A benzoquinolizine coumarin-based fluorescent probe was developed for detecting thiophenols, demonstrating the superior fluorescence properties caused by the decay of the twisting effect of N,N-diethylamino group of coumarin. It discriminated thiophenols from various analytes including aliphatic thiols with good selectivity and displayed ∼700-fold fluorescence intensity enhancement and a remarkable limit of detection (4.5 nM). The new probe also can be applied to quantitative determine the concentrations of thiophenol in water samples and living cells.

Selenocysteine (Sec), encoded as the 21st amino acid, is the predominant chemical form of selenium that is closely related to various human diseases. Thus, it is of high importance to identify novel probes for sensitive and selective recognition of Sec and Sec-containing proteins. Although a few probes have been reported to detect artificially introduced selenols in cells or tissues, none of them has been shown to be sensitive enough to detect endogenous selenols. We report the characterization and application of a new fluorogenic molecular probe for the detection of intracellular selenols. This probe exhibits near-zero background fluorescence but produces remarkable fluorescence enhancement upon reacting with selenols in a fast chemical reaction. It is highly specific and sensitive for intracellular selenium-containing molecules such as Sec and selenoproteins. When combined with flow cytometry, this probe is able to detect endogenous selenols in various human cancer cells. It is also able to image endogenous selenol-containing molecules in zebrafish under a fluorescence microscope. These results demonstrate that this molecular probe can function as a useful molecular tool for intracellular selenol sensing, which is valuable in the clinical diagnosis for human diseases associated with Sec-deficiency or overdose.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important target for new bleaching herbicides discovery. As a continuous work to discover novel crop selective HPPD inhibitor, a series of 2-(aryloxyacetyl)cyclohexane-1,3-diones were rationally designed and synthesized by an efficient one-pot procedure using N,N′-carbonyldiimidazole (CDI), triethylamine, and acetone cyanohydrin in CH2Cl2. A total of 58 triketone compounds were synthesized in good to excellent yields. Some of the triketones displayed potent in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. 2-(2-((1-Bromonaphthalen-2-yl)oxy)acetyl)-3-hydroxycyclohex-2-en-1-one, II-13, displayed high, broad-spectrum, and postemergent herbicidal activity at the dosage of 37.5–150 g ai/ha, nearly as potent as mesotrione against some weeds. Furthermore, II-13 showed good crop safety against maize and canola at the rate of 150 g ai/ha, indicating that II-13 might have potential as a herbicide for weed control in maize and canola fields. II-13 is the first HPPD inhibitor showing good crop safety toward canola.Keywords: 4-hydroxyphenylpyruvate dioxygenase; herbicidal activity; one-pot synthesis; structure−activity relationship; triketone;

•A series of pyrazole-benzimidazolone hybrids were designed by scaffold hopping strategy.•Most of the new compounds showed good activity against recombinant human HPPD.•Compound 9l was identified as the most potent candidate (IC50 = 21 nM), about 3-fold higher than NTBC.4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 9l was identified as the most potent candidate with IC50 value of 0.021 μM against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia.A series of pyrazole-benzimidazolone hybrids were designed and synthesized as potent 4-hydroxyphenylpyruvate dioxygenase inhibitors. Compound 9l (IC50 = 21 nM) was the most potent candidate.

Copper is a crucial transition metal ion that plays an essential role in environmental, biological, and chemical systems. Therefore an efficient method for detection of copper ions is significant. In this work, a sulfonamide-based probe containing a dansyl fluorophore was synthesized in good yield. This probe exhibited good selectivity and sensitivity for copper ions in aqueous solution without any interference from other metal ions. And it displayed a very low detection limit (2.91 × 10−8 M) for Cu2+, which supported its further application in bioimaging. Its good water-solubility, bio-compatibility and cell permeability leads it to be employed as an efficient biomarker to monitor the level of Cu2+ in living cells. The binding model between fluorescent probe and Cu2+ was evaluated by density functional theory calculations.

The development of probes for specific thiophenol detection is of great importance, due to the toxicity of thiophenols and their derivatives in the environment. In the present study, a novel fluorescent probe was rationally designed for detecting thiophenols via an intramolecular charge transfer mechanism. The developed probe selectively and sensitively distinguished thiophenols from aliphatic thiols. It displayed a large Stokes shift (145 nm) and >280-fold fluorescence enhancement. Moreover, the new probe not only displayed excellent cell permeability for the successful detection of thiophenol in HEK293 cells but also quantitatively measured thiophenols in water samples with good recovery (more than 90%), indicating that it has promising prospects for application for thiophenol sensing in environmental and biological sciences.

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer’s disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine–coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki = 16.7 nM) against human AChE and about 2-fold lower potency (Ki = 16.1 nM) against BChE than tacrine (Ki = 35.7 nM for AChE, Ki = 8.7 nM for BChE), respectively. In addition, some of the tacrine–coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine–coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.

Exploring novel 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors is one of the most promising research directions in herbicide discovery. To discover new triketone herbicides with broad-spectrum weed control as well as excellent crop selectivity, a series of (total 52) novel triketone-containing quinazoline-2,4-dione derivatives were synthesized and further bioevaluated. The greenhouse testing indicated that many of the newly synthesized compounds showed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds at the dosages of 37.5–150 g of active ingredient (ai)/ha. The structure and activity relationship in this study indicated that the triketone-containing quinazoline-2,4-dione motif has possessed great impact on herbicide activity and may be used for further optimization. Among the new compounds, III-b and VI-a–VI-d displayed a broader spectrum of weed control than mesotrione. In addition, the compound III-b also demonstrated comparatively superior crop selectivity to mesotrione, thus possessing great potential for weed control in the field.

Two novel coumarin-derived fluorescent probes were designed and synthesized for the quantitative determination of biothiols, such as cysteine (Cys), glutathione (GSH) and homocysteine (Hcy). Both probes selectively and sensitively detected biothiols in vitro, and successfully sensed biothiols in vivo with low cytotoxicity, suggesting their potential application for biothiol detection.

Alzheimer’s disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with Ki of 6.47 nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.