Thiazole derivatives as inhibitors of cyclooxygenases in vitro and in vivo (original) (raw)
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Molecules
Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed h...
Thiazoles and Thiazolidinones as COX/LOX Inhibitors
Molecules, 2018
Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors.
Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases
Pharmaceuticals, 2022
The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cy...
Oriental journal of chemistry, 2015
A new series of thiadiazole linked pyrazole benzenesulfonamide derivatives were synthesized by the condensation of aldehydic pyrazole with aryl substituted thiadiazole amine followed by Schiff base reaction. The synthesized compounds (6a-o) were characterized by IR, NMR, and Mass spectral data, further evaluated their in-vivo anti-inflammatory, analgesic and invitro COX-II inhibition assay. The compounds 6b and 6m showed most significant in-vivo antiinflammatory with 72.33 &71.17% inhibition along analgesic activity having 67.89% and 71.37 % respectively. Their selectivity against COX-II enzyme with selectivity index 67.81 and 66.38 was established for 6b and 6m, which is compared with Celecoxib. During the gastric ulceration study, selected compounds couldn’t observed any ulcerogenic effect on gastric mucosa.The in-silico pharmacokinetic profile and molecular docking study exposed very good binding affinity towards the Cyclooxygenase (COX-II) enzyme (PDB Id: 3PGH), therefore the co...
Journal of Medicinal Chemistry, 2008
New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/ LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-(m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-(m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.
Computational Biology and Chemistry, 2016
Searching novel, safe and effective anti-inflammatory agents has remained an evolving research enquiry in the mainstream of inflammatory disorders. In the present investigation series of thiazoles bearing pyrazole as a possible pharmacophore were synthesized and assessed for their anti inflammatory activity using in vitro and in vivo methods. In order to decipher the possible anti-inflammatory mechanism of action of the synthesized compounds, cyclooxygenase I and II (COX-I and COX-II) inhibition assays were also carried out. The results obtained clearly focus the significance of compounds 5d, 5h and 5i as selective COX-II inhibitors. Moreover, compound 5h was also identified as a lead molecule for inhibition of the carrageenin induced rat paw edema in animal model studies. Molecular docking results revealed significant interactions of the test compounds with the active site of COX-II, which perhaps can be explored for design and development of novel COX-II selective anti-inflammatory agents.
COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles
Molecules
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.
Bioorganic & Medicinal Chemistry Letters, 1999
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors.
3,4-diarylpyrazoles: Potent and selective inhibitors of cyclooxygenase-2
Bioorganic & Medicinal Chemistry Letters, 1997
A series of 3,4-diarylpyrazoles was synthesized and evaluated lor their ability to selectively inhibit cyclooxygenase-2 (COX-2). A number of potent and selective inhibitors were identified and found to have oral anti-inflammatory activity in a rat carrageenan-induced foot pad edema assay. © 1997 Elsevier Science Ltd.
2020
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered the most excessively particular drugs for inflammation treatment including pain releasing, anti-pyretic and rheumatoid arthritis. They inhibit synthesis of prostaglandin by blocking the cyclooxygenation of arachidonic acid (AA) to prostaglandin G2 (PGG2)1. This inhibition process is catalyzed by means of the enzyme cyclooxygenase (COX) of which (COX-1) and (COX-2) are two similar but diverse isoforms of the enzyme24.COX-2 is prompted upon inflammatory motivators and is responsible for