Dietmar Rakowitz

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. Our induced-fit docking studies suggested that 5-(4-hydroxybenzylidene)-substituted derivatives may bind the polar recognition region of the ALR2 active site by means of the deprotonated phenol group, while their acetic chain and carbonyl group at position 2 of the thiazolidinedione ring form a tight net of hydrogen bonds with amino acid residues of the lipophilic specificity pocket of the enzyme.

The Inhibitory Activity of Diazinyl-Substituted Thiourea Derivatives on Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Starting from 2-(2-aminoethyl)pyridine, a series of N-diazinyl-N′-[2-(2-pyridyl)ethyl]thioureas was prepared via the (2-pyridyl)ethylisothiocyanate and was screened as non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors. Derivatives bearing a 3-pyridazinyl or a 4-pyrimidinyl moiety turned out to be the most potent compounds. However, they exhibited less activity than nevirapine or trovirdine.

On the prodrug potential of novel aldose reductase inhibitors with diphenylmethyleneaminooxycarboxylic acid structure

Diphenylmethyleneaminooxycarboxylic acids were found to represent novel type inhibitors of the enzyme aldose reductase. Ester derivatives of the most active compound (3c) (IC(50)=33 microM) were prepared as potential prodrugs and the rate of degradation was studied by treatment with buffers, plasma, and various hydrolytic enzymes. Whereas all compounds were not hydrolysed at physiological pH, incubation in the presence of enzyme led to hydrolysis. The rate of enzymatic degradation, however, depended on the nature of the ester function. Whereas the isopropyl ester (4) turned out to be the most stable compound, the ethyl ester (2c) could be cleaved in the presence of esterase and lipase, respectively. The benzylic and aromatic esters were found to be hydrolysed rapidly in the presence of lipase (benzyl ester, 7), or in plasma, by cholinesterase and esterase (phenyl ester, 6), respectively.

Thienocinnolinone alkanoic acid derivatives as aldose reductase inhibitors.

A new series of 8-halogen-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolinone-N2-alkanoic acids was prepared and tested for aldose reductase (ALR2) inhibitory activities. These compounds showed significant inhibitory activity against bovine lens ALR2, with the best compound 2e showing an IC(50) value of 31.4 microM. The presence of the C8-substituents here studied (Cl, Br) on the thienocinnolinone scaffold caused a decrease of the inhibitory potency by a factor of about 4 with respect to the unsubstituted parent compound, while the presence of a C8-methyl group, considered in a previous paper decreased the activity by a factor of about 2. Moreover, the length of the N2 alkanoic chain influences strongly the enzyme inhibitory activity. While most of the carboxylic acids ALR2 inhibitors are acetic acid derivatives, in the case of thienocinnolinone compounds, homologues higher than acetic acids showed to be more active.