Accumulating evidence suggests that formation of peroxynitrite (ONOO–) in the cerebral vasculature contributes to the progression of ischemic damage, while the underlying molecular mechanisms remain elusive. To fully understand ONOO– biology, efficient tools that can realize the real-time tracing of endogenous ONOO– fluxes are indispensable. While a few ONOO– fluorescent probes have been reported, direct visualization of ONOO– fluxes in the cerebral vasculature of live mice remains a challenge. Herein, we present a fluorescent switch-on probe (NP3) for ONOO– imaging. NP3 exhibits good specificity, fast response, and high sensitivity toward ONOO– both in vitro and in vivo. Moreover, NP3 is two-photon excitable and readily blood–brain barrier penetrable. These desired photophysical and pharmacokinetic properties endow NP3 with the capability to monitor brain vascular ONOO– generation after injury with excellent temporal and spatial resolution. As a proof of concept, NP3 has enabled the direct visualization of neurovascular ONOO– formation in ischemia progression in live mouse brain by use of two-photon laser scanning microscopy. Due to these favorable properties, NP3 holds great promise for visualizing endogenous peroxynitrite fluxes in a variety of pathophysiological progressions in vitro and in vivo.

Analogues of the natural product (−)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (−)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure–activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.Keywords: 2-deoxyglucose uptake in L6 myotubes; amelioration of metabolic disorders; arctigenin analogues; Natural product

A microwave assisted tandem Heck–Sonogashira cross-coupling reaction between 6-N,N-di-Boc-amino-5-iodo-2-methyl pyrimidin-4-ol and various aryl alkynyl substrates has been developed. This process generates novel 5-enynyl substituted pyrimidines, which can be transformed to novel functionalized pyrido[2,3-d]pyrimidines by way of a silver catalyzed cyclization reaction.

An efficient, palladium-catalyzed cascade reaction, which leads to formation of annulated xanthones, was devised. The process, which uses readily available 3-iodochromones, aryl iodides and norbornadiene as starting materials, takes place via a tandem Heck reaction/double C–H activation/retro-Diels–Alder pathway. The high chemoselectivity of the process is mechanistically unique and it serves as a new approach to achieve regioselective control of C–H activation in Pd/norbornene or norbornadiene systems. Its broad substrate scope, including heteroaryl coupling partners, enables access to diverse annulated xanthones.

A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-catalyzed aerobic C–H intramolecular cycloetherification. Notably, this process does not require the presence of strong para electron-withdrawing groups on the phenol component. Also, the results of this effort show that acyl phenols containing electron-rich heterocycles participate in an efficient C–H activation/C–O formation process.

2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BuChE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.Graphical abstractA series of pyridazinones was evaluated and optimized for their AChE inhibitory activity in an enzyme assay. High AChE/BuChE selectivity of the lead compound was achieved.Highlights► Pyridazinone derivatives as novel AChE inhibitors were synthesized. ► High AChE/BuChE selectivity of the lead compound was achieved. ► Novel 6-ortho-tolylamino substitution which involved in π–π stacking and hydrophobic ‘Magic Methyl’ effect was investigated. ► Novel 4-substituted piperidine motif for CAS binding was reported. ► Docking study revealed that these pyridazinone derivatives might function as dual binding site inhibitors.

A highly efficient CuBr-catalyzed domino reaction of 2-substituted-3-(1-alkynyl)chromones to synthesize functionalized 3-acylfurans has been developed. The reaction is mild, environmentally friendly and easily handled without the necessity for dry solvents and inert atmosphere.

A practical and mild strategy has been developed for the selective O-arylation on C-6 substituted pyridin-2-ones with a series of arylboronic acids, using Cu(OTf)2 as the catalyst, DABCO as the ligand, Et3N as the base, and K2HPO4 as the additive. This method affords O-arylated pyridin-2-ones with good selectivity and yields

NH aldimines, generated in situ from the corresponding aldehydes by reaction with ammonium acetate, serve as nitrogen nucleophiles in reactions with 3-(1-alkynyl)chromones and 3-cyanochromones that generate functionalized azaxanthones. These processes take place under mild conditions that do not require dry solvents. The products of the reactions described represent new chemical entities. We believe that the newly developed cascade process will serve as a potent method for the synthesis of N-heterocycles and in diversity-oriented synthesis.

A novel cascade reaction was developed for the synthesis of diverse members of a series of benzofuro[3,2-d]pyrimidine derivatives. The process utilizes readily prepared 3-chlorochromenones and various commercially available amidines and their analogues as starting materials. This tandem reaction is promoted by using a simple copper(I) reagent and involves a chemoselective Michael addition–heterocyclization–intramolecular cyclization sequence.

A small organic molecule phenylacetonitrile promoted chemoselective cyclization of (chromen-3-yl)alkynylnitriles to generate a novel tetracyclic or tricyclic chromone scaffold has been discovered. Importantly, the phenylacetonitrile serves as an anion transfer reagent changing the normal reaction of the substrate.

The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC50 = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure–antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC50 = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.

Domino reactions of 2-methyl substituted chromones containing an electron withdrawing group at the 3-position with chromone-fused dienes synthesized a diverse range of benzo[a]xanthones and complicated chromone derivatives. These multiple-step reactions result in either two or three new C–C bonds without a transition metal catalyst or an inert atmosphere.

Using Au catalyst and ethyl Hantzsch ester as a hydrogen source, 3-(1-alkynyl)chromones were directly transformed to 4H-benzofuro[3,2-c]pyrans in good to excellent yields through a cascade process by addition, cyclization and hydrogen transfer under mild conditions.

A novel firefly luciferase inhibitor (3a) with a pyrrolo[2,3-d]pyrimidine core was identified in a cell-based NF-κB luciferase reporter gene assay. It potently inhibited the firefly luciferase derived from Photinus pyralis with an IC50 value of 0.36 ± 0.05 μM. Kinetic analysis of 3a inhibition showed that it is predominantly competitive with respect to d-luciferin and uncompetitive with respect to ATP. Therefore, several pyrrolo[2,3-d]pyrimidine analogues were prepared to further investigate the structure-activity relationship (SAR) for luciferase inhibition. The most potent inhibitor of this series was 4c, which showed an IC50 value of 0.06 ± 0.01 μM. In addition, molecular docking studies suggested that both 3a and 4c could be accommodated in the d-luciferin binding pocket, which is expected for a predominantly competitive inhibitor with respect to d-luciferin.

A series of P1-substituted biaryl amprenavir derivatives was designed and synthesized. These compounds were evaluated for enzyme inhibition and antiviral activity in vitro. Several compounds showed highly efficient antiviral activity with EC50 values down to 0.10 nM, which are more potent than marketed HIV-1 protease inhibitors. Docking study indicated that 12c has similar binding mode to amprenavir with full occupancy in P1.

Members of a series of 2,4,5-substituted pyrimidine derivatives were synthesized, and their interactions with tubulin and their antiproliferative activities against the human hepatocellular carcinoma cells of liver (BEL-7402) were evaluated. One member of this family, the indole-pyrimidine 4k, having an indole-aryl-substituted aminopyrimidine structure, was observed to be an excellent inhibitor of tubulin polymerization (IC50 = 0.79 μM) and to display significantly high antiproliferative activities against several cancer cell lines with IC50 values ranging from 16 to 62 nM. This substance displayed a high propensity to arrests cells at the G2/M phase of the cell cycle (EC50 = 20 nM). In addition, 4k was found to competitively inhibit colchicine binding to tubulin, indicating that it binds to the colchicine-binding site of tubulin. The observations made in this investigation demonstrate that 2,4,5-substituted pyrimidines represent a new class of tubulin polymerization inhibitors with significant antiproliferative activity.

A base-promoted, microwave-assisted one-pot tandem reaction from simple 3-(1-alkynyl)chromones with 2-halobenzylic nitriles (esters or amides) for the synthesis of novel functional polycyclic chromenones has been developed. This tandem process involves multiple reactions, such as Michael addition and double cyclizations without a transition metal catalyst.

A base-promoted one-pot tandem reaction sequence has been developed to transform electron-deficient chromone-fused dienes 1 and 1,3-dicarbonyl compounds 2 to functionalized 2-hydroxybenzophenones 3 under mild conditions. This domino process, which involves multiple reactions, including Michael addition/cyclization/elimination, serves as an efficient, economic, and eco-friendly method for the construction of diversified 2-hydroxybenzophenone scaffolds without a transition-metal catalyst and inert atmosphere.

A novel base-promoted cascade reaction of 2-methyl-3-(1-alkynyl)chromones to produce a 3C-xanthone-linked 3C-chromone scaffold has been developed. This tandem process involves multiple reactions such as Michael additions/cyclizations under mild conditions without a transition metal catalyst and inert atmosphere.

An efficient tandem process was developed to synthesize diversified benzo[a]xanthones from 2-methyl-3-(1-alkynyl)chromones with electron-deficient chromone-fused dienes. This unusual reaction, involving multiple steps and not requiring the use of transition metal catalysts or an inert atmosphere, results in the formation of three new C−C bonds and one C−O bond.

A novel base-promoted cascade desalicyloylative dimerization of 3-(1-alkynyl)chromones to produce 2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as Michael additions/cyclizations/desalicyloylation without a transition metal catalyst and inert atmosphere.

A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic compounds library.

A base-promoted one-pot tandem reaction has been developed from 3-(1-alkynyl)chromones with various acetonitriles to afford functionalized amino-substituted xanthones 3 under microwave irradiation. This tandem process involves multiple reactions, such as Michael addition/cyclization/1,2-addition, without a transition metal catalyst. This method provides an efficient approach to build up natural product-like diversified amino-substituted xanthone scaffolds rapidly.

A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC50 value less than 0.10 μM. Structure–activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC50 values from 0.024 to 0.55 μM.A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line.

Hepatic stellate cells (HSCs) play an important role in the development of hepatic fibrosis. Heat shock protein 90 (Hsp90) is essential for the maturation and activity of a varied group of proteins involved in signal transduction and cell cycle regulation. In this study, we found that two Hsp90 inhibitors, VER-49009 and its analog VER-49009M, inhibited the proliferation of hepatic stellate cell line CFSC cells, and both of them induced G2 phase arrest in CFSC cells. Akt expression was decreased by the treatment of Hsp90 inhibitors in CFSC cells. Based on these findings, we propose that the inhibition of Hsp90 might be a rational approach in the prevention of liver fibrosis.

A novel one-pot cascade addition–cyclization–oxidation for the regioselective synthesis of furo[3,2-c]coumarins has been developed; the reaction is mild and easily handled without the necessity for dry solvents and inert atmosphere.

A novel base-promoted cascade desalicyloylative dimerization of 3-(1-alkynyl)chromones to produce 2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as Michael additions/cyclizations/desalicyloylation without a transition metal catalyst and inert atmosphere.

An efficient, palladium-catalyzed cascade reaction, which leads to formation of annulated xanthones, was devised. The process, which uses readily available 3-iodochromones, aryl iodides and norbornadiene as starting materials, takes place via a tandem Heck reaction/double C–H activation/retro-Diels–Alder pathway. The high chemoselectivity of the process is mechanistically unique and it serves as a new approach to achieve regioselective control of C–H activation in Pd/norbornene or norbornadiene systems. Its broad substrate scope, including heteroaryl coupling partners, enables access to diverse annulated xanthones.

A base-promoted, microwave-assisted one-pot tandem reaction from simple 3-(1-alkynyl)chromones with 2-halobenzylic nitriles (esters or amides) for the synthesis of novel functional polycyclic chromenones has been developed. This tandem process involves multiple reactions, such as Michael addition and double cyclizations without a transition metal catalyst.

Domino reactions of 2-methyl substituted chromones containing an electron withdrawing group at the 3-position with chromone-fused dienes synthesized a diverse range of benzo[a]xanthones and complicated chromone derivatives. These multiple-step reactions result in either two or three new C–C bonds without a transition metal catalyst or an inert atmosphere.

A novel one-pot cascade addition–cyclization–oxidation for the regioselective synthesis of furo[3,2-c]coumarins has been developed; the reaction is mild and easily handled without the necessity for dry solvents and inert atmosphere.