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Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy nano-formulation
Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. T...
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Published in: | RSC advances 2024-10, Vol.14 (45), p.32721-32732 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | |
Online Access: | Get full text |
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Summary: | Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-
N
-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-
N
-(4-fluorophenyl)thiophene-3-carboxamide
VIIa
demonstrated selective COX-2 inhibition with an IC
50
value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC
50
value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound
VIIa
displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound
VIIa
showed potent anti-inflammatory activity with 93% inhibition and an IC
50
value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC
50
value 0.89 μM. Although molecule
VIIa
demonstrated significant
in vitro
anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor
in vivo
activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for
in vivo
use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.
This study designs novel 2-benzamido-
N |
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ISSN: | 2046-2069 |
DOI: | 10.1039/d4ra06295g |