Rosaria Ottanà

Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). The most active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic side chain on N-3 of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery of a very potent ARI (4c), whose activity level (IC50=0.13 microM) was in the same range of Tolrestat. Moreover, the corresponding methyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstituted compounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of N-unsubstituted 2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than the para-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.

Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity. Part 9

Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and nickel(II) 3 octahedral complexes of stoichiometry [MeL2(H2O)2]. Their antimycobacterial in vitro activity was evaluated against Mycobacterium tuberculosis H37Rv in comparison with the ligands. Complexes 2a, 2b, 2f, 3b, 3d and 3g displayed MIC values < or = 0.2 microg/mL.

In Vitro Antimycobacterial Activities of 2′-Monosubstituted Isonicotinohydrazides and Their Cyanoborane Adducts

ABSTRACT As a result of our search for new isoniazid derivatives with extended spectra of activity, we evaluated the in vitro antimycobacterial activities of isonicotinohydrazides (compounds 2) and their cyanoborane adducts (compounds 3), both obtained by the reaction of isonicotinoylhydrazones (compounds 1) with sodium cyanoborohydride. Most of the tested compounds displayed moderate to high activity against Mycobacterium tuberculosis H37Rv, with MICs ranging from 0.2 to 12.5 μg/ml. In particular, some hydrazides showed activity similar to that of rifampin (MIC = 0.2 μg/ml) and rather low cytotoxicity, so that they were generally shown to possess high safety indices. In contrast, the coordination to a cyanoborane (BH2CN) group (compounds 3) in general brought about a decrease in antimycobacterial activity, while cytotoxicity increased. Interestingly, selected compounds 1 to 3, mostly hydrazides (compounds 2), were effective in killing M. tuberculosis growing within macrophages at concentrations in culture medium which were much lower than the corresponding MICs. These compounds also displayed good activity against drug-resistant M. tuberculosis strains.

5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors

As part of a project aimed at identifying effective low molecular weight nonphosphorus monoanionic inhibitors of PTPs, we have synthesized 4-[(5-arylidene-4-oxo-2-phenyliminothiazolidin-3-yl)methyl]benzoic acids (4) and evaluated their inhibitory activity against human PTP1B and LMW-PTP enzymes. The introduction of a 2-phenylimino moiety onto the 4-thiazolidinone ring was designed to enhance the inhibitor/enzyme affinity by means of further favourable interactions with residues of the active site and the surrounding loops. Some of the compounds (4a-d, f) showed interesting inhibition levels in the low micromolar range. The 5-arylidene moiety of acids 4 proved to markedly influence the potency of these inhibitors. Molecular modeling experiments inside the binding sites of both enzymes were performed.

Targeting Aldose Reductase for the Treatment of Diabetes Complications and Inflammatory Diseases: New Insights and Future Directions

Aldose reductase (AR) is an aldo-keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of chronic complications associated with diabetes mellitus. Recently it was established that AR also acts as a key mediator of certain oxidative and inflammatory signaling pathways that are involved in the development of different human pathologies, such as cardiovascular disorders, sepsis, and cancer. These findings have renewed interest in the search for new AR inhibitors (ARIs) with improved profiles as potential therapeutic agents. In this review, recent advances in the field and promising future directions for developing ARIs are discussed.

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.

Nickel(II) 2,6-diacetylpyridine bis(isonicotinoylhydrazonate) and bis(benzoylhydrazonate) complexes : Structure and antimycobacterial evaluation. Part XI

The reaction of 2,6-diacetylpyridine (dap) and isonicotinoyl- or benzoylhydrazide leads to bishydrazones H(2)dapin (1a) and H(2)dapb (1b), respectively. The condensation can either take place as a bimolecular kinetic process between the two reactants or as a monomolecular metal-templated synthesis in the presence of nickel(II) ions. In the latter case the reaction products are charged 2,6-diacetylpyridine bis(hydrazone) nickel(II) complexes, which can be easily deprotonated to neutral hydrazonates. Diffractometric analysis of one of these [Ni(dapb)](2) (8b) has shown a binuclear structure with two octahedral nickel(II) ions bridged by two helicoidal dap (bishydrazonates) in a spheroidal structure of C(2V) symmetry. The synthesized complexes 8 are promising as antimycobacterial agents against M. tuberculosis H37Rv. In particular, 8b displays significant activity (MIC=0.025 microg/mL) 10-fold higher than rifampin and equal to isoniazid, while its ligand is ineffective. Compound 8b is also capable of reducing HIV-induced cytopathogenic effect in human T(4 )lymphocytes.

In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors

2-Thioxo-4-thiazolidinone derivatives were evaluated as aldose reductase inhibitors (ARIs) and most of them exhibited good or excellent in vitro efficacy. Out of the tested compounds, most N-unsubstituted analogues were found to possess inhibitory effects at low micromolar doses and two of them exhibited higher potency than sorbinil, used as a reference drug. The insertion of an acetic chain on N-3 of the thiazolidinone scaffold led to analogues with submicromolar affinity for ALR2 and IC(50) values very similar to that of epalrestat, the only ARI currently used in therapy.

Synthesis, biological activity and structure–activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells

Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRβ phosphorylation and 2-deoxyglucose cellular uptake.

Identification of new non-carboxylic acid containing inhibitors of aldose reductase

Non-carboxylic acid containing bioisosteres of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetic acids, which are active as aldose reductase (ALR2) inhibitors, were designed by replacing the carboxylic group with the trifluoromethyl ketone moiety. The in vitro evaluation of the ALR2 inhibitory effects of these trifluoromethyl substituted derivatives led to the identification of two inhibitors effective at low micromolar doses. It was further confirmed that a carboxylic chain on N-3 of the thiazolidinedione scaffold is a determining requisite to obtain the highest efficacy levels; however, it is not essential for the interaction with the target enzyme and it can be replaced by different polar groups, thus obtaining less ionised or unionised inhibitors.