<i>N</i>‑Tosyl Hydrazone Benzopyran,\na New Ligand of PPARα Obtained from Mapping the Conformational\nSpace of Its Active Site

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