Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors

Luca Costantino, Giulio Rastelli, M. Cristina Gamberini, M. Paola Giovannoni, Vittorio Dal Piaz, Paola Vianello, Daniela Barlocco

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Abstract

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5,6- dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the presence at position 6 of a phenyl carrying an electron-withdrawing substituent proved to be beneficial, independently from its position on the ring (5g,j-l). Acetic acid derivatives were more effective than propionic and butyric analogues. On the contrary, all the monocyclic compounds (6-8) were either inactive or only weakly active. The 3- methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H)-one acetic acid (5g), which proved to be the most potent derivative, was also investigated in molecular modeling studies, to assess possible similarities in its interaction with the enzyme, with respect to the model 1.

Original languageEnglish
Pages (from-to)1894-1900
Number of pages7
JournalJournal of Medicinal Chemistry
Volume42
Issue number11
DOIs
Publication statusPublished - Jun 3 1999

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Costantino, L., Rastelli, G., Gamberini, M. C., Giovannoni, M. P., Piaz, V. D., Vianello, P., & Barlocco, D. (1999). Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors. Journal of Medicinal Chemistry, 42(11), 1894-1900. https://doi.org/10.1021/jm981107o