<i>N</i>-Tosyl Hydrazone Benzopyran, a New Ligand of PPARα Obtained from Mapping the Conformational Space of Its Active Site

We report here a new ligand for the peroxisome-proliferator-activated receptor type α (PPARα), an N-tosyl hydrazone benzopyran that was designed throughout the mapping of the polar zone of the binding site of PPARα; such a compound displays a strong activity on this receptor that is comparable to that of the reference compound WY-14643. For the design of the <i>N</i>-tosyl hydrazone benzopyran, we have carried out an exhaustive conformational study of WY-14643 and a previously reported hydrazine benzopyran derivative using conformational potential energy surfaces (PES). This study allowed us to map in a systematic way the entire binding site of the PPARα. PESs allowed us to evaluate all of the critical points on the surface (minimum, transition states, and maxima) and determine the different conformational interconversion paths. Once the geometries of the different complexes were determined, we carried out the study of the different molecular interactions that stabilize these complexes through the use of QTAIM calculations. We report here for the first time the molecular behavior of WY-14643 and two compounds synthesized in our lab interacting in the active site of the PPARα providing all of the details about the different interactions that stabilize the formation of these complexes. On the basis of such information, we were able to design and synthesize a new N-tosyl hydrazone benzopyran possessing a strong agonist effect on PPARα. The information provided by this study is very useful to get a better understanding of the behavior with this type of ligand on the PPARα, giving also interesting information as a guide for the design of new ligands for this receptor.