Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies (original) (raw)

Computer aided discovery of potential anti-inflammatory (S)-naproxen analogs as COX-2 inhibitors

Medicinal chemistry (Shāriqah (United Arab Emirates)), 2013

A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol-2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of -0.40kcal/mol and ulcerogenic index as least as 1.19.

In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Molecules

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to con...

Derivatives : Synthesis , Anti-inflammatory , Analgesic , Quantitative Structure – Activity Relationship and in Vitro Studies

2013

Some 1-(4-chlorophenyl or benzenesulfonamide)-2,3and/or 4-substituted-1H-pyrazol-5(4H)-one derivatives were synthesized and screened for their anti-inflammatory and analgesic activities, in addition to their ulcerogenic liability. They were found to be active as anti-inflammatory and analgesic agents. Compound 6b was found to be the most active as anti-inflammatory agent and compound 9b was found to be the most active one as anti-inflammatory and analgesic agent. On the other hand, cyclooxygenase-1/-2 (COX-1)/COX-2 isozyme selectivity was also done and the tested compounds showed equal inhibition to both isoforms. Moreover, 2D-quantitative structure–activity relationship (QSAR) studies revealed well predictive and statistically significant and cross validated QSAR model that helps to explore some expectedly potent compounds.

Synthesis and anti-inflammatory activity of novel aspirin and ibuprofen amide derivatives

2016

This study includes design and synthesis of new non -steroidal anti-inflammatory agents (NSAIDs) to ach ieve better activity and low gastric side effects. Two series o f c mpounds have been designed and synthesized as p otential NSAIDs, these are: aspirin derivatives (compounds 1, 2) and ibuprofen derivatives (compounds 3&4). The major side effects associated with all currently availabl e NSAIDS are gastrointestinal tract (GIT) hemorrhag e and ulceration, due to inhibition of COX-1, which is re sponsible for biosynthesis of cyto-protective prost aglandins E2, while COX–2 is synthesized in response to proinflam m tory stimuli such as, cytokines. Structural modif ication of available traditional NSAIDS, might be improve thei r specificity for COX–2 enzyme selectivity. These d erivatives were prepared from Aspirin and Ibuprofen that con jugated with 2-Amino-5 – ethyl —1, 3, 4-thiadiazole, and 2Amino-5trifluoromethyl -1, 3, 4-thiadiazole resp ctively using N, N-dicyclohexylcarbodiimide ...

Computational Design, Synthesis, and Pharmacological Evaluation of Naproxen-Guaiacol Chimera for Gastro-Sparing Anti-Inflammatory Response by Selective COX2 Inhibition

Molecules

The 4-allyl guaiacol is a natural phenolic molecule that has been widely studied for its antioxidant capacity against reactive-oxygen-species-mediated cellular damage. Therefore, we hypothesized that concomitant use of an antioxidant and NSAID may decrease the risk of gastrointestinal toxicity and make the therapy safer. To address the gastrointestinal toxicity of conventional NSAIDs, a new S-naproxen-4-allyl guaiacol chimera (MAS-1696) was computationally developed, chemically synthesized, and tested for anti-inflammatory effectiveness and gastrointestinal safety. The inhibitory potency of MAS-1696 tested against cyclooxygenase-2 (COX2), 15-lipoxygenase-2 (15-LOX2), and lipoxygenase-5 (5-LOX) in vitro revealed a stronger inhibition of COX2. Furthermore, the MAS-1696 chimera increased the COX selectivity index by 23% as compared to the parent compound naproxen, implying higher efficacy and gastric safety. In vivo data showed that MAS-1696 was less likely to cause gastrointestinal ha...