Experimental and theoretical studies on the tautomerism and reactivity of isoxazolo[3,4-b]quinolin-3(1H)-ones

A variety of substituted isoxazolo[3,4-b]quinolin-3(1H)-ones incorporating an ambident amidine functionality was synthesized by a two-step procedure starting from the corresponding 2-chloroquinoline-3-carboxylic acids. Alkylation and acylation reactions carried out in DMF solution in the presence of Et3N occurred preferentially on the available sigma lone pair of the pyridine-type N1 nitrogen atom of the most stable 9H-oxo tautomer. The use of sodium hydroxide in place of Et3N led to isoxazolone ring cleavage with the formation of alkyl 2-(alkoxy(alkyl)amino)quinoline-3-carboxylates. The electronic structure of the three possible N1-oxo, N9-oxo and 3-hydroxy tautomeric forms, and the NaOH-induced cleavage of the isoxazolone ring were studied theoretically with use of the B3LYP/6-31+G* density functional method and SM8 (DMF) solvation model. The synthesized N1-alkyl and N1-acyl derivatives of isoxazolo [3,4-b]quinolin-3(1H)-one were evaluated for their in vitro antifungal activity against 19 pathogenic yeast-like fungal strains. (C) 2015 Elsevier Ltd. All rights reserved.