Design, synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

Abdellatif, Khaled R.A.; Abdelgawad, Mohamed A.; Elshemy, Heba A.H.; Alsayed, Shahinda S.R.

doi:10.1016/j.bioorg.2015.11.001

Cited by 64 publications

(22 citation statements)

References 47 publications

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“…Since the gastrointestinal (GI) toxicity, as well as renal toxicity, were identified as the main adverse effect of the chronic use of the known (NSAIDs), which were mediated by COX-1 enzyme inhibition, attempt was made to develop COX-2 selective inhibitors (coxibs), which possess the therapeutic effect devoid of gastrointestinal (GI) and renal toxicity. (1)(2)(3)(4)(5)(6) 3-Dimensional structures analysis for the two isomers of COX enzyme demonstrated differences in the hydrophobic channel structure, as well as a rather larger orifice and the presence of an additional pocket lying away from the catalytic site, this makes the selective COX-2 inhibitors to require longer time to fit the COX-2 active site, but when they bind the enzyme, their bond may become permanent. They also may become competitive COX-1 inhibitors when given at high doses (7) .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Acute Anti-inflammatory Evaluation of New Mefenamic Acid Derivatives Having 4-Thiazolidinone Nucleus

Alsafi

Farhan²

2019

IJPS

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Mefenamic acid (MA) is one of the non-steroidal anti-inflammatory drugs, it is widely used probably due to having both anti-inflammatory and analgesic activity, the main side effects of mefenamic acid include gastrointestinal tract (GIT) disturbance mainly diarrhea, peptic ulceration, and gastric bleeding. The analgesic effects of NSAIDs are probably linked to COX-2 inhibition, while COX-1 inhibition is the major cause of this classic adverse effects. Introduction of thiazolidinone may lead to the increase in the bulkiness leads to the preferential inhibition of COX-2 rather than COX-1 enzyme. The study aimed to synthesize derivatives of mefenamic acid with more potency and to decrease the drug's potential side effects, new series of 4-thiazolidinone derivatives of mefenamic acid were synthesized IVa-g. The synthetic procedures for target compounds and their intermediates are designed to be as follows: acylation of secondary amine of mefenamic acid by chloroacetylchloride to produce compound (I), then reaction between compound (I) and hydrazine hydrate to form hydrazine derivative of mefenamic acid (compound II). After that, Schiff base formation by addition of seven benzaldehyde derivatives and finally, cyclization in presence of thioglycolic acid to form 4-thiazolidinone heterocyclic ring. The characterization of the titled compounds has been established on the basis of their spectral FTIR, 1 HNMR data, and by measurements of their physical properties. In vivo acute anti-inflammatory effect of the synthesized compounds was evaluated in rats using egg-white induced edema model of inflammation. The tested compounds and the reference drug produced significant reduction of paw edema with respect to the effect of dimethyl sulfoxide 10%v/v (control group). Compound IVe showed more potent effect than mefenamic acid at 240-300 min, while at time 300 min, compounds IVa and IVd exhibit more potent anti-inflammatory effect than mefenamic acid (50mg/kg, i.p.) as they reduced paw edema significantly more than mefenamic acid at mentioned intervals (p<0.05) . On the other hand compound IVc exhibited lower anti-inflammatory effect.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Acute Anti-inflammatory Evaluation of New Mefenamic Acid Derivatives Having 4-Thiazolidinone Nucleus

Alsafi

Farhan²

2019

IJPS

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“…Various natural products and biologically active synthetic compounds have five member, nitrogen and sulphur containing heterocyclic ring in their structures [3], such important class of compound is thiazolidn-4-one [4], this nucleus appears in the structure of thiamine [5], penicillin [6], antibiotics such as micrococcin [7], compounds possessing cardiac and glycemic benefit such as troglitazone [8] and many metabolic products of fungi and primitive marine animals, including 2-(aminoalkyl)-thiazole-4-carboxylic acids [9]. This moiety can also be found in various well known drugs with the desired therapeutic uses [10] and shows considerable physiological effects such as sedative [11], antiinflammatory [12], antibacterial [13], antifungal [14], antitubercular [15], analgesic and hypothermic [16], local [17] and spinal [18] anesthetic, CNS stimulant [19], anti-HIV [20] and nematicidal [21]. Further, thiazolidinones have also been used for the treatment of cardiac diseases [22], diabetic complications like cataracts, nephropathy and neuropathy [23] and selective antiplatelet activating factor [24].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Bis-pyrimidines Linked with Thiazolidin-4-one as New Antibacterial Agents

et al. 2019

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A series of novel 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)phenyl]-6-phenyl-2-pyrimidinyl-2-(aryl)-1,3-thiazolan-4-ones 5(a-j) have been synthesized and assayed for their antibacterial activity against B. subtilis, B. sphaericus, S. aureus, P. aeruginosa, K. Aerogenes and C. violaceum. The inhibition zones and minimal inhibitory concentrations were measured and compared with the streptomycin. The antibacterial screening data reveal that the compounds containing 4-nitrophenyl (5c), 3-nitrophenyl (5d), 4-dimethylaminophenyl (5g) and 1,3-benzodioxole (5j) moiety at 2-position of the thiazolidin-4-one ring exhibited potent inhibitory activity towards all the tested microorganism, which is higher than streptomycin. The other compounds also showed moderate to good activity.

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“…Thus, inhibition of COX‐2 accounts for the anti‐inflammatory effects of NSAIDs, whereas interruption of COX‐1 leads to gastrointestinal toxicity ranging from ulcers to perforation and bleeding . Time‐honored non‐selective NSAIDs such as indomethacin, ibuprofen, and aspirin interact with both forms (COX‐1 and COX‐2), accounting for their anti‐inflammatory activity in addition to their pronounced side effects, resulting from the inhibition of gastroprotective PGs synthesized through COX‐1 pathway . Hence, a number of selective COX‐2 inhibitors such as celecoxib I, rofecoxib II, and valdecoxib III (coxibs) have been developed and approved for marketing by virtue of their fewer gastrointestinal side effects compared with traditional NSAIDs (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…The pyrazole nucleus is known to exhibit wide range of biological activities such as antimicrobial , antiviral , antitumor , anti‐depressant , and anti‐inflammatory activity. Among these, four functionalized pyrazoles occupy a distinctive position in medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Anti‐inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX‐2 Selectivity and Enhanced Gastric Safety Profile

Pavase

Mane

Baheti³

2018

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).Novel sulfonamide containing diaryl pyrazoles were synthesized and were subsequently tested for their in vitro cyclooxygenase inhibitory assay. Compounds that showed promising in vitro COX-2 IC 50 values and selectivity indices were then evaluated for their in vivo anti-inflammatory inhibition assay using standard carrageenan-induced rat paw edema method. Two promising inhibitors were evaluated for ulcerogenic liability. X-ray crystal structure of COX-2 was taken from PDB entry COX-2 (3LN1) having a resolution of 2.80 Å (Angstroms). Structural preparations for docking studies were accomplished using protein preparation wizard in Maestro 9.0. Compound 10b displayed reasonable COX-2 inhibition (COX-2 IC 50 = 0.52 μM) and COX-2 selectivity index (SI = 10.73) when compared with celecoxib (COX-2 IC 50 = 0.78 μM) and (SI = 9.51). In vivo anti-inflammatory studies demonstrated 64.28% inhibition for 10b in comparison with the 57.14% for that of celecoxib itself. The results of ulcerogenic liability were also found comparable with standard celecoxib. Molecular docking studies revealed that all the designed molecules showed good interactions with receptor active site with glide scores in the range À13.130 to À10.624. 69%); mp = 192-194°C; 1 H NMR (DMSO-d 6, 400 MHz) δ 7.84 (d, 2H, J = 8.4 Hz, Ar─H), 7.49-7.51 (m, 4H, Ar─H), 7.38-7.39 (m, 2H, Ar─H), 7.27-7.29 (m, 2H, Ar─H), 7.13 (s, 1H, Pyrazole-H), 4.34 (q, 2H, J = 6.8 Hz, ─OCH 2 ─CH 3 ), 1.30 (t, 3H, ─OCH 2 ─CH 3, J = 7.2 Hz); ES-MS: m/z 372.2 (M + H) + . 4-(3-Hydrazinocarbonyl-5-phenylpyrazol-1-yl)benzenesulfonamide (9).To a suspension of ester intermediate (10 g, 269 mmol) 8 in ethanol (50 mL) was added hydrazine hydrate (6.72 g, 134 mmol) and refluxed the reaction mixture for 6 h. Reaction mixture becomes clear at the completion of the reaction under reflux.

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Design, synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

Cited by 64 publications

References 47 publications

Synthesis, Characterization and Acute Anti-inflammatory Evaluation of New Mefenamic Acid Derivatives Having 4-Thiazolidinone Nucleus

Synthesis, Characterization and Acute Anti-inflammatory Evaluation of New Mefenamic Acid Derivatives Having 4-Thiazolidinone Nucleus

Design and Synthesis of Bis-pyrimidines Linked with Thiazolidin-4-one as New Antibacterial Agents

Anti‐inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX‐2 Selectivity and Enhanced Gastric Safety Profile

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