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QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues

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Summary

The new nonsteroidal antiinflammatory drug (NSAID) arylacetic amfenac (2-amino-3-benzoylphenylacetic acid) and 19 substituted derivatives were studied in order to correlate the biological activities with the structure-related parameters.

The geometry of amfenac in neutral and anionic form was totally optimized, starting from standard geometries and crystallographic data, using semiempirical AM1 and MNDO quantum-mechanical methods. Conformational analysis shows the existence of a rigid structure for rotations of the acetic acid chain (α°) and the central carbonyl group (γ°) around the bonds with the phenylamine ring, whereas the carboxyl group (β°) and the phenyl ring of the benzoyl group (δ°) can rotate almost freely.

Electrostatic potential maps were analyzed and showed that the electrostatic orientation effect seems to make an important contribution to the binding of the active compounds to prostaglandin synthase. An electrostatic orientation model of the binding site is proposed. The frontier orbital charge distribution was also described for each compound. On the other hand, steric, electronic and hydrophobic (log P) parameters were calculated and QSAR analysis showed that the most significant parameter for the antiinflammatory activity was the π-electron density of the HOMO orbital in the second aromatic ring. These results suggest a possible electronic charge transfer between the aromatic fragments and the receptor.

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Authors and Affiliations

  1. Unitat Fisicoquímica, Departament Farmàcia, Facultat de Farmàcia, Universitat de Barcelona, Avinguda Diagonal 643, E-08028, Barcelona, Spain

    Juan Ruiz, Manuel López, Josefa Milà, Estrella Lozoya, Juan José Lozano & Ramon Pouplana

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  1. Juan Ruiz
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  2. Manuel López
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  3. Josefa Milà
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  4. Estrella Lozoya
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  6. Ramon Pouplana
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Ruiz, J., López, M., Milà, J. et al. QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues. J Computer-Aided Mol Des 7, 183–198 (1993). https://doi.org/10.1007/BF00126444

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