Objective(s): Allylbenzenes have been recently developed as inhibitors of lipoxygenases. They decrease peroxidation activity via mimicking 1, 4-unsaturated bonds of fatty acids by their allyl portion. We designed and synthesized new derivatives of allyl benzenes (6a-f) with isopropoxy and amide substituents at ortho and meta positions towards allyl group, respectively. The inhibitory potency of the synthetized allylbenzenes against soybean 15-lipoxygenase (SLO) and subsequently structureactivity relationships was assessed. Materials and Methods: 3-allyl-4-isopropoxybenzenamine (5) as starting material was synthesized by coupling of 4-nitropheol with allyl bromide, performing Claisen rearrangement and finally reduction of the nitro moiety. Final products 6a-f were prepared via amidation of 5 with the desired acyl chloride. Results: Among the compounds, N-(3-allyl-4-isopropoxyphenyl)adamantan carboxamide (6f) potentially showed best inhibition (IC50 = 1. 35 μ M) while 6a with cyclopropyl carboxamide moiety was the weakest inhibitor and 6e with phenyl carboxamide moiety showed no effect. Energy minimized 3D structures of the compounds were docked into the active site pocket of SLO. For the aliphatic amides, docking results showed compatibility between inhibitory potency and average Ki of the cluster conformers, in which their allyl moiety oriented towards SLO iron core. For the aliphatic analogs, by enlargement of the amide moiety size the inhibitory potency was increased. Conclusion: Docking results showed that orientation of the amide and allyl moieties of the inhibitors in the active site pocket is the major factor in inhibitory potency variation. Based on the mentioned orientation, for cycloaliphatic amides, by enlargement of the amide moiety both inhibition potency and calculated binding energy increases.

Objective(s): Recently we reported that the soybean 15-lipoxygenase (SLO) inhibitory activity of pyrimido[4,5-b][l,4]benzothiazines largely depends on the orientation of sulfur atom of thiazine core towards FeIII-OH in the active site pocket of the enzyme with subsequent oxidation of sulfur to sulfoxide. In this paper the results of a comparative study on the SLO inhibitory activities of the mentioned compounds using ab initio calculations and docking analyses has been reported.Materials and Methods: Structure optimization and docking analyses were performed using HyperChem 7.5 and AutoDock Tools 4.0 respectively. Enzyme assessment was reduced using spectrophotometric MBTH-DMAB method.Results: The inhibitory activity of synthetic 2-substituted pyrimido[4,5-b][l,4]benzothiazines against soybean 15-lipoxygenase (SLO) was evaluated and structure activity relationships and binding modes of their 4-H and 4-methyl analogs were studied using docking analysis and ab initio calculations.Discussion: The results of these studies showed that the lack of 4-methyl substituent in the pyrimido[4,5-b][1,4]benzothiazine molecules greatly reduces their lipoxygenase inhibitory activities and it was also found that the HOMO energy difference between the 4-H and 4-Methyl analogs can be responsible for the observed inhibitory activity reduction.Conclusion: Our molecular modeling studies shows that by using more flexible amino acids during the docking process, more rational results can be obtained. The method of measuring the lipoxygenase activity is also of prime importance for the study of structure activity relationship.