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Title: Design and Synthesis of Novel Coumarin based Lignans as Pro inflammatory Cytokine Inhibitors for the Treatment of Chronic Inflammatory Diseases
Researcher: Kumar Santhosh
Guide(s): A. Sajeli Begum
Keywords: Clinical Pre Clinical and Health
Pharmacology and Pharmacy
Pharmacology and Toxicology
University: Birla Institute of Technology and Science
Completed Date: 2018
Abstract: The 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
Pagination: 213p.
Appears in Departments:Pharmacy

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