QSAR study of dual cyclooxygenase and 5-lipoxygenase inhibitors 2,6-di-tert-butylphenol derivatives

The dual or selective ability of 24 derived mono- and 2,6-di-tert-butylphenols (DTBP) to act as inhibitors of cyclooxygenase (COX) and/or 5-lipoxygenase (LOX) enzymes is investigated. Firstly, we explored the conformational variability of the compounds. It is found that dual inhibitors can adopt four minimum energy conformations: cis or trans, depending on the orientation of the carbonyl oxygen atom (localized in the para position) relative to the hydroxyl hydrogen, and alpha or beta, depending on whether the carbonyl oxygen is below or above the phenyl plane. The possible bioactive conformations are selected by molecular superimposition to the optimised structure of tebufelone, a dual inhibitor in the clinical trial phase. From this selected conformation, different molecular parameters were calculated and correlated with both COX/LOX inhibitory activities. The MEP and GRID maps for different probes (hydrogen bond donor/acceptor, hydrophobic and ferric/ferrous interaction areas) are represented and discussed. The results point out the importance of the hydrogen donation and the hydrophobic properties in the COX inhibition whereas, for LOX inhibition, a redox mechanism might be involved. Finally, the predictive ability of the proposed QSAR equations is tested analysing a set of selective COX or LOX inhibitors.