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Theoretical and Experimental Studies on the Structure-Antioxidant Activity Relationship of Synthetic 4-Methylcoumarins

A. Barzegar^a,*, M.D. Davari^b, N. Chaparzadeh^c, N. Zarghami^d, J.Z. Pedersen^e, S. Incerpi^f, L. Saso^g, A.A. Moosavi-Movahedi^h

^aResearch Institute for Fundamental Sciences (RIFS), University of Tabriz, Tabriz, Iran
^bDepartment of Chemistry, Faculty of Sciences, Shahid Beheshti University, Tehran, Iran
^cDepartment of Biology, University of Tarbiat Moallem Azarbaijan, Tabriz, Iran
^dDepartment of Clinical Biochemistry, Tabriz University of Medical Science, Tabriz, Iran
^eDepartment of Biology, University Tor Vergata, Rome, Italy
^fDepartment of Biology, University Roma Tre, Rome, Italy
^gDepartment of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, Rome, Italy
^hInstitute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran  

The development of antioxidants as useful drugs for the treatment of neurodegenerative diseases such as Alzheimer's is extremely challenging in medicinal chemistry. Coumarins have attracted great attention as possible therapeutic tools against oxygen radicals in human degenerative diseases. In order to establish the possible structure-antioxidant activity relationship, a series of twenty four 4-methylcoumarin derivatives were examined by employing reducing power measurements, and comparison with bond dissociation enthalpy and ionization potential calculations. Based on the reducing potency of 4-methylcoumarin derivatives with respect to trolox, these compounds were classified into five groups as “most active”, “more active”, “moderately active”, “less active” and “inactive” derivatives. The presence of hydroxyl groups is an essential requirement for the activity, and substitution of hydroxyl groups by methoxy groups leads to non-active derivatives. The results revealed that dihydroxyl groups in the ortho position show a better antioxidant activity with respect to dihydroxyl groups in the meta position. This is ascribed to the ability to construct more stable 4-methylcoumarin radical intermediates by rearrangement of intra-molecular hydrogen bonding. Our findings indicate that other important factors to enhance the antioxidant activity of coumarins are the number of hydroxyl groups, the presence of ester substitutions and a thiono functional group on the pyrone ring. However, bond dissociation enthalpy and ionization potential calculations alone are not sufficient to identify the best antioxidant structures. As a result, chemical and functional properties of molecules such as 4-methylcoumarins should be examined as a whole entity, considering all substitutions versus a single substitution to design functional compounds with good antioxidant activity.

Keywords: Coumarins, Reactive oxygen species, Antioxidant, Reducing power, Free radical, B3LYP method