Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy.

Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.

Electrochemical oxidative cyclization of N-allylamides for the synthesis of CF3-containing benzoxazines and oxazolines.

The introduction of trifluoromethyl (-CF3) groups into compounds is a common synthetic strategy in organic chemistry. Commonly used methods for introducing trifluoromethyl groups are limited by harsh reaction conditions, low regioselectivity, or the need for excess reagents. In this study, a facile electrochemical oxidative and radical cascade cyclization of N-(2-vinylphenyl)amides for the synthesis of CF3-containing benzoxazines and oxazolines was obtained. This sustainable protocol features inexpensive and durable electrodes, a wide range of substrates, diverse functional group compatibility under transition-metal-free, external-oxidant-free, and additive-free conditions, and can be applied in an open environment.

Rh(III)-Catalyzed Synthesis of Substituted Isoindoles through a Direct C-H Activation/[4 + 1] Annulation and Acyl Migration Cascade of Oxadiazolones with Diazo Compounds.

A Rh(III)-catalyzed C-H bond activation for the synthesis of fused 2H-isoindole scaffolds from oxadiazolones with diazo compounds was developed. The reaction proceeded through C-H activation of oxadiazolones/[4 + 1] annulation, intramolecular cyclization, and an unusual acyl migration cascade to afford target scaffolds with good yields. These 2H-isoindole derivatives could be further transformed into intriguing drug privileged scaffolds.

Synthesis and biological evaluation of 9-fluorenone derivatives for SPECT imaging of α7-nicotinic acetylcholine receptor.

The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for α7-nAChRs. Among the derivatives, the best member of the series 10 (Ki = 2.23 nM) were radiolabeled with 125I for in vitro and in vivo studies. The radiotracer [125I]10 exhibited robust brain uptake and specifically labeled α7-nAChRs with a peak uptake value of 9.49 ±â€¯0.87%ID/g in brain. Blocking studies demonstrated that the tracer was highly specific toward α7-nAChR. Furthermore, ex vivo autoradiography and micro-SPECT/CT dynamic imaging in mice confirmed the excellent imaging properties. In addition, molecular docking was also performed to rationalize the potency of the chosen compounds towards α7-nAChRs. To conclude, compound 10 could serve as a promising radiotracer for the α7-nAChRs.

Direct Synthesis of 3-Acylindoles through Rhodium(III)-Catalyzed Annulation of N-Phenylamidines with α-Cl Ketones.

In the present study, a novel synthetic strategy to directly produce versatile 3-acylindoles through Rh(III)-catalyzed C-H activation and annulation cascade of N-phenylamidines with α-Cl ketones was developed, in which α-Cl ketones serve as unusual one-carbon (sp3) synthons. This strategy features high regioselectivity, efficiency, wide substrate tolerance, and mild reaction conditions, which further underscore its synthetic utility in drug molecule synthesis.

A Method for Synthesis of 3-Hydroxy-1-indanones via Cu-Catalyzed Intramolecular Annulation Reactions.

We report a facile and highly efficient method that copper-catalyzed intramolecular annulation to synthesize 3-hydroxy-1-indanones employing simple 2-ethynylbenzaldehyde as starting materials was achieved successfully. This protocol provided a simple synthetic approach to afford 3-hydroxy-1-indanones under mild conditions in good to excellent yields.

Gold(III)-Catalyzed Selective Cyclization of Alkynyl Quinazolinone-Tethered Pyrroles: Synthesis of Fused Quinazolinone Scaffolds.

A series of 1,2- and 2,3-fused quinazolinones have been synthesized in good to excellent yields through gold-catalyzed selective hydroarylations of alkynyl quinazolinone-tethered pyrroles. The studies revealed that 1,2-fused quinazolinones were obtained through a 1,3-rearrangement and sequential 6- exo-trig cyclization of N1-alkynyl quinazolinone-tethered pyrroles, while N3-alkynyl quinazolinone-tethered pyrroles went through 6- exo-dig or 7- endo-dig cyclizations directly to afford 2,3-fused quinazolinones. The fused quinazolinones could be prepared at gram scale in three steps from commercial ortho-aminobenzamide.

Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles To Prepare Rutaecarpine Derivatives.

An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride.

Synthesis and antitumor evaluation of 2,3-diarylbenzofuran derivatives on HeLa cells.

2,2-Dihydroxyarylethanones, readily prepared from the commercially available aromatic ethyl ketones, were reacted with resorcinol, 3-methoxyphenol or 2-methoxyphenol in multi steps one-pot manner promoted by trifluoroacetic acid to furnish the 2,3-diarylbenzofuran derivatives in 22-95% yield. Sixteen targeted compounds were synthesized and characterized by 1H NMR, 13C NMR and HRMS. MTT assay indicated that most compounds possessed effectively inhibitory activities against the proliferation of HeLa cell. Among them, 4f had the highest inhibitory activities, with the IC50 being 13.40±2.04µmol/L. Cell cycle analysis, Annexin V-FITC/propidium iodide dual staining assay and western blotting analysis revealed that 4f inhibited the proliferation of Hela cell through apoptosis induction in a dose-dependent manner via obviously up-regulated the levels of Bak and Bim, while striking down-regulated the level of Bcl-2 and Bcl-xL protein.