9-Fluorenon-4-carboxamides: Synthesis, conformational analysis, anti-HSV-2, and immunomodulatory evaluation. Note II

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An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications

Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1–17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes

In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications - A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates

Libere considerazioni sul Poema pedagogico di Anton Semënovi? Makarenko

In occasione della pubblicazione di una nuova edizione italiana del Poema Pedaogogico di Anton Semenovic Makarenko, curata da Nicola Siciliani de Cumis (Albatros editore, Roma, 2010), a ventotto anni di distanza dalla precedente (curata nel 1982 da Vincenzo Sarracino, per le edizioni Fratelli Ferraro), proponiamo l'intevento dello studioso Francesco Ottanà, appassionato cultore dell'opera makarankiana

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

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 (BH(2)CN) 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

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

Abstract—Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). Themost active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic sidechain on N-3of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery ofa very potent ARI (4c), whose activity level (IC50=0.13 mM) was in the same range of Tolrestat. Moreover, the correspondingmethyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstitutedcompounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of Nunsubstituted2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than thepara-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4