Bioorganic & Medicinal Chemistry 2009-03-15

Design and synthesis of 4-methoxyphenylacetic acid esters as 15-lipoxygenase inhibitors and SAR comparative studies of them.

Hamid Sadeghian, Neda Attaran, Zeinab Jafari, Mohammad Reza Saberi, Seyed Mohammad Seyedi, Hossein Eshghi, Mehdi Pordel, Mohammad Mahdi Riazi

Index: Bioorg. Med. Chem. 17 , 2327-35, (2009)

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Abstract

A group of 4-methoxyphenylacetic acid esters were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compounds 7d-e showed the best IC(50) in SLO inhibition (IC(50)=3.8 and 1.9 microM, respectively). All compounds were docked in SLO active site and showed that carbonyl group of compounds is oriented toward the Fe(III)-OH moiety in the active site of enzyme and fixed by hydrogen bonding with hydroxyl group. It is assumed that lipophilic interaction of ligand-enzyme would be in charge of inhibiting the enzyme activity. The selectivity of the synthetic esters in inhibiting of 15-HLOb was also compared with 15-HLOa by molecular modeling and multiple alignment techniques.