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

Ashraf, Zaman,Alamgeer,,Rasool, Raqiqatur,Hassan, Mubashir,Ahsan, Haseeb,Afzal, Samina,Afzal, Khurram,Cho, Hongsik,Kim, Song Ja,Zhang, Ge,Lu, Aiping MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.12
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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.
2
Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies

Abbas, Qamar,Ashraf, Zaman,Hassan, Mubashir,Nadeem, Humaira,Latif, Muhammad,Afzal, Samina,Seo, Sung-Yum Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-
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The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound 6d is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides 4a–e and 6a–e were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound 6d showed excellent activity (IC50 0.15 µM) compared to standard kojic acid (IC50 16.69 µM). Lineweaver–Burk plots were used for the determination of kinetic mechanism, and it was found that compounds 4c and 6d showed non-competitive inhibition while 6a and 6b showed mixed-type inhibition. The kinetic mechanism further revealed that compound 6d formed irreversible complex with the target enzyme tyrosinase. The Ki values determined for compounds 4c, 6a, 6b and 6d are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound 6d exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound 6d in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound 6d possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound 6d showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of −7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide 6d formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound 6d is a promising candidate for the development of safe cosmetic agent.
3
Application of weighted average cardinality measure of intuitionistic fuzzy sets in ranking of intuitionistic fuzzy sets

Madiha Qayyum,Atiq Ur Rehman,Etienne E Kerre,Samina Ashraf 원광대학교 기초자연과학연구소 2018 ANNALS OF FUZZY MATHEMATICS AND INFORMATICS Vol.16 No.1
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In this paper, we have explored different aspects of weighted average cardinality of finite intuitionistic fuzzy sets with aid of necessity and possibility operators. Also we have defined the concept of scalar valued relative sigma count of intuitionistic fuzzy sets, which in turn is utilized to define a ranking technique for intuitionistic fuzzy sets and the concept of intuitionistic fuzzy quantifiers.

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