Biological Activity of Amidino-Substituted Imidazo [4,5-]pyridines.

A series of cyano- and amidino-substituted imidazo[4,5-]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound , which contained an unsubstituted amidino group, and compound , which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC 0.

Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.

The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 () and HTL0029882 (), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that binds to the CGRP receptor in a precedented manner but that binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 () and HTL0028125 (), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction.

Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system.

Experimental and Computational Study of the Antioxidative Potential of Novel Nitro and Amino Substituted Benzimidazole/Benzothiazole-2-Carboxamides with Antiproliferative Activity.

We present the synthesis of a range of benzimidazole/benzothiazole-2-carboxamides with a variable number of methoxy and hydroxy groups, substituted with nitro, amino, or amino protonated moieties, which were evaluated for their antiproliferative activity in vitro and the antioxidant capacity. Antiproliferative features were tested on three human cancer cells, while the antioxidative activity was measured using 1,1-diphenyl-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays. Trimethoxy substituted benzimidazole-2-carboxamide showed the most promising antiproliferative activity (IC = 0.

Photochemical and thermal intramolecular 1,3-dipolar cycloaddition reactions of new o-stilbene-methylene-3-sydnones and their synthesis.

New trans- and cis-o-stilbene-methylene-sydnones 3a,b were synthesized by transforming the trans- and cis-o-aminomethylstilbene derivative, obtained by reduction of corresponding o-cyano derivatives, into glycine ester derivatives (43 and 31% yield) followed by hydrolysis (90 and 96% yield), nitrosation and ring closure with acetic acid anhydride (30 and 40% yield). The products were submitted to photochemical and thermal intramolecular [3 + 2] cycloadditions to afford diverse heteropolycyclic compounds. Photochemical reactions afforded cis-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (11, 12.

Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties.

Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics.

Complete 1H and 13C NMR spectral assignment of cis- and trans- 3-(2-[2-(4-methylphenyl)ethenyl]phenyl])sydnones.

1H and 13C NMR spectra of cis- and trans-3-(2-[2-(4-methylphenyl)ethenyl]phenyl])sydnones, the first stilbene-substituted mezoionic oxadiazolium rings, were fully assigned combining the information in various solvents, such as deuterated benzene, acetone and chloroform, using 2D NMR techniques.