O-alkylated/acylated coumarin analogues: synthesis, anti-diabetic evaluation and docking studies.

Abstract

Diabetes mellitus (DM) represents a group of chronic disorders with diverse multiple etiology. It is characterized by high blood glucose (hyperglycemia) resulting from the malfunctioning in insulin secretion and/or insulin action, leading to impaired metabolism of carbohydrates, lipids and proteins in the body. According to 2013 WHO report, approximately 4.9 million people have died thus far and around 415 million are currently suffering from DM worldwide. Different approaches such as anti-diabetic drugs, insulin injection, and lifestyle modification are currently being used to control/treat diabetes. However, these techniques are not so effective and suffer a number of limitations which is why the development of novel potent anti-diabetic drugs is highly anticipated. Recent literature review revealed that the coumarins have potential to act as anti-diabetic agents with excellent pharmacological profile. Hence, the aim of this project was to synthesize variedly substituted coumarin analogues and to test their anti-diabetic potential under in vitro conditions. Accordingly, three 4-methylcoumarins bearing hydroxyl moiety were synthesized using substituted phenols and a β-ketoester using the Pechmann reaction. The hydroxyl group of synthesized coumarins was then engaged in further transformations by its alkylation and acylation using a variety of alkyl/acyl halides under basic conditions. The synthesized compounds were structurally characterized using different spectroscopic techniques viz. proton nuclear magnetic resonance spectroscopy (1H NMR, FT-IR and HR-MS). 2D NMR such as heteronuclear multiple bond correlation (HMBC), heteronuclear single quantum coherence spectroscopy (HSQC) and correlation spectroscopy (COSY) were also conducted to assign each proton and carbon resonances of the compounds synthesized. All the synthesized compounds were tested in vitro for their anti-diabetic activity using the standard drug (acarbose) as a control. Some of the coumarin derivatives exhibited excellent anti-diabetic activity, even better than the standard drug, based on the IC50 data. The effect of alkyl chain length and electronic nature (electron-donating/withdrawing) of substituents attached to coumarin ring on the anti-diabetic activity was monitored, and a detailed structure activity relationship (SAR) was established. The in vitro anti-oxidant activity of compounds further revealed the importance of hydroxyl (-OH) groups in coumarins for their antioxidant activity. The alkylation or acylation of coumarins significantly reduced their antioxidant activity. On the other hand, the attachment of nitro (-NO2) group to the aromatic ring of coumarin, impressively increased the antioxidant activity. Molecular docking simulations were finally conducted to predict the binding propensities of the compounds in the binding site of -glucosidase, an enzyme that regulates the sugar level in the body. Since, the X-ray data for this protein is not available in protein data bank, its 3D model was generated using homology modelling technique. The predicted free binding energies predicted these compounds to be good inhibitors for the protein. Docking data suggested the importance of both the hydrogen bonding and hydrophobic forces in their host-guest relationship.