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ABSTRACT:The formation energies of a series of substituted derivatives in ␣-position of ibuprofen (2-p-isobutyl-phenyl-propionic acid) are determined, at the ab initio level RHF/6-311G** with full geometry optimization, in their neutral and anionic forms and in the gas phase and water solution to correlate their physical-chemical properties with their anti-inflammatory activity. Conformational calculations on the acidic moiety were also performed on five of them. The ab initio methods foresee that all these molecules present two preferred conformations in which the substituting atom in ␣-position is lying approximately in the aromatic ring plane, in contrast with the results obtained with semiempirical methods. In this article, the protonation energy in solution, the solvation energy, the HOMO energy of the neutral form, and the lipophilicity will be considered as possible factors of anti-inflammatory activity. The protonation energy in solution, together with the lipophilicity, are verified to be good activity factors: The smaller the protonation energy and the lipophilicity, the larger the anti-inflammatory activity. In contrast, the larger the solvation energy, the smaller the activity.