Showing papers by "Giuseppe Paglietti published in 2013"
TL;DR: Different molecular mechanisms of inhibition of the HCV and BVDV RdRps by 227G are suggested and indicate the importance of understanding ligand-enzyme interactions at the molecular level for the rational design of new and more potent leads.
Abstract: The virus-encoded RNA-dependent RNA polymerase (RdRp) has emerged as a primary target in the search for selective inhibitors of Flaviviridae. Recently, we reported on the selective inhibition, in cell-based assays, of both BVDV (EC50 = 0.80 ± 0.06 μM) and HCV (EC50 = 1.11 ± 0.15 μM) by 2-{1-[2-(2,4-dimethoxyphenyl)-1H-benzimidazol-5-yl]ethylidene}hydrazinecarbothioamide (227G). Here we show that, in enzyme assays with recombinant enzymes, 227G inhibits, in a dose-dependent manner, the RdRp of both BVDV (IC50 = 0.0020 ± 0.0004 μM) and HCV (IC50 = 0.40 ± 0.04 μM). Furthermore, we report on the selection and molecular analysis of a BVDV-resistant mutant, characterized by the presence of the I261M mutation. By applying a multilevel computational approach, we identified different 227G binding sites on the two RdRps. They were further validated by the good agreement between the calculated affinities and those extrapolated from IC50 values. Our findings suggest different molecular mechanisms of inhibition of the HCV and BVDV RdRps by 227G and indicate the importance of understanding ligand-enzyme interactions at the molecular level for the rational design of new and more potent leads.
36 citations
TL;DR: Twenty benzimidazole derivatives bearing in position 1 a ($$\omega $$-tert-amino)alkyl chain and in position 2 an aromatic moiety (phenyl, benzyl or benzotriazol-1/2-ylmethyl) were evaluated for anti-proliferative activity against a panel of 60 human cancer cell lines.
Abstract: Twenty benzimidazole derivatives bearing in position 1 a (
$$\omega $$
-tert-amino)alkyl chain (mainly quinolizidin-1-ylmethyl) and in position 2 an aromatic moiety (phenyl, benzyl or benzotriazol-1/2-ylmethyl) were evaluated at the National Cancer Institute (NCI) for anti-proliferative activity against a panel of 60 human cancer cell lines. Four compounds (6, 7, 9 and 10) displayed a large spectrum of activity with $$\text{ GI }_{50}<$$
10
$$\upmu \text{ M }$$
on 24–57 cell lines, while thirteen compounds exhibited sub-micromolar or even nanomolar activity against single cell lines, such as leukemia CCRF-CEM, HL-60 and MOLT-4, CNS cancer SF-268 and, particularly, renal cancer UO-31, sometimes with outstanding selectivity (compounds 5-7, 11, 13 and 18).
8 citations