Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.This work was financially supported by the Galician Government (Spain), Projects: 09CSA016234PR and GPC-2014-PG037. J.A. thanks FUNDAYACUCHO (Venezuela) for a predoctoral grant and Deputación da Coruña (Spain) for a postdoctoral research grant. A.N.-V. thanks the Spanish government for a Ramón y Cajal research contract

3D-Printing of Capsule Devices as Compartmentalization Tools for Supported Reagents in the Search of Antiproliferative Isatins

The application of high throughput synthesis methodologies in the generation of active pharmaceutical ingredients (APIs) currently requires the use of automated and easily scalable systems, easy dispensing of supported reagents in solution phase organic synthesis (SPOS), and elimination of purification and extraction steps. The recyclability and recoverability of supported reagents and/or catalysts in a rapid and individualized manner is a challenge in the pharmaceutical industry. This objective can be achieved through a suitable compartmentalization of these pulverulent reagents in suitable devices for it. This work deals with the use of customized polypropylene permeable-capsule devices manufactured by 3D printing, using the fused deposition modeling (FDM) technique, adaptable to any type of flask or reactor. The capsules fabricated in this work were easily loaded “in one step” with polymeric reagents for use as scavengers of isocyanides in the work-up process of Ugi multicomponent reactions or as compartmentalized and reusable catalysts in copper-catalyzed cycloadditions (CuAAC) or Heck palladium catalyzed cross-coupling reactions (PCCCRs). The reaction products are different series of diversely substituted isatins, which were tested in cancerous cervical HeLa and murine 3T3 Balb fibroblast cells, obtaining potent antiproliferative activity. This work demonstrates the applicability of 3D printing in chemical processes to obtain anticancer APIs

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their/naffinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/or/nD3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structural/ncharacteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexes/nbetween some of the most representative compounds of this series and the D2 and D3 receptors were/nobtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds/nshowed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidal/nside effects as potential antipsychotics

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget/nstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an/neffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through/nbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residues/nS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity between/nthese new compounds for this group of receptors. Specifically, the ability of these compounds to establish/none or two H-bonds with these key residues appears to explain their difference in affinity. In addition, we/ndescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychotic/neffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinities/nfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile

Enantiospecific Recognition at the A_2B Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates

A novel family of structurally simple, potent, and selective nonxanthine A_2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (<b>16</b>) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (<b>16</b>) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)<b>16b</b>, <i>K</i>_i <b>=</b> 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A_2BAR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity (<i>K</i>_i <b>=</b> 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A_2B adenosine receptor and opens new possibilities in ligand design for this receptor

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their/naffinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/or/nD3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structural/ncharacteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexes/nbetween some of the most representative compounds of this series and the D2 and D3 receptors were/nobtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds/nshowed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidal/nside effects as potential antipsychotics