Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a Potential Substrate for New Aldose Reductase Inhibitors

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.

Synthesis, crystal structures and properties of the novel mononuclear copper(II) and tetranuclear cobalt(II) complexes with 3,6-bis-(3,5-dimethylpyrazolyl)-pyridazine

“…In most cases, bridging azide groups take end-to-end (EE, l-1,3) and end-on (EO, l-1,1) coordination modes. The pyridazine and it's derivatives as the functional ligands have shown much useful function, such as application in magnetic exchange effects [4][5][6][7][8][9], pharmaceutical importance [10][11][12] and antimicrobial [13][14][15]. 3,6-bis-(3,5-dimethylpyrazolyl)-pyridazine (L) is one of the pyridazine derivatives, which as a function ligand has shown versatile properties in respect of the formation of monouclear and polynuclear complexes due to the formation of the five-membered metallacycles stabilizing the configurations around the metal center [16].…”

Screening and evaluation of rat kidney aldose reductase inhibitory activity of some pyridazine derivatives

“…Because of a shortage of drugs currently available for the treatment diabetic complications, the search for new ARIs with more favorable biological properties is still a major pharmaceutical challenge (Pau et al, 2004). Since some ARIs showing a pyridazinone anchor group were reported to possess excellent affinity and tissue penetration properties, significant research has been conducted (Courdet et al, 1991(Courdet et al, , 1992Buyukbingol et al, 1994;Constantino et al, 1999;Mavvari et al, 2005;Steuber et al, 2006). In light of , 2005) were evaluated via an in vitro spectrophotometric assay for their ability to inhibit rat kidney AR.…”

A neural networks-based drug discovery approach and its application for designing aldose reductase inhibitors

“…Both experimental studies and computer simulation have been carried out to find potent ARIs. However, compounds that have been identified as potent ARIs in both vitro and vivo are few [13][14][15][16]. All these found ARIs can be classified into several types such as flavonoids, spirohydantoins, substituted acetic acid and phenylsulfonylnitromethane derivations [5,17,18].…”