Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

Abstract

Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies

“…The carvacrol derivatives 4a-f and 6a-d were obtained by following the previouslydescribed method [ 32 ] with slight modification shown insupporting informations ( S1 and S2 Figs). The carvacrol in the first step is converted in tointermediate 2 by esterification reaction with chloroacetyl chloride in the presence of (C 2 H 5 ) 3 N and anhydrous methylene chloride as solvent.…”

Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration

“…Needle-like crystals of crude 2-chloro-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide were obtained, which were further purified through recrystallization in ethanol. The melting point was recorded as 99-102 • C; yield 82% [32]. In the third step, the equimolar ratios of the intermediate product, triethylamine ((CH 3 ) 3 N), potassium iodide (KI), and substituted amines (a and b), respectively, were stirred in dimethylformamide (DMF) (30 mL) at room temperature for 5 h (Figure 1: general scheme).…”

Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives

“…There are a number of tyrosinase inhibitors; hydroquinone and kojic acid and, potent antioxidants; tert-butyl hydroxyanisole (BHA) and tert-butyl hydroxytoluene (BHT) which may show undesirable side effects; cytotoxicity, dermatitis and skin cancer 21 . Recently, methoxy phenyl thiourea, thiazole derivatives and kojic acid derivatives have been reported as the tyrosinase inhibitor ( Figure 1) [22][23][24] . Therefore, search for safe and effective depigmenting agents is required which may address these issues and serve as a better solution for treating pigment related dermatological disorders.…”