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 oxlinic acid analog was synthesized to evaluate the role, if any, played by the N-1 atom in putative modes of action of antimicrobial DNA gyrase inhibitors. Carba analogs were prepared because these have no possibility of an internal resonance contribution of the N 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 analogs prevents aromatization at the cost of nonplanarity. Only the unsubstituted parent compound, 1,2-dihydro-4,4-dimethyl-1-oxo-2-naphthalenecarboxylic acid (9e), possessed any appreciable antimicrobial activity in vitro. This may be due to a different mode of action, however, since 9e 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 O atoms.