Novel stable configurations and tautomers of the neutral and deprotonated hydroxamic acids predicted from high-level ab initio calculations

Hydroxamic acids, best known as iron chelators, have recently been widely u sed as a key functional group of potential therapeutics targeting at zinc-b ound matrix metalloproteinases involved in cancers. To investigate the opti mal structural variations of hydroxamic acids that confer the maximal selec tivity for zinc over iron for rational design of cancer drugs, we have firs t performed calculations of hydroxamic acids in the absence of metal ions e mploying density functional, Moller-Plesset, and coupled cluster theories. Herein we report the high-level ab initio calculations of hydroxamic acids that offer new insights into the intricate structures of acetohydroxamic ac id. The results suggest that in the gas phase acetohydroxamic acid exists i n the E- and Z-keto forms and the Z-iminol form that are in equilibrium, wh ereas the deprotonated acetohydroxamic acid exists in the nitrogen-deproton ated Z-keto form and the C-hydroxy oxygen-deprotonated Z-iminol form that a re in resonance. Substitution of the nitrogen proton of acetohydroxamic aci d by a methyl group does not change the structures and relative stability o f the neutral and deprotonated acetohydroxamic acid in different configurat ions and tautomers.