Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives.

In continuation of our studies, we here report a series of non-carboxylic acid containing 2,4-thiazolidinedione derivatives, analogues of previously synthesized carboxylic acids which we had found to be very active in vitro aldose reductase (ALR2) inhibitors. Although the replacement of the carboxylic group with the carboxamide or N-hydroxycarboxamide one decreased the in vitro ALR2 inhibitory effect, this led to the identification of mainly non-ionized derivatives with micromolar ALR2 affinity. The 5-arylidene moiety deeply influenced the activity of these 2,4-thiazolidinediones.

N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids as aldose reductase inhibitors.

Novel N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids characterized by formal replacement of the substituted benzyl moiety by cyclohexylmethyl and n-heptyl residues, respectively, were synthesized and evaluated as aldose reductase inhibitors.

Evaluation of in vitro aldose redutase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

A number of 5-arylidene-2,4-thiazolidinediones containing a hydroxy or a carboxymethoxy group in their 5-benzylidene moiety have been synthesised and evaluated as in vitro aldose reductase (ALR2) inhibitors. Most of them exhibited strong inhibitory activity, with IC(50) values in the range between 0.20 and 0.

Novel aldose reductase inhibitors derived from 6-[[(diphenylmethylene)amino]oxy]hexanoic acid.

Starting from the recently identified aldose reductase inhibitor 6-[[(diphenylmethylene)amino]oxy]hexanoic acid 1, the following systematic structural modifications were performed: (a) formal substitution of the phenyl rings, (b) isosteric replacement of the benzene core by the heteroarenes pyridine and thiophene, (c) formal reduction of the aromatic substructure and subsequent diminution of the cyclohexyl ring, (d) introduction of methylene spacer between C=N and the phenyl rings, and finally (e) formal ring closure in order to get derivatives of the tricycles fluorenone, xanthone, and thioxanthone, respectively. Out of these series, compounds 22-24 bearing disubstituted phenyl rings exhibit the highest inhibitory activity (IC(50 )value approx. 3 muM) which lie almost in the range of the reference sorbinil.

Discovery of novel aldose reductase inhibitors characterized by an alkoxy-substituted phenylacetic acid core.

In continuation of our effort aimed towards the development of novel aldose reductase inhibitors, several phenylacetic acids bearing an alkoxy substituent in position 3 or 4, respectively, were prepared and screened. The latter represent formal ring opening products of the cyclohexylmethyloxyphenylacetic acids IIa and IIb, recently elaborated in our group. Out of these series, compounds 4aa and 4ba characterized by an n-heptyloxy subunit turned out to be the most potent inhibitors.