A protocol for hydrogenation of aldehydes and ketones to alcohols in aqueous media at room temperature in high yields and purity.

In this paper, the hydrogenation of aldehydes and ketones using the RANEY® nickel catalyst was successfully applied for the synthesis of alcohol compounds without additional column chromatographic purification. This synthetic strategy features a wide range of substrates, excellent atom economy, high chemical discrimination and the use of a ligand-free catalytic system. Reactions were performed at room temperature in water providing alcohols in high yields and purity.

A mild protocol for efficient preparation of functional molecules containing triazole.

The construction of a class of novel triazole molecules containing sulfonyl fluoride functionalities was achieved through Cu-catalyzed click chemistry in good to excellent yields. The sulfonyl fluoride moieties were cleaved completely under base conditions to produce N-unsubstituted triazoles quantitatively, which provides a strategy to combine SuFEx click chemistry with Cu-catalyzed click chemistry ingeniously.

One-Pot Three-Component Synthesis of Indolyl-4H-chromene-3-sulfonyl Fluoride: A Class of Important Pharmacophore.

A one-pot, sequential three-component reaction between salicylaldehyde, indole, and 2-bromoprop-2-ene-1-sulfonyl fluoride (BPESF) has been demonstrated for the synthesis of sulfonyl fluoride substituted 4H-chromene derivatives in moderate to excellent yields (45%-94%). This one-pot sequential method features easily available starting materials, wide substrate scope, mild conditions, and great efficiency.

Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors.

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aß1 - 42-induced cognitive impairment, significantly prevented the effects of Aß1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Synthesis and biological evaluation of novel ß-lactam-metallo ß-lactamase inhibitors.

ß-lactamases are enzymes that deactivate ß-lactam antibiotics through a hydrolysis mechanism. There are two known types of ß-lactamases: serine ß-lactamases (SBLs) and metallo ß-lactamases (MBLs). The two existing strategies to overcome ß-lactamase-mediated resistance are (a) to develop novel ß-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop ß-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (≤2 mg L-1) against New Delhi metallo-ß-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available ß-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (Ki = 0.85 and 1.87, respectively). This study has revealed a novel series of ß-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs.

Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO2F2).

A SO2F2-mediated ring-opening cross-coupling of cyclobutanone oxime derivatives with alkenes was developed for the construction of a range of δ-olefin-containing aliphatic nitriles with (E)-configuration selectivity. This new method features wide substrate scope, mild conditions, and direct N-O activation.

Green and efficient synthesis of pure ß-sulfonyl aliphatic sulfonyl fluorides through simple filtration in aqueous media.

A green and efficient method for the synthesis of ß-sulfonyl aliphatic sulfonyl fluorides was developed. This reaction works in aqueous media under mild and environmentally benign conditions without any ligand or additive. The efficiency of this method is demonstrated by isolating the desired products obtained through simple filtration.

Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies.

SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable properties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO2F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC50 = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in Aß1-42-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates.

Synthesis of Pyrazolo[1,5-a]pyridinyl, Pyrazolo[1,5-a]quinolinyl, and Pyrazolo[5,1-a]isoquinolinyl Sulfonyl Fluorides via a [3 + 2] Annulation.

A [3 + 2] cycloaddition reaction of N-aminopyridines, N-aminoquinolines, and N-aminoisoquinolines with 1-bromoethene-1-sulfonyl fluoride (BESF) was performed to obtain optimum yields of various useful pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]quinolinyl, and pyrazolo[5,1-a]isoquinolinyl sulfonyl fluorides (43-90% yield). The transformation process showed broad substrate specificity, mild reaction conditions, and operational simplicity. Therefore, the reaction has great applicable value in the field of medicinal chemistry and other disciplines.

Discovery of (E)-2-Methoxyethene-1-sulfonyl Fluoride for the Construction of Enaminyl Sulfonyl Fluoride.

A new sulfonyl fluoride reagent (E)-2-methoxyethene-1-sulfonyl fluoride (MeO-ESF) was developed and successfully applied for the construction of enaminyl sulfonyl fluoride (N-ESF). This protocol provides highly atom-economical access to diverse N-ESF and produces CH3OH as the sole byproduct under mild and environmentally benign conditions.

Arterial remodeling: the role of mitochondrial metabolism in vascular smooth muscle cells.

Arterial remodeling is a common pathological basis of cardiovascular diseases such as atherosclerosis, vascular restenosis, hypertension, pulmonary hypertension, aortic dissection, and aneurysm. Vascular smooth muscle cells (VSMCs) are not only the main cellular components in the middle layer of the arterial wall but also the main cells involved in arterial remodeling. Dedifferentiated VSMCs lose their contractile properties and are converted to a synthetic, secretory, proliferative, and migratory phenotype, playing key roles in the pathogenesis of arterial remodeling. As mitochondria are the main site of biological oxidation and energy transformation in eukaryotic cells, mitochondrial numbers and function are very important in maintaining the metabolic processes in VSMCs. Mitochondrial dysfunction and oxidative stress are novel triggers of the phenotypic transformation of VSMCs, leading to the onset and development of arterial remodeling. Therefore, pharmacological measures that alleviate mitochondrial dysfunction reverse arterial remodeling by ameliorating VSMCs metabolic dysfunction and phenotypic transformation, providing new options for the treatment of cardiovascular diseases related to arterial remodeling. This review summarizes the relationship between mitochondrial dysfunction and cardiovascular diseases associated with arterial remodeling and then discusses the potential mechanism by which mitochondrial dysfunction participates in pathological arterial remodeling. Furthermore, maintaining or improving mitochondrial function may be a new intervention strategy to prevent the progression of arterial remodeling.

Chemical and biology of sulfur fluoride exchange (SuFEx) click chemistry for drug discovery.

Compounds containing an SF bond have garnered intense interest in the chemical and biological literature. In particular, sulfonyl fluorides (RSO2F) are commonly used as covalent protein inhibitors and biological probes. The introduction of the fluorine atom into drugs often leads to significantly promoted medicinal properties, which revolutionized the development of pharmaceuticals and gained attention because of the beneficial properties of these small and highly electro-negative halogens. The sulfonyl fluoride functional group has also been widely adopted throughout the field of chemical biology due to its unique balance between reactivity and stability under physiological conditions. This comprehensive review highlights the recent developments of sulfonyl fluorides based compounds in a massive range of therapeutic applications. We believe this review article will be helpful to inspire new ideas for structural design and developments of less toxic and potent Sulfur based drugs against the numerous death-causing diseases.

A General Procedure for the Construction of 2-Alkyl-Substituted Vinyl Sulfonyl Fluoride.

A series of compact and multifunctional 2-alkyl-substituted vinyl sulfonyl fluorides were efficiently prepared from the corresponding alkyl iodides and 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF). This Giese-type radical approach provided new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established methods. A correspondingly large collection of derivatization reactions was also demonstrated on the alkenyl sulfonyl fluorides.

A reductive dehalogenative process for chemo- and stereoselective synthesis of 1,3-dienylsulfonyl fluorides.

A method for the mild and efficient synthesis of 1,3-dienylsulfonyl fluorides was developed via dehalogenation of α-halo-1,3-dienylsulfonyl fluorides in the presence of zinc powder and acetic acid, achieving exclusive chemo- and stereoselectivities. This protocol was successfully applied to the synthesis of heterocyclic dienylsulfonyl fluorides and polyene sulfonyl fluoride.

Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease.

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 µM and 6.59 µM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 µM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aß1 - 42-induced cognitive impairment, and significantly prevented the effects of Aß1 - 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

A regio- and stereoselective Heck-Matsuda process for construction of γ-aryl allylsulfonyl fluorides.

A highly efficient regio- and stereoselective Heck-Matsuda method was developed employing aryl diazoniums and allylsulfonyl fluorides for the construction of a class of novel γ-aryl allylsulfonyl fluorides in the presence of Pd(OAc)2 and PPh3. The method features excellent regio- and stereoselectivity (up to 100% E-selectivity), broad substrate scope and mild reaction conditions. Further application of γ-aryl allylsulfonyl fluoride in SuFEx reactions was achieved to provide their corresponding sulfonates and sulfonamides in excellent yields.

Regio- and Stereoselective Installation of Bromide onto Vinyl Sulfonyl Fluorides: Construction of a Class of Versatile Sulfur Fluoride Exchange Hubs.

A convenient protocol for the exclusively regio- and stereoselective installation of a bromine atom on the 2-arylvinylsulfonyl fluorides using lithium bromide (LiBr) as the bromine source was described, providing (Z)-1-bromo-2-arylethene-1-sulfonyl fluorides (Z-BASF) with versatile reactive handles (bromide, vinyl, and sulfonyl fluoride) in ≤88% yield. Meanwhile, Z-BASF molecules displayed various reactivities in a series of chemical transformations.

A cascade reaction for regioselective construction of pyrazole-containing aliphatic sulfonyl fluorides.

A copper-catalyzed cascade reaction of α-diazocarbonyl compounds with ethenesulfonyl fluoride (ESF) is developed, affording a variety of highly functionalized pyrazolyl aliphatic sulfonyl fluorides in good to excellent yields (66-98%). This transformation features broad substrates, exclusive regioselectivity, high atom economy and operational simplicity, thus providing a straightforward method for the direct construction of pyrazole-containing aliphatic sulfonyl fluorides, which will provide great applicable value in medicinal chemistry and other related disciplines.

Copper-Promoted Conjugate Addition of Carboxylic Acids to Ethenesulfonyl Fluoride (ESF) for Constructing Aliphatic Sulfonyl Fluorides.

A CuO-promoted direct hydrocarboxylation of ethenesulfonyl fluoride (ESF) was developed using carboxylic acid as a nucleophile under mild conditions. A variety of molecules containing both ester group and aliphatic sulfonyl fluoride moiety exhibit great potential in medicinal chemistry and chemical biology. Furthermore, the modification of the known drugs Ibuprofen and Aspirin was also demonstrated.

Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease.

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 µM for eqBChE, 3.62 µM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aß1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aß1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.