Structure-activity relationships among DNA gyrase inhibitors. Synthesis and biological evaluation of 1,2-dihydro-4, 4-dimethyl-1-oxo-2-naphthalenecarboxylic acids as 1-carba bioisosteres of oxolinic acid

Abstract

A series of oxolinic acid analogues was synthesized in an attempt to evaluate the role, if any, played by the N-1 atom in putative modes of action of antimicrobial DNA gyrase inhibitors. Carba analogues were prepared because these have no possibility of an internal resonance contribution of the nitrogen atom and yet could otherwise satisfy electronic requirements of putative modes of action. Successful routes were developed involving Friedel-Craft's cycloaddition of suitable aromatic compounds with 4,4-dimethylbutyrolactone, followed by ethoxycarbonylation, oxidation with dichlorodicyanobenzoquinone, and careful saponification. The gem-dimethyl group of these analogues prevents aromatization at the cost of nonplanarity. Only the unsubstituted parent compound, 1,2-dihydro-4,4-dimethyl-1-oxo-2-naphthalenecarboxylic acid, possessed any appreciable antimicrobial activity in vitro. This may be due to a different mode of action, however, since gave no measurable inhibition of DNA gyrase in vitro. Thus, the N-1 atom plays a significant role in enzymic and bacteriological inhibition that cannot be compensated for by the presence of C-6 oxygen atoms.