Two cyclopropanecarbonyl derivatives were independently found to be 15 and 14 times more potent than the corresponding isopropylcarbonyl analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase and dihydroorotate dehydrogenase, respectively. A thorough examination of the co-crystal structures of available enzyme inhibitor complexes and the conformation of X-ray crystal structures of several synthesized cyclopropanecarbonyl derivatives revealed that this enhancement by one order of magnitude of inhibition potency exhibited by cyclopropanecarbonyl derivatives in both enzymes is probably caused by respective metal chelating and hydrogen bonding interactions at the ligand-receptor binding site. These specific interactions subsequently cause the cyclopropyl group of the molecules to adopt a fixed bisected conformation, which is unavailable for isopropylcarbonyl derivatives. ? 2006 Elsevier Ltd. All rights reserved.
Relation:
Bioorganic and Medicinal Chemistry Letters Volume 16, Issue 23, 1 December 2006, Pages 6024-6027
