Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors

Abstract

A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]- 2,2'5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'-halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'-chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline] -2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure-activity relationships in this series are also discussed.

Polycyclic heterocycles with acidic N-H group VI. The synthesis of some polycyclic heterocyclic compounds related to 3-phenyl-1,2-dihydro-quinoxaline-2-one

“…18,19 The cyclocondensation reaction of isatin 1a with 1,2-diaminobenzene was not successful; however, the cyclocondensation reaction of the protected N-acetylisatin 2a proceeded cyclocondensation reaction of 1b with 1,2-diaminobenzene afforded the quinoxaline 4b in one step.…”

Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

“…There exist a variety of structurally diverse aldose reductase inhibitors (ARIs) (Figure 2). These compounds can be divided into two general classes, those containing a carboxylic acid moiety and those having a cyclic imide represented by a spirohydantoin or related ring system [14,15,16,17]. Recently, however, arylsulphonylnitromethanes have emerged as a new class.…”

Methods of synthesis of nitrogen-containing heterocycles using ureas and related compounds

“…126 ± 129 The cyclisation in the presence of ZnCl 2 affords 1-R H -6-R-4phenylquinazolin-2-ones, 128 ± 130 while 6-R-4-phenylquinazolines are formed in the presence of formic acid. 131,132 It has been shown that N-allyl-N-nitrosourea is converted into pyrazole in 18% yield via the intermediate vinyldiazomethane. 125 6-Chloro-2-quinazolone-4-carboxylic acid 146 has been synthesised by condensing 5-chloroisatin with urea in 1-pentanol in the presence of aqueous KOH.…”