PHOTOPHYSICAL BEHAVIOR OF COUMARIN DERIVATIVES AND THEIR INHIBITORY EFFECT ON AChE ACTIVITY Prayasee Baruah, Sivaprasad Mitra* Centre for Advanced Studies, Department of Chemistry, North-Eastern Hill University, Shillong – 793022, India E-mail:
[email protected]
The Michaelis Menten constant, KM and maximum hydrolysis rate, Vmax were obtained with the corresponding relations for normal and inhibition cases given by the following equations. V0= Vmax [S0]/ Km + [S0 ] V0= Vmax'[S0]/ Km'+ [S0 ]
Fluorescent class of compounds.
Shows a high degree of sensitivity in their local environment like viscosity and polarity. Used extensively in biological and analytical approaches as anti-HIV, anti-tumor, anti-helminitic and as
Michaelis Menten (above) and Lineweaver Burk (below) plots of AChE hydrolysis in varying concentrations of CC, MHC and standard AD drug Donepezil.
inhibitors for different enzymatic systems. Ability to inhibit acetylcholinesterase (AChE), key path of Alzheimer’s disease, well-documented. Detection of crucial structural features within the coumarin template and reviews on SAR relationships have helped in designing new coumarin analogs with enhanced AChE inhibitory activity.
+
O
O
N N
O
OH
O
H2N HO O
Chromenyl Coumarate (CC)
O
O
•Memory loss. •Difficulty recognizing things, doing simple math. •Aggression, agitation, difficulty with self-care. • Depression, loneliness, mood swings. •Inability to combine muscle movements, loss of appetite, jumbled speech.
HO
3,3'-Methylene-bis(4-hydroxy coumarin) (MHC)
The spectral observables (P) like absorption and emission maxima, Stoke’s shift, quantum yield, fluorescence lifetime, radiative and non-radiative decay rates of both the compounds have been calculated from the steady-state and time-resolved fluorescence measurements.
CHOLINERGIC HYPOTHESIS
O
Both CC and MHC exhibit substantial inhibitory efficacy on AChE.
Investigated Coumarin derivatives
The 4-parameter modified Kamlet Taft equation was used for monitoring the solvatochromic contributions: P=P0+ sπ* + aα + bβ + cγ Where π*, α, β and γ represents solvent polarisability, acidity, basicity, and solvent dipolarity; the constants a, b, s and c represent the contributions of the solvent properties.
Vmax decreases. Magnitude of unaltered.
Km
remains
Non-competitive type of inhibition. Inhibitor binds to the enzyme irrespective of whether the enzyme has bound to the substrate or not.
AChE inhibitors prevent breakdown of ACh increasing its availability in the brain Leads improved cognition.
to
Acetylcholine (ACh)
Contribution of solvatochromic parameters on spectral observables of CC (left) and MHC (right).
Modified Hill relation
Both CC and MHC bind to Peripheral Anionic Site (PAS) off AChE, which correlates with experimental findings and literature reports. CC is found to have the highest binding affinity with AchE (-9.1 kcal/ mol), followed by MHC (-8.5 kcal/mol) and AMC (-7.8 kcal/ mol) indicating CC to be the most potent inhibitor of the three.
All the investigated systems were found to inhibit AChE in a non-competitive manner. CC shows the highest inhibition potency. CC shows greater inhibition potency than standard cholinergic drug DON in free aqueous medium. The strong binding with the peripheral anionic site of AChE is predicted to be the reason of the higher inhibitory activities of the coumarin compounds. These conjectures envisage the potential application of these coumarin compounds with judicious synthetic fabrication as possible drug leads for the treatment of AD.
1. M. J. Kamlet, J. L. M. Abboud, M. H. Abraham and R. W. Taft, J. Org. Chem., 1983 (48), 2877-2887.
2. G.L. Ellman, D.K. Courtney, V. Andreas and R.M. Featherstone, Biochem. Pharmacol., 1961 (7), 88-89. 3. M. M. Islam, A. B. Gurung, A. Bhattacharjee, K. Aguan and S. Mitra, Chemico-Biological Interactions,2016 (249), 1-9.
Department of Chemistry, NEHU. Department of Biotechnology, NEHU. Dept. of Science & Technology (DST), Govt. of India.
