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The studies on Momordica charantia fruits and the synthesis of pyrazolyl substituted benzylidene indanone derivatives as dengue virus type-2 NS2B/NS3 protease inhibitor

Abstract : There are neither curative nor preventive therapies of dengue fever (DF). Only supplemental medical care and fluid therapy are available to fight DF. Some patients opt for prevention and treatment measure used by the ancient people or folk remedy to treat sickness. One of folk remedy used among patients with dengue fever in the Malaysia hospital is consumption of frog meat soup with bitter melon (Momordica charantia). The fruits flesh and seeds of Momordica charantia (M. charantia) were utilized in this study. The oil of M. charantia seeds were extracted via aqueous enzymatic extraction (AEE) and the oil yield increased with optimum condition to extract the seed oil was to use HEL1:X7 (5:1.25). The seeds oil as well as the lignin, hemicelullose, soluble sugars, and uronic acids content were different accordance to the type of enzyme cocktail ratio. On the other hand, the M. charantia fruits flesh ethyl acetate extract was found to inhibit 38.11 ± 1.06 % of the DENV-2 NS2B/NS3 protease. Based on the GC-MS analysis the trace of gallic acid was found and was selected the basic structural frameworks for synthesis of the DENV-2 NS2B/NS3 protease inhibitor. The pyrazolyl substituted indanone derivatives, 90a-t were synthesized and characterized using FTIR, NMR, and LC-MS analysis. An appropriate percentage of yield of the compounds were obtained. The compounds 90a-t underwent in silico study using AutoDock4.2 to identify the binding mode and conformation with the Wichapong homology protein crystal structure. Five compounds were found to obtained free energy of binding (FEB) less than -7.55 kcal/mol. Compound 90p showed eight hydrogen bond interactions, one π-π stacking interaction, and one π-alkyl interaction with the amino acid residue in the DENV-2 NS2B/NS3 protease. Lastly, the in vitro studies of top five docked synthesized compound towards DENV-2 NS2B/NS3 protease by using fluorogenic peptide substrate Boc-Gly-Arg-7-amino-4-methylcoumarin were conducted. The panduratin A was used as the positive control. Compound 90p showed a high DENV-2 NS2B/NS3 protease inhibitor activity (65.61 ± 0.98 %), while panduratin A (47.59 ± 1.03 %), and gallic acid (25.11 ± 1.11 %). The IC50 value for compound 90p was observed to be 78.87 µM which is lower compared to the panduratin A, 290.27 µM. The compound 90p is concluded to be a potent hit-to-led compound in the development of DENV-2 NS2B/NS3 protease inhibitor.
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Submitted on : Saturday, October 17, 2020 - 10:21:35 AM
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Nadirah Zawani Mohd Nesfu. The studies on Momordica charantia fruits and the synthesis of pyrazolyl substituted benzylidene indanone derivatives as dengue virus type-2 NS2B/NS3 protease inhibitor. Organic chemistry. Université de Lorraine; Universiti Sains Malaysia (Malaisie), 2020. English. ⟨NNT : 2020LORR0092⟩. ⟨tel-02969953⟩



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