Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

Qian, Shihu; Huang, Yuanzheng; Li, Jiaming; Zhang, Yanchun; Zhang, Bin; Fan, Jiulun

doi:10.6023/cjoc202007073

Cited by 3 publications

(2 citation statements)

References 11 publications

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“…The phenoxy acetamide, indole, chalcone thiosemicarbazone, and quinoline are important groups in anti-inflammatory agents [47,107,108]. Huang, Qian, and coworkers designed indole-2-amides as anti-inflammatory drugs [33,109]. Results showed that 40, 41, 42 and 43 (Figure 4) present interesting anti-inflammatory properties, with 40 being the most promising compound with COX-2 selectivity and dual COX-2/5-LOX activity binding in the same way as coxibs into the COX-2 active site [33].…”

Section: Multitarget Drugsmentioning

confidence: 99%

The Role of Organic Small Molecules in Pain Management

Cuesta

Meneses

2021

Molecules

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In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.

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Section: Multitarget Drugsmentioning

confidence: 99%

The Role of Organic Small Molecules in Pain Management

Cuesta

Meneses

2021

Molecules

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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%

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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Synthesis and fungicidal activity of novel benzimidazole derivatives bearing pyrimidine‐thioether moiety against Botrytis cinerea

Sun

Zhang

Qian

et al. 2021

Pest Management Science

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BACKGROUND: Botrytis cinerea is a serious plant fungus and strongly affects the yield and quality of crops. The main control strategy is the employment of fungicides. To research for efficient fungicide with novel structure, a series of novel benzimidazole derivatives bearing pyrimidine and thioether moieties were designed and synthesized.RESULTS: Some target compounds such as 4h, 4i, 4k, 4l, 4m, 4s, 4t and 4u exhibited notable fungicidal activities, with half maximal effective concentration (EC 50 ) values in the range 0.13-0.24 ∼g mL −1 , which means that their activities were comparable or higher than that of carbendazim (EC 50 = 0.21 ∼g mL −1 ). Among them, N-(4-fluorophenyl)-2-((4-(1H-benzimidazol-2-yl)-6-(4-methoxyphenyl) pyrimidin-2-yl)thio)acetamide (4m) displayed the best activity (EC 50 = 0.13 ∼g mL −1 ). Molecular electrostatic potential analysis of 4m elucidated that the NH moiety of benzimidazole ring was located in the positive potential region and may generate hydrogen bond with target amino acid residue. Molecular docking analysis revealed that there was one hydrogen bond and one π-π interaction between 4m and target protein.CONCLUSIONS: This study demonstrated that the benzimidazole derivatives bearing pyrimidine and thioether moieties can be further optimized as a lead compound for the control of B. cinerea. The combination of molecular electrostatic potential and molecular docking analyses may provide a valuable reference for studying the interaction between the ligand and target protein.

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Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

Cited by 3 publications

References 11 publications

The Role of Organic Small Molecules in Pain Management

The Role of Organic Small Molecules in Pain Management

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

Synthesis and fungicidal activity of novel benzimidazole derivatives bearing pyrimidine‐thioether moiety against Botrytis cinerea

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