile (no ulceration) as celecoxib and diclofenac sodium in the population of fasted rats. In conclusion, compounds 4a , 8b, and 8g achieved the target goal. They elicited in vitro dual inhibition of COX-2/5-LOX higher than celecoxib and quercetin, in vivo potent anti-inflammatory activity higher than celecoxib and in vivo superior gastrointestinal safety profile (no ulceration) as celecoxib.

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Section: Resultsmentioning

confidence: 99%

Towards safer anti-inflammatory therapy: synthesis of new thymol–pyrazole hybrids as dual COX-2/5-LOX inhibitors

El-Miligy

Al-Kubeisi²,

Bekhit

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Currently, only selected COXIBs such as celecoxib, etoricoxib, or the prodrug parecoxib are on the market due to an increased risk for cardiovascular incidents such as stroke and heart attacks described after long-term treatment with, e.g., rofecoxib or valdecoxib. In this context, ongoing efforts are made to identify COXIBs with optimized pharmacological properties, among them are molecular hybrids, such as dual inhibitors targeting simultaneously the COX and LOX pathway [ 14 , 15 ] or, additionally, releasing gasotransmitters such as H 2 S [ 16 ] or, as targeted herein, nitric oxide (NO • ) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Starting from naproxcinod [ 36 , 37 ], a variety of novel compounds now known as COX-inhibiting nitric oxide donors (CINODs) or nitric oxide-releasing COXIBs (NO-COXIBs) have been developed [ 31 ]. As a common principle for this class, known NSAIDs or COXIBs were functionalized directly or indirectly via a linker structure to an nitric oxide releasing moiety, e.g., nitro ester [ 38 , 39 , 40 , 41 ], diazeniumdiolate “NONO” [ 23 ], furoxane [ 40 ], or sulfohydroxame [ 41 , 42 ] functionalities ( Figure 1 ). NO • shares many actions of cytoprotective prostaglandins, as it stimulates mucus secretion from gastric cells.…”

Section: Introductionmentioning

confidence: 99%

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells

et al. 2022

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COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.

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Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety

Cited by 2 publications

References 36 publications

Towards safer anti-inflammatory therapy: synthesis of new thymol–pyrazole hybrids as dual COX-2/5-LOX inhibitors

Towards safer anti-inflammatory therapy: synthesis of new thymol–pyrazole hybrids as dual COX-2/5-LOX inhibitors

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells

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