Synthesis of novel substituted N-aryl benzamides as hA3G stabilizers and their inhibitory activities against hepatitis C virus replication

AbstractA series of novel amino-substituted N-aryl benzamide analogs were synthesized and evaluated for their ability to inhibit hepatitis C virus (HCV) replication in acutely infected Huh7.5 cells. Most of the substituted N-aryl benzamide compounds showed convincing anti-HCV activities. Compounds 1f, 1g and 4c exhibited potent anti-replicative activity at low micromolar levels (IC50=1.0–2.0μM) with selective indices (SI) greater than 40. Mechanistic analysis indicated that the active compounds increased intracellular hA3G protein levels and inhibited HCV replication in a dose-dependent manner. The results demonstrate that this series of substituted N-aryl benzamide compounds warrant further investigation as inhibitors of HCV replication

Synthesis and Antiprotozoal Activity of Dicationic 2, 6-Diphenylpyrazines and Aza-Analogues

Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8 to 37 nM) and P. f. (10 to 52 nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results

Structural Based Screening of Antiandrogen Targeting Activation Function-2 Binding Site

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current antiandrogen therapies induce resistant mutations at the hormone binding pocket (HBP) that convert the activity of these agents from antagonist to agonist. Thus, there is a high unmet medical need for the development of novel antiandrogens which circumvent mutation-based resistance. Herein, through the analysis of AR structures with ligands binding to the activation function-2 (AF2) site, we built a combined pharmacophore model. In silico screening and the subsequent biological evaluation lead to the discovery of the novel lead compound IMB-A6 that binds to the AF2 site, which inhibits the activity of either wild-type (WT) or resistance mutated ARs. Our work demonstrates structure-based drug design is an efficient strategy to discover new antiandrogens, and provides a new class of small molecular antiandrogens for the development of novel treatment agents against PCa

N-(2,6-Dimethoxypyridin-3-yl)-9-methyl-9H-carbazole-3-sulfonamide

In the title compound, C20H19N3O4S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87 (10)°. In the crystal, the molecules are held together by N—H...O and C—H...O hydrogen bonds into layers, which are assembled into a three-dimensional network via π–π stacking interactions between inversion-related pyridine rings, with centroid–centroid distances of 3.5101 (12) Å

Identification of Triptophenolide from <i>Tripterygium wilfordii</i> as a Pan-antagonist of Androgen Receptor

A compound, triptophenolide, derived from <i>Tripterygium wilfordii</i> was identified as an antiandrogen. Triptophenolide inhibits the activity of both wild-type and F876L mutant androgen receptors. Triptophenolide exhibits its antiandrogenic activity through competitive binding with androgen in the hormone-binding pocket, decreasing the expression of androgen receptor, and reducing the nuclear translocation of androgen receptor

Design of DNA minor groove binding diamidines that recognize GC base pair sequences: a dimeric-hinge interaction motif.

The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, binds specifically to a GC-rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in the development of DNA sequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs