Novel imidazo[1,5-a]quinoxaline derivatives: SAR, selectivity and modeling challenges en route to the identification of an α5-GABAA receptor NAM.

Initial optimization of a series of novel imidazo[1,5-a]quinoxaline compounds originated from a heuristic approach combining two known structural moieties towards α5-GABAA receptor is shown. This work reveals one-digit nanomolar active compounds as well as positive and negative allosteric modulators resulted from our exploratory approach. To deepen our understanding, their diverse mechanistic nature resulted from in silico modeling is also disclosed.

Identification of Triazolopyridines as Selective α5-GABAA Receptor Negative Allosteric Modulators by a Hybridization Approach.

The identification and characterization of novel triazolopyridine derivatives with selective α5 subunit-containing GABAA receptor negative allosteric modulator (NAM) activity are disclosed. As a result of in silico screening of our corporate compound deck, we identified a moderately potent hit that was converted to an advanced hit bearing better physicochemical and pharmacological properties using a hybridization approach. Subsequent optimization led to the identification of in vitro potent and subtype-selective α5-GABAA receptor NAMs representing a new chemotype in this area.

Acylated mono-, bis- and tris- cinchona-based amines containing ferrocene or organic residues: synthesis, structure and in vitro antitumor activity on selected human cancer cell lines.

A series of novel functionalized mono-, bis- and tris-(S)-{[(2S,4R,8R)-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl)}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60), human neuroblastoma (SH-SY5Y), human hepatoma (HepG2) and human breast cancer (MCF-7) cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay and the 50% inhibitory concentration (IC(50)) values were determined. Our data indicate that the precursor amine has no antitumor activity in vitro, but the bis-methanamines with ureido-, thioureido and amide-type linkers display attractive in vitro cytotoxicity and cytostatic effects on HL-60, HepG2, MCF-7 and SH-SY5Y cells. Besides 1H- and 13C-NMR methods the structures of the new model compounds were also studied by DFT calculations.