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Synthesis, Biological Evaluation and 3D-QSAR of 1,3,5-Trisubstituted-4,5- Dihydro-(1H)-Pyrazole Derivatives as Potent and Highly Selective Monoamine Oxidase A Inhibitors

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The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5 - trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives.

Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10-8 - 9.0 x 10-9M range. Moreover, it should be pointed out that for most of them a high IC50 ≥ 10-9M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000 - 16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds.

The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers.

The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.
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Keywords: (1H)-pyrazole derivatives; 3D-QSAR; Monoamine oxidase; Reversible monoamine oxidase-A inhibitors; Selective monoamine oxidase-A inhibitors

Document Type: Research Article

Affiliations: Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita "La Sapienza" P.le Aldo Moro 5, 00185 Roma, Italy.

Publication date: 2006-05-01

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