Synthesis, Bioactivities and In-silico Docking Studies of Azaleatin-A Quercetin Partial Methyl Ether: SAR Study

摘要

Background: During last two decades, good progress has been made for the flavonoids inmetabolic and infectious diseases. However, expectations have not been fulfilled when these compoundswere extended to the in vivo studies, particularly in humans. This could due to low bioavailability andless absorption of flavonoids in the biological systems. A recent study revealed that methylation of flavonoidscan bring about dramatic changes in pharmacokinetic and biochemical properties. Often, thepartially methylated flavonoids show better activities by improving their metabolic stability, membranetransport capacity, facilitating absorption and for oral bio-availability. Though, partial methyl ethersoccupy a large chemical space, their biological properties has not been well established. Azaleatin(quercetin-5-O-methyl ether) is one of such group of naturally occurring molecules.Methods: In the present study, we have utilized methoxymethyl (MOM) protecting groups for thepreparation of azaleatin. Synthesized compounds and their derivatives were subjected for α-Amylaseand DPPH activities. α-Amylase activity can be measured in vitro by hydrolysis of starch in presence ofα-amylase enzyme. Antioxidant capacity was evaluated by measuring the scavenging activity ofazaleatin and related compounds on the 2,2- diphenyl-l-1-picrylhydrazil (DPPH) radical. In order toidentify the binding mode of the compound azaleatin, Auto Dock Tools (http://mgltools.scripps.edu)were used.Results: Quercetin, along with their derivatives, monomethyl ethers i.e. azaleatin, isorhamnetin,tamarixetin; dimethyl ether i.e. quercetin-3,7-dimethyl ether; quercetin-3,3',7-trimethyletherpachypodol;quercetin-3,3',4'7-tetramethyl ether and quercetin pentamethyl ether were taken for α-amylase inhibitory activity. The study showed that azaleatin was found to be comparable with the standardfor the inhibition of α-amylase amongst the tested compounds. Since, azaleatin is a best for theinhibition of α-amylase, this compound was taken for the in-silico molecular modelling studies.Azaleatin, showed a good docking energy (-8.8 Kcalmol-1) with the α-amylase receptor. Similarly, otherclosely related derivatives were studied for their antioxidant capacity. It was found that amongst thecompound tested quercetin was found to be best (EC50 of 30μg/mL) for their antioxidant capacity andsecond best compound was azaleatin; which showed EC50 of 36.1μg/mL.Conclusion: An efficient synthesis of azaleatin, a lesser known flavone has been achieved from quercetin.Amongst the compounds tested, azaleatin was found to inhibit α-amylase with the acceptableradical scavenging activity. Further, in-silico modelling studies indicated that azaleatin found to havevery good affinity with the key residues i.e. Gln63, Asp197 and Arg195 of α-amylase receptor. Since,azaleatin has other free hydroxyls in their template, it can be effectively utilized for the activity improvementthrough further structural modifications.