Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety.
Benzil has been identified as a potent selective inhibitor of carboxylesterases (CEs). Essential components of the molecule required for inhibitory activity include the dione moiety and the benzene rings, and substitution within the rings affords increased selectivity toward CEs from different species. Replacement of the benzene rings with heterocyclic substituents increased the K(i) values for the compounds toward three mammalian CEs when using o-nitrophenyl acetate as a substrate. Logarithmic plots of the K(i) values versus the empirical resonance energy, the heat of union of formation energy, or the aromatic stabilization energy determined from molecular orbital calculations for the ring structures yielded linear relationships that allowed prediction of the efficacy of the diones toward CE inhibition. Using these data, we predicted that 2,2'-naphthil would be an excellent inhibitor of mammalian CEs. This was demonstrated to be correct with a K(i) value of 1 nM being observed for a rabbit liver CE. In addition, molecular simulations of the movement of the ring structures around the dione dihedral indicated that the ability of the compounds to inhibit CEs was due, in part, to rotational constraints enforced by the dione moiety. Overall, these studies identify subdomains within the aromatic ethane-1,2-diones, that are responsible for CE inhibition.
Hyatt
Janice L
JL
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA.
Stacy
Vanessa
V
Wadkins
Randy M
RM
Yoon
Kyoung Jin P
KJ
Wierdl
Monika
M
Edwards
Carol C
CC
Zeller
Matthias
M
Hunter
Allen D
AD
Danks
Mary K
MK
Crundwell
Guy
G
Potter
Philip M
PM
D000818:Animals; D001573:Benzoin / Q000737:chemistry; D001966:Bromine / Q000737:chemistry; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry; D010658:Phenylglyoxal / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D011789:Quantum Theory; D011817:Rabbits; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry*
D005663:Furans; D009281:Naphthalenes; D011725:Pyridines; D013876:Thiophenes; D002265:Carboxylic Ester Hydrolases; D001573:Benzoin; D010658:Phenylglyoxal; C006697:benzil; D001966:Bromine