QSAR AND CONFORMATIONAL-ANALYSIS OF THE ANTIINFLAMMATORY AGENT AMFENAC AND ANALOGS

The new nonsteroidal antiinflammatory drug (NSAID) arylacetic amfenac (2-amino-3-benzoylphenylacetic acid) and 19 substituted derivatives we re studied in order to correlate the biological activities with the st ructure-related parameters. The geometry of amfenac in neutral and ani onic form was totally optimized, starting from standard geometries and crystallographic data, using semiempirical AM1 and MNDO quantum-mecha nical methods. Conformational analysis shows the existence of a rigid structure for rotations of the acetic acid chain (alpha-degrees) and t he central carbonyl group (gamma-degrees) around the bonds with the ph enylamine ring, whereas the carboxyl group (beta-degrees) and the phen yl ring of the benzoyl group (delta-degrees) can rotate almost freely. Electrostatic potential maps were analyzed and showed that the electr ostatic orientation effect seems to make an important contribution to the binding of the active compounds to prostaglandin synthase. An elec trostatic orientation model of the binding site is proposed. The front ier orbital charge distribution was also described for each compound. On the other hand, steric, electronic and hydrophobic (log P) paramete rs were calculated and QSAR analysis showed that the most significant parameter for the antiinflammatory activity was the pi-electron densit y of the HOMO orbital in the second aromatic ring. These results sugge st a possible electronic charge transfer between the aromatic fragment s and the receptor.