Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies.
Thirty derivatives of flavone hydrazone (5-34) had been synthesized through a five-step reaction and screened for their α-glucosidase inhibition activity. Chalcone 1 was synthesized through aldol condensation then subjected through oxidative cyclization, esterification, and condensation reaction to afford the final products. The result for baker's yeast α-glucosidase (EC 3.2.1.20) inhibition assay showed that all compounds are active with reference to the IC50 value of the acarbose (standard drug) except for compound 3. Increase in activity observed for compounds 2 to 34 clearly highlights the importance of flavone, hydrazide and hydrazone linkage in suppressing the activity of α-glucosidase. Additional functional group on N-benzylidene moiety further enhances the activity significantly. Compound 5 (15.4 ± 0.22 μM), a 2,4,6-trihydroxy substituted compound, is the most active compound in the series. Other compounds which were found to be active are those having chlorine, fluorine, and nitro substituents. Compounds with methoxy, pyridine, and methyl substituents are weakly active. Further studies showed that they are not active in inhibiting histone deacetylase activity and do not possess any cytotoxic properties. QSAR model was being developed to further identify the structural requirements contributing to the activity. Using Discovery Studio (DS) 2.5, various 2D descriptors were being used to develop the model. The QSAR model is able to predict the pIC50 and could be used as a prediction tool for compounds having the same skeletal framework. Molecular docking was done for all compounds using homology model of α-glucosidase to identify important binding modes responsible for inhibition activity.
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300, Selangor D.E., Malaysia; Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, 40450, Selangor D.E., Malaysia.
Syahrul
S
Imran
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300, Selangor D.E., Malaysia; Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, 40450, Selangor D.E., Malaysia. Electronic address: taha_hej@yahoo.com.
Muhammad
M
Taha
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300, Selangor D.E., Malaysia; Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, 40450, Selangor D.E., Malaysia. Electronic address: norhadiani@puncakalam.uitm.edu.my.
Nor Hadiani
NH
Ismail
Institute of Advance Research Studies in Chemical Sciences, University of Sindh, 76080, Jamshoro, Pakistan.
Syed Muhammad
SM
Kashif
Department of Chemistry, Hazara University, 21300, Mansehra, Pakistan.
Fazal
F
Rahim
Institute of Advance Research Studies in Chemical Sciences, University of Sindh, 76080, Jamshoro, Pakistan.
Waqas
W
Jamil
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Pulau Pinang, Malaysia.
Maywan
M
Hariono
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Pulau Pinang, Malaysia.
Muhammad
M
Yusuf
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Pulau Pinang, Malaysia.
Habibah
H
Wahab
D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology*; D000520:alpha-Glucosidases / Q000378:metabolism*
D047309:Flavones; D065089:Glycoside Hydrolase Inhibitors; D006835:Hydrazones; D000520:alpha-Glucosidases; C043562:flavone
2D-QSAR; Docking; Flavone; Hydrazone; α-Glucosidase