Sulfur-mediated synthesis of unsymmetrically substituted N-aryl oxalamides by the cascade thioamidation/cyclocondensation and hydrolysis reaction.

A facile and straightforward synthesis of unsymmetrically substituted N-aryl oxalamides from 2,2'-biphenyldiamines, 2-chloroacetic acid derivatives, elemental sulfur, and water has been developed. This protocol is distinguished by efficiency in water under metal-free conditions for N-aryl oxalamides bearing a side-chain NH2-group; it can be adapted for scale-up synthesis. The scope and limitations of this transformation have been investigated.

Development of 1,3-thiazole analogues of imidazopyridines as potent positive allosteric modulators of GABAA receptors.

Structure-activity relationship studies were conducted in the search for 1,3-thiazole isosteric analogs of imidazopyridine drugs (Zolpidem, Alpidem). Three series of novel γ-aminobutyric acid receptor (GABAAR) ligands belonging to imidazo[2,1-b]thiazoles, imidazo[2,1-b][1,3,4]thiadiazoles, and benzo[d]imidazo[2,1-b]thiazoles were synthesized and characterized as active agents against GABAAR benzodiazepine-binding site. In each of these series, potent compounds were discovered using a radioligand competition binding assay. The functional properties of highest-affinity compounds 28 and 37 as GABAAR positive allosteric modulators (PAMs) were determined by electrophysiological measurements. In vivo studies on zebrafish demonstrated their potential for the further development of anxiolytics. Using the OECD "Fish, Acute Toxicity Test" active compounds were found safe and non-toxic. Structural bases for activity of benzo[d]imidazo[2,1-b]thiazoles were proposed using molecular docking studies. The isosteric replacement of the pyridine nuclei by 1,3-thiazole, 1,3,4-thiadiazole, or 1,3-benzothiazole in the ring-fused imidazole class of GABAAR PAMs was shown to be promising for the development of novel hypnotics, anxiolytics, anticonvulsants, and sedatives drug-candidates.

Synthesis of Dibenzo[d,f][1,3]Diazepines via Elemental Sulfur-Mediated Cyclocondensation of 2,2'-Biphenyldiamines with 2-Chloroacetic Acid Derivatives.

The three-component reaction of 2,2'-biphenyldiamines with 2-chloroacetic acid derivatives and elemental sulfur was developed for the practical synthesis of unknown 2-carboxamide-substituted dibenzo[d,f][1,3]diazepines. This protocol is distinguished by efficiency in water and good tolerance to functional groups and can be adapted to a large-scale synthesis. The chemoselective preparation of a variety of 2-S,N,O-substituted dibenzo[d,f][1,3]diazepines was accomplished using the developed method.

Synthesis of Imidazo[2,1-b]thiazoles via Copper-Catalyzed A3-Coupling in Batch and Continuous Flow.

A straightforward method for the synthesis of functionalized imidazo[2,1-b]thiazoles starting from benzaldehydes, 2-aminothiazoles, and alkynes under copper(I,II) catalysis was developed. The protocol allows the construction of a variety of aryl-substituted imidazo[2,1-b]benzothiazoles, -[2,1-b]thiazoles, and -[2,1-b][1,3,4]thiadiazoles. The reactions were easy to perform affording most of the desired products in 33-93% yields. The intensification of the process in a continuous-flow reactor increases the products' yields up to quantitative.