Background:
During last two decades, good progress has been made for the flavonoids in
metabolic and infectious diseases. However, expectations have not been fulfilled when these compounds
were extended to the in vivo studies, particularly in humans. This could due to low bioavailability and
less absorption of flavonoids in the biological systems. A recent study revealed that methylation of flavonoids
can bring about dramatic changes in pharmacokinetic and biochemical properties. Often, the
partially methylated flavonoids show better activities by improving their metabolic stability, membrane
transport capacity, facilitating absorption and for oral bio-availability. Though, partial methyl ethers
occupy 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 the
preparation of azaleatin. Synthesized compounds and their derivatives were subjected for α-Amylase
and DPPH activities. α-Amylase activity can be measured in vitro by hydrolysis of starch in presence of
α-amylase enzyme. Antioxidant capacity was evaluated by measuring the scavenging activity of
azaleatin and related compounds on the 2,2- diphenyl-l-1-picrylhydrazil (DPPH) radical. In order to
identify 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 standard
for the inhibition of α-amylase amongst the tested compounds. Since, azaleatin is a best for the
inhibition 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, other
closely related derivatives were studied for their antioxidant capacity. It was found that amongst the
compound tested quercetin was found to be best (EC50 of 30µg/mL) for their antioxidant capacity and
second 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 acceptable
radical scavenging activity. Further, in-silico modelling studies indicated that azaleatin found to have
very 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 improvement
through further structural modifications.
Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple)
