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

Author(s): Nanjan Pandurangan*, Chinchu Bose, Sreejith Meppoyilam, Veni C. Kalathil, Anjana Murali, Anjana R. Prameela

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 1 , 2019

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Graphical Abstract:


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 ( 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.

Keywords: Partial synthesis, azaleatin, α-amylase inhibitor, antioxidant, SAR study, prodrugs.

Harvey, A.L.; Edrada-Ebel, R.; Quinn, R.J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov., 2015, 14(2), 111-129.
Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting on natural products for drug design. Nat. Chem., 2016, 8(6), 531-541.
Koirala, N.; Thuan, N.H.; Ghimire, G.P.; Thang, D.V.; Sohng, J.K. Methylation of flavonoids: Chemical structures, bioactivities, progress and perspectives for biotechnological production. Enzyme Microb. Technol., 2016, 86, 103-116.
Biasutto, L.; Zoratti, M. Prodrugs of quercetin and resveratrol: a strategy under development. Curr. Drug Metab., 2014, 15(1), 77-95.
Zhang, B.N.; Hou, Y.L.; Liu, B.J.; Liu, Q.M.; Qiao, G.F. The Rhododendron dauricum L. Flavonoids exert vasodilation and myocardial preservation. Iran. J. Pharm. Res., 2010, 9(3), 303-311.
Harborne, J.B. Plant polyphenols. 5. Occurrence of azalein and related pigments in flowers of Plumbago and Rhododendron species. Arch. Biochem. Biophys., 1962, 96, 171-178.
Don, R.G. On a flavonol glycoside isolated from flowers of a white azalea. J. Am. Chem. Soc., 1956, 1582, 77-78.
Kurkin, V.A. Saffloroside, a new flavonoid from flowers of Carthamus tinctorius L., J. Pharmacogn. Phytochem., 2015, 4, 29-31.
de Lima, C.C.; Lyra Lemos, R.P.; Conserva, L.M. Chemical constituents, larvicidal effects and radical scavenging activity of Tetracera breyniana schltdl. (Dilleniaceae). J. Appl. Pharm. Sci., 2013, 3, 14-18.
Pachaly, P.; Tan, H.L. Simple synthesis of azaleatin from quercetin. Arch. Pharm. (Weinheim), 1994, 8, 535-537.
Banerji, A. Bio-inspired syntheses of partially methylated flavonoids – untapped source of bioactivities. J. Expl. Res. Pharm., 2017, 2, 16-20.
Xiao, Z.; Storms, R.; Tsang, A. A quantitative starch-iodine method for measuring alpha-amylase and glucoamylase activities. Anal. Biochem., 2006, 351(1), 146-148.
Sharad, V.; Raka, K. Identification of flavonoids from plant parts and callus culture of Gymnema sylvestre R.Br. an antidiabetic plant. Curr. Bioact. Compd., 2016, 12, 264-268.
Arjouniab, M.Y.; Romane, A.; Felsbc, A.E.; Boukird, A.; Algabre, M. Antioxidant activity and chemical composition of essential oil of Cupressus atlantica Gaussen, antioxidant activity and chemical composition of essential oil. Curr. Bioact. Compd., 2015, 11, 56-60.
Polyana, B.F.B.; Fabiana, C.; Fernando, Z.; Lucas, U.R.C.; Eduardo, J.P.; Ivanor, N.P.; Jesuí, V.V. Antioxidant capacity and identification of bioactive compounds by GC-MS of essential oils from spices, herbs and citrus. Curr. Bioact. Compd., 2017, 13, 137-143.
Soumia, B.; Naima, B.; Messaoud, H.; Hamada, H. Investigation of in vitro antioxidant activity and in vivo antipyretic and anti-inflammatory activities of Algerian eryngium campestre L. Curr. Bioact. Compd., 2017, 13, 340-346.
Nanjan, P.; Nambiar, J.; Nair, B.G.; Banerji, A. Synthesis and discovery of (I-3,II-3)-biacacetin as a novel non-zinc binding inhibitor of MMP-2 and MMP-9. Bioorg. Med. Chem., 2015, 23(13), 3781-3787.

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Article Details

Year: 2019
Page: [103 - 108]
Pages: 6
DOI: 10.2174/1573407214666171226155509
Price: $65

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