Drug Design, Docking Studies, Synthesis and In-Vitro Evaluation of Certain Novel Isoxazole Incorporated Coumarin Derivatives as Potent α - Amylase Inhibitors

Fahima, S (2021) Drug Design, Docking Studies, Synthesis and In-Vitro Evaluation of Certain Novel Isoxazole Incorporated Coumarin Derivatives as Potent α - Amylase Inhibitors. Masters thesis, J.K.K. Nattaraja College of Pharmacy, Kumarapalayam.


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The present work was focused on the designing and synthesis of novel isoxazole derivatives incorporated with coumarin moiety having α-amylase enzyme inhibitory activity. For this, following approach has been adopted. PHASE I: LITERATURE REVIEW Literature survey showed that coumarin is a drug like scaffold and is a core skeleton for the active sites involved in enzyme inhibiton in Type 2 diabetes. It also revealed that isoxazole possess enzyme inhibition for Type 2 diabetes. PHASE II: DRUG DESIGN APPROACH It involves the following stages: Stage 1: Identification of target α-amylase was selected as the target enzyme as its inhibition will prevent carbohydrate hydrolysis. The target enzyme (1UA7) was downloaded from RCBs Protein Databank. Stage 2: Lead optimization Lead optimisation was done by computation of drug likness score. Isoxazole derivatives of coumarin were the desired compounds with good molecular properties and bioactivity score, ie., the compounds A1, A3, A4 and K1, K3, K5 showed good scores. PHASE III: SYNTHESIS AND PHYSICAL CHARACTERIZATION A) Synthesis of the designed compounds In this work, ten new compounds are designed in which Six different isoxazole derivatives were synthesized by using three aromatic aldehydes and three aromatic ketones with coumarin moiety. The first step involved the synthesis of 6- acetyl 7- hydroxy 4- methyl coumarin by acetylation. Chalcones were prepared from 6- acetyl 7- hydroxy 4-methyl coumarin by using different aromatic aldehydes and aromatic ketones. Finally, the chalcones were reacted with hydroxylamine hydrochloride to form isoxazoles. B) Physical characterization Melting point of all the newly synthesised compounds was determined by capillary tube method. Rf values were determined by fixing various suitable solvent system on precoated silicagel- G plates. PHASE IV: SPECTRAL STUDIES The structure of the synthesised compounds was established by using IR, 1H NMR, and Mass spectral data. PHASE V: EVALUATION OF BIOLOGICAL ACTIVITIES Evaluation of α-amylase inhibitory activity All the newly sysnthesised compounds were screened for in vitro α-amylase inhibitory activity. All compounds showed significant activity in inhibition of the α-amylase enzyme. Comparatively A1 and K1 showed good % of inhibition activity, while A3, A4, K3, K5 showed moderate activity. CONCLUSION • The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. • α-amylase enzyme was selected as target and virtual screening made selection of lead compounds easier and coumarin was selected as lead molecule. • From among the ten docked molecules, six molecules with good Binding affinity were chosen for further laboratory synthesis. Drug likeness was predicted insilico before proceeding for synthesis. • Compounds A1, A3, A4 and K1, K3, K5 were found to have significant binding score against target enzyme α-amylase. compared to standard drug Acarbose. The selected derivatives were planned for synthesis. • The proposed Six compounds of isoxazole derivatives with coumarin ring system were synthesised in good yield using the developed schemes. • All the reactions were monitored by TLC one spot technique and the structures of the synthesised compounds were confirmed by IR, 1H NMR, Mass spectra. • Compounds A1, K1 and K3 exhibited maximum α-amylase inhibitory activity. Among the synthesized compounds, A1 and K1 can be taken for further studies as the lead molecule and acute toxicity studies are to be done on these promising compounds.

Item Type: Thesis (Masters)
Additional Information: 261915203
Uncontrolled Keywords: Drug Design, Docking Studies, Synthesis, In-Vitro Evaluation, Certain Novel Isoxazole, Coumarin Derivatives, Potent α - Amylase Inhibitors.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Subramani R
Date Deposited: 02 Nov 2022 17:33
Last Modified: 02 Nov 2022 18:12
URI: http://repository-tnmgrmu.ac.in/id/eprint/20920

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