Selective α-oxidation of amides via visible-light-driven iron catalysis.

Hydroxyl radicals (˙OH) as one of the highly reactive species can react unselectively with a wide range of chemicals. The ˙OH radicals are typically generated under harsh conditions. Herein, we report hydroxyl radical-induced selective N-α C(sp3)-H bond oxidation of amides under greener and mild conditions via an Fe(NO3)3·9H2O catalyst inner sphere pathway upon irradiation with a 30 W blue LED light strip (λ = 455 nm) using NaBrO3 as the oxidant. This protocol exhibited high chemoselectivity and excellent functional group tolerance. A preliminary mechanism investigation demonstrated that the iron catalyst afforded hydroxyl radicals via the visible-light-induced homolysis (VLIH) of iron complexes followed by a hydrogen atom transfer (HAT) process to realize this transformation.

Aerobic Copper-Catalyzed Salicylaldehydic Cformyl -H Arylations with Arylboronic Acids.

We report a challenging copper-catalyzed Cformyl -H arylation of salicylaldehydes with arylboronic acids that involves unique salicylaldehydic copper species that differ from reported salicylaldehydic rhodacycles and palladacycles. This protocol has high chemoselectivity for the Cformyl -H bond compared to the phenolic O-H bond involving copper catalysis under high reaction temperatures. This approach is compatible with a wide range of salicylaldehyde and arylboronic acid substrates, including estrone and carbazole derivatives, which leads to the corresponding arylation products. Mechanistic studies show that the 2-hydroxy group of the salicylaldehyde substrate triggers the formation of salicylaldehydic copper complexes through a CuI /CuII /CuIII catalytic cycle.

Pd-Catalyzed Remote Site-Selective and Stereoselective C(Alkenyl)-H Alkenylation of Unactivated Cycloalkenes.

A palladium-catalyzed alkenylation involving remote δ-position C(alkenyl)-H activation of cycloalkenes reacting with electron-deficient alkenes is described. This method features excellent site selectivity and stereoselectivity to efficiently afford only E-selective highly substituted 1,3-diene derivatives with extra-ligand-free and good functional group tolerance including estrone and free N-H tryptamine under weakly alkaline conditions. Mechanistic studies suggest that picolinamide as a bidentate directing group enables the formation of unique alkenyl palladacycle intermediates.

Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove.

A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 µg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c-DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.

Copper-Catalyzed Inter/Intramolecular N-Alkenylation of Benzimidazoles via Tandem Processes Involving Selectively Mild Iodination of sp3 C-H Bond at α-Position of Ester.

Inter/intramolecular approaches to sp2 C-N bond formation of N-alkenyl benzimidazoles have been accomplished in the presence of an iodide anion associated with a copper catalyst. Both intermolecular and intramolecular reactions included tandem processes, in which selective iodination of sp3 C-H bond at the α-position of ester under mild conditions was demonstrated for the first time. Tandem reactions involving sp3 C-H activation via α-iodo ester intermediate under copper catalysis efficiently provided more than 20 novel azole compounds, and free radicals were not involved in this transformation.

Sequential Michael addition/retro-Claisen condensation of aromatic ß-diketones with α,ß-unsaturated esters: an approach to obtain 1,5-ketoesters.

A K2CO3-catalyzed one-pot protocol involving sequential C-C bond formation and cleavage of aromatic ß-diketones with α,ß-unsaturated esters is developed to obtain 1,5-ketoesters. The sequential reaction via Michael addition and retro-Claisen condensation proceeds smoothly under mild conditions in up to 98% isolated yield. The mechanism study disclosed that the cascade process involved C-C bond cleavage of aromatic ß-diketone as a phenacyl donor under alcoholic alkalescent conditions.

Synthesis and bioactive evaluation of a novel series of coumarinazoles.

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d-e showed better anti-Candida utilis activity than mono-azole derivatives 4a and 4d-e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-Candida albicans and anti-Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti-Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.

Identification of unique indolylcyanoethylenyl sulfonylanilines as novel structural scaffolds of potential antibacterial agents.

The increasing incidence of antibiotic resistance has forced the development of unique antimicrobials with novel multitargeting mechanisms to combat infectious diseases caused by multidrug-resistant pathogens. Structurally unique indolylcyanoethylenyl sulfonylanilines (ISs) were exploited as novel promising antibacterial agents to confront stubborn drug resistance. Some prepared ISs possessed favorable bacteriostatic action towards the tested bacteria. Especially, hydroxyethyl IS 14a exerted 8-fold more potent inhibitory efficacy against multidrug-resistant A. baumannii and E. coli 25922 with the low MIC of 0.5 µg/mL than norfloxacin, and showed low cell toxicity and rapid bactericidal property. Moreover, this compound also possessed obvious effect of eradicating bacterial biofilm, which could effectually relieve the development of drug resistance. A preliminary assessment of the antibacterial mechanism indicated that compound 14a could disintegrate membrane integrity leading to the leakage of intracellular protein, inactivation of lactate dehydrogenase and metabolism inhibition. Hydroxyethyl IS 14a mediated the accumulation of excess reactive oxygen species, which further contributed to reducing glutathione, resulting in oxidative damage to bacteria. Furthermore, IS 14a could intercalate into DNA to hinder the biological function of DNA. Quantum chemical study disclosed that IS 14a with the lowest energy gap was conducive to displaying high bioactivity. These findings demonstrated that hydroxyethyl IS 14a as a prospective antimicrobial candidate for combating A. baumannii and E. coli 25922 would be a promising starting point.

CuCl2 -Catalyzed α-Chloroketonation of Aromatic Alkenes via Visible-Light-Induced LMCT.

Here we report a copper-catalyzed protocol for the synthesis of α-chloroketones from aromatic alkenes including electron-deficient olefins under visible-light irradiation. Preliminary mechanistic studies show that the peroxo Cu(II) species is the key intermediate and hydroperoxyl (HOO⋅) and chlorine (Cl⋅) radicals can be generated by ligand-to-metal charge transfer (LMCT).

An unanticipated discovery towards novel naphthalimide corbelled aminothiazoximes as potential anti-MRSA agents and allosteric modulators for PBP2a.

Available therapeutic strategies are urgently needed to conquer multidrug resistance of MRSA. A visible effort was guided towards the advancement of novel antibacterial framework of naphthalimide corbelled aminothiazoximes, and desired to assert some insight on the conjunction of individual pharmacophore with distinct biological activities and unique action mechanism. Preliminary assessment displayed that dimethylenediamine derivative 13d presented a wonderful inhibition on MRSA (MIC = 0.5 µg/mL), and showed excellent membrane selectivity (HC50 > 200 µg/mL) from an electrostatic distinction of the electronegative bacterial membranes and the electroneutral mammalian membranes. Moreover, 13d could effectually relieve the development of MRSA resistance. Investigations into explaining the mechanism of anti-MRSA disclosed that 13d displayed strong lipase affinity, which facilitated its permeation into cell membrane, causing membrane depolarization, leakage of cytoplasmic contents and lactate dehydrogenase (LDH) inhibition. Meanwhile, 13d could exert interaction with DNA to hinder biological function of DNA, and disrupt the antioxidant defense system of MRSA through up-regulation of ROS subjected the strain to oxidative stress. In particular, the unanticipated mechanism for naphthalimide corbelled aminothiazoximes that 13d could suppress the expression of PBP2a by inducing allosteric modulation of PBP2a and triggering the open of the active site, was discovered for the first time. These findings of naphthalimide corbelled aminothiazoximes as a small-molecule class of anti-MRSA agents held promise in strategies for treatment of MRSA infections.

Natural Berberine-derived Azolyl Ethanols as New Structural Antibacterial Agents against Drug-Resistant Escherichia coli.

Natural berberine-derived azolyl ethanols as new structural antibacterial agents were designed and synthesized for fighting with dreadful bacterial resistance. Partial target molecules exhibited potent activity against the tested strains, particularly, nitroimidazole derivative 4d and benzothiazole-2-thoil compound 18b, with low cytotoxicity both exerted strong antibacterial activities against multidrug-resistant Escherichia coli at low concentrations as 0.007 and 0.006 mM, respectively. Meanwhile, the active compounds 4d and 18b possessed the ability to rapidly kill bacteria and observably eradicate the E. coli biofilm by reducing exopolysaccharide content to prevent bacterial adhesion, which was conducive to alleviating the development of E. coli resistance. Preliminary mechanistic explorations suggested that the excellent antibacterial potential of molecules 4d and 18b might be attributed to their ability to disintegrate membrane, accelerate ROS accumulation, reduce bacterial metabolism, and intercalate into DNA groove. These results provided powerful information for the further exploitation of natural berberine derivatives against bacterial pathogens.

A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV.

This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV-DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.

Intra/intermolecular direct allylic alkylation via Pd(II)-catalyzed allylic C-H activation.

The first catalytic direct alkylation of allylic C-H bonds via Pd(II)-catalysis is described in the absence of base. Polysubstituted cyclic compounds can also be constructed by the intramolecular direct allylic alkylation.

Discovery of Benzimidazole-Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA.

A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.

Palladium-catalyzed aerobic regio- and stereo-selective olefination reactions of phenols and acrylates via direct dehydrogenative C(sp2)-O cross-coupling.

An efficient olefination protocol for the oxidative dehydrogenation of phenols and acrylates has been achieved using a palladium catalyst and O2 as the sole oxidant. This reaction exhibits high regio- and stereo-selectivity (E-isomers) with moderate to excellent isolated yields and a wide substrate scope (32 examples) including ethyl vinyl ketone and endofolliculina.

Gold(I)-catalyzed oxidative cleavage of a C-C double bond in water.

[reaction: see text] Oxidative cleavage of the C=C bond to afford ketone or aldehyde products with tert-butyl hydrogenperoxide (TBHP) as the oxidant can be catalyzed by AuCl with neocuproine (1) in water.

Discovery of membrane active benzimidazole quinolones-based topoisomerase inhibitors as potential DNA-binding antimicrobial agents.

A series of novel benzimidazole quinolones as potential antimicrobial agents were designed and synthesized. Most of the prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. The most potent compound 15m was membrane active and did not trigger the development of resistance in bacteria. It not only inhibited the formation of biofilms but also disrupted the established Staphylococcus aureus and Escherichia coli biofilms. It was able to inhibit the relaxation activity of E. coli topoisomerase IV at 10 µM concentration. Moreover, this compound also showed low toxicity against mammalian cells. Molecular modeling and experimental investigation of compound 15m with DNA suggested that this compound could effectively bind with DNA to form a steady 15m-DNA complex which might further block DNA replication to exert the powerful bioactivities.

Recent developments in azole compounds as antibacterial and antifungal agents.

Azole compounds are an important class of nitrogen heterocycles with electron-rich property. This special structure endows azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions such as hydrogen bonds, coordination bonds, ion-dipole, cation-π,π-π stacking and hydrophobic effect as well as van der Waals force etc., thereby possessing various applications in medicinal chemistry, especially their protrudent effects such as imidazoles and triazoles against fungal strains. The design, synthesis and antimicrobial activity of azole derivatives have been extensively investigated and have become one of the highly active highlights in recent years, and the progress is quite rapid. In particular, a large number of azole-based antibacterial and antifungal agents have been penetratingly studied as candidates and even some of them have been used in clinic, which have shown the great potential and development value of azole compounds. Based on our researches on azole compounds and referring to other literature, this work scientifically reviewed the researches and developments of azole-based compounds as antibacterial and antifungal agents, including oxazole, imidazole, benzimidazole, triazole, benzotriazole, pyrazole, thiazole, carbazole as well as tetrazole in recent three years. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antibacterial and antifungal drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.

Design, synthesis and antimicrobial evaluation of novel benzimidazole type of Fluconazole analogues and their synergistic effects with Chloromycin, Norfloxacin and Fluconazole.

A novel series of benzimidazole type of Fluconazole analogues were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution technique. The bioactive evaluation showed that 3,5-bis(trifluoromethyl)phenyl benzimidazoles gave comparable or even stronger antibacterial and antifungal efficiency in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. The combination of 2,4-difluorobenzyl benzimidazole derivative 5m and its hydrochloride 7 respectively with antibacterial Chloromycin, Norfloxacin or antifungal Fluconazole showed better antimicrobial efficiency with less dosage and broader antimicrobial spectrum than the separated use of them alone. Notably, these combined systems were more sensitive to Fluconazole-insensitive Aspergillus flavus and methicillin-resistant MRSA.

A proton shelter inspired by the sugar coating of acidophilic archaea.

The acidophilic archaeons are a group of single-celled microorganisms that flourish in hot acid springs (usually pH < 3) but maintain their internal pH near neutral. Although there is a lack of direct evidence, the abundance of sugar modifications on the cell surface has been suggested to provide the acidophiles with protection against proton invasion. In this study, a hydroxyl (OH)-rich polymer brush layer was prepared to mimic the OH-rich sugar coating. Using a novel pH-sensitive dithioacetal molecule as a probe, we studied the proton-resisting property and found that a 10-nm-thick polymer layer was able to raise the pH from 1.0 to > 5.0, indicating that the densely packed OH-rich layer is a proton shelter. As strong evidence for the role of sugar coatings as proton barriers, this biomimetic study provides insight into evolutionary biology, and the results also could be expanded for the development of biocompatible anti-acid materials.