L. Carro

Synthesis and binding affinity of potential atypical antipsychotics with the tetrahydroquinazolinone motif

A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D2 and 5-HT2A human receptors; in addition, some properties related to blood-brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D1, D3, and 5-HT2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D1, D2, and D3 receptors, high affinity for 5-HT2A, low affinity for 5-HT2C receptors, and a Meltzers ratio characteristic of an atypical antipsychotic profile.

The Synthesis of Quinolone Natural Products from Pseudonocardia sp.

Abstract The synthesis of four quinolone natural products from the actinomycete Pseudonocardia sp. is reported. The key step involved a sp2–sp3 Suzuki–Miyaura reaction between a common boronic ester lateral chain and various functionalised quinolone cores. The quinolones slowed growth of E. coli and S. aureus by inducing extended lag phases.

Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands.

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT(2A) and D₂ receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an amino group resulted in privileged 5-HT(2A) affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT(2A) higher than 8.3 and good binding affinities for D₂ receptor leading to a Meltzers ratio characteristic of an atypical antipsychotic profile. Additionally, a small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their affinities and selectivities as 5-HT(2A)/D₂ dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT(2A) and D₂ receptors leading to a Meltzers ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT(2A) and D₂ receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D₂ ligands.

Synthesis and binding affinity of new 1,4-disubstituted triazoles as potential dopamine D3 receptor ligands

A series of new 1,4-disubstituted triazoles was prepared from appropriate arylacetylenes and aminoalkylazides using click chemistry methodology. These compounds were evaluated as potential ligands on several subtypes of dopamine receptors in in vitro competition assays, showing high affinity for dopamine D3 receptors, lower affinity for D2 and D4, and no affinity for the D1 receptors. Compound 18 displayed the highest affinity at the D3 receptor with a Ki value of 2.7 nM, selectivity over D2 (70-fold) and D4 (200-fold), and behaviour as a competitive antagonist in the low nanomolar range.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid‐catalysed 1,3‐allylic‐alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.

Novel non-ATP competitive small molecules targeting the CK2 α/β interface

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