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dc.description.abstractThe present thesis work discloses some potentially active coumarin-based lignan derivatives that are small molecule pro-inflammatory cytokine inhibitors for the treatment of chronic inflammatory conditions. In phase I, natural product derivatives like 7,8-dihydroxy-4-methyl coumarin (1a) and phenyl propanoids (3b, 4b, 5b) were identified to be significantly active against cytokines such as Tumor necrosis factor alpha (TNF-and#945;), Interleukin-1 Beta (IL-1and#946;) and Interleukin-6 (IL-6) through synthesis and in-vitro lipopolysaccharides (LPS)-induced cell based assays (ELISA). Based on these observations, some structural analogues (1a-7c) of coumarins and phenyl propanoids were designed and docking studies were performed over TNF-and#945;, IL-1and#946; and IL-6 proteins using GOLD 5.2 software. Cinnamic acid derivatives displayed higher GOLDScore_fitness and more number of non-bonding interactions with TNF-and#945;, IL-1and#946;, and IL-6 target proteins as compared to coumarins, especially the ethyl cinnamates possessing acetyl units. With this background, the coumarins (1a and 1b) and cinnamic acid derivatives (3-7c) were fused in different permutations and combinations to generate sixty novel fused-cyclic coumarin-based lignans (8-13k), which mimicked natural coumarinolignans. Docking studies on 8-13k unravelled some interesting compounds which had high GoldScore_fitness, interesting active site interactions and distinctive and#960;-and#960; interactions when compared to the standards (cleomiscosin A, diclofenac sodium and prednisolone). In phase II, some representative hit molecules (9d, 10d, 11d and 11e) from phase I were selected for synthesis and pharmacological studies. Compounds 9d, 10d, 11d and 11e were synthesized newlinev newlineby oxidative coupling of 7,8-dihydroxy-4-methyl coumarin (1a) and ethyl cinnamate ester newlinederivatives (3b, 4b and 5b) using diphenyl selenoxide as catalyst. All the compounds were found newlineto show excellent inhibition effect under in-vitro TNF-and#945;, IL-1and#946; and IL-6 protein estimation assay newlineby ELISA using LPS-stimulated RAW 264.7 cell lines, compare
dc.titleDesign and Synthesis of Novel Coumarin based Lignans as Pro inflammatory Cytokine Inhibitors for the Treatment of Chronic Inflammatory Diseases
dc.creator.researcherKumar Santhosh
dc.subject.keywordClinical Pre Clinical and Health
dc.subject.keywordPharmacology and Pharmacy
dc.subject.keywordPharmacology and Toxicology
dc.contributor.guideA. Sajeli Begum
dc.publisher.universityBirla Institute of Technology and Science
Appears in Departments:Pharmacy

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