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1.
J Org Chem ; 88(16): 12064-12068, 2023 Aug 18.
Article in English | MEDLINE | ID: mdl-37556402

ABSTRACT

A rapid and highly practical one-flask procedure for the positionally selective preparation of (acyloxy)methyl N-(2-hydroxybenzyl)iminodiacetate and related diesters from iminodiacetic acid and phenols is described. The key to this multicomponent phenol-Mannich condensation resides in the use of cesium iminodiacetate as the reaction partner. This protocol has been applied in an unusually direct synthesis of the intracellular fluorescent dye Calcein blue AM, for which scant experimental and spectroscopic data are presently available.

2.
Molecules ; 27(14)2022 Jul 17.
Article in English | MEDLINE | ID: mdl-35889434

ABSTRACT

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et2Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented.


Subject(s)
Copper , Heterocyclic Compounds , Catalysis , Indicators and Reagents , Nitrogen
3.
Synth Commun ; 52(2): 185-189, 2022.
Article in English | MEDLINE | ID: mdl-37693841

ABSTRACT

A convenient method for the reduction of N,N-dimethylhydrazones using amine borane complexes generated in situ is described. It was found that primary amine borane complexes performed exceedingly well at reducing N,N-dimethylhydrazones in as little as 1.1 equivalents, furnishing the corresponding air-sensitive hydrazine products in excellent yields.

4.
Antibiotics (Basel) ; 10(7)2021 Jul 14.
Article in English | MEDLINE | ID: mdl-34356776

ABSTRACT

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure-activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies.

5.
Chem Biol Drug Des ; 97(1): 134-147, 2021 01.
Article in English | MEDLINE | ID: mdl-32844569

ABSTRACT

Prodrugs are pharmacologically attenuated derivatives of drugs that undergo bioconversion into the active compound once reaching the targeted site, thereby maximizing their efficiency. This strategy has been implemented in pharmaceuticals to overcome obstacles related to absorption, distribution, and metabolism, as well as with intracellular dyes to ensure concentration within cells. In this study, we provide the first examples of a prodrug strategy that can be applied to simple phenolic antimicrobials to increase their potency against mature biofilms. The addition of (acetoxy)methyl iminodiacetate groups increases the otherwise modest potency of simple phenols. Biofilm-forming bacteria exhibit a heightened tolerance toward antimicrobial agents, thereby accentuating the need for new antibiotics as well as those, which incorporate novel delivery strategies to enhance activity toward biofilms.


Subject(s)
Anti-Infective Agents/pharmacology , Biofilms/drug effects , Imino Acids/chemistry , Phenols/chemistry , Prodrugs/pharmacology , Anti-Infective Agents/chemistry , Microbial Sensitivity Tests , Phenols/pharmacology , Prodrugs/chemistry , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/physiology , Structure-Activity Relationship
6.
ACS Omega ; 5(11): 6010-6020, 2020 Mar 24.
Article in English | MEDLINE | ID: mdl-32226882

ABSTRACT

The recalcitrance exhibited by microbial biofilms to conventional disinfectants has motivated the development of new chemical strategies to control and eradicate biofilms. The activities of several small phenolic compounds and their trichloromethylsulfenyl ester derivatives were evaluated against planktonic cells and mature biofilms of Staphylococcus epidermidis and Pseudomonas aeruginosa. Some of the phenolic parent compounds are well-studied constituents of plant essential oils, for example, eugenol, menthol, carvacrol, and thymol. The potency of sulfenate ester derivatives was markedly and consistently increased toward both planktonic cells and biofilms. The mean fold difference between the parent and derivative minimum inhibitory concentration against planktonic cells was 44 for S. epidermidis and 16 for P. aeruginosa. The mean fold difference between the parent and derivative biofilm eradication concentration for 22 tested compounds against both S. epidermidis and P. aeruginosa was 3. This work demonstrates the possibilities of a new class of biofilm-targeting disinfectants deploying a sulfenate ester functional group to increase the antimicrobial potency toward microorganisms in biofilms.

7.
Front Chem ; 7: 653, 2019.
Article in English | MEDLINE | ID: mdl-31632948

ABSTRACT

Biofilm-forming bacteria present formidable challenges across diverse settings, and there is a need for new antimicrobial agents that are both environmentally acceptable and relatively potent against microorganisms in the biofilm state. The antimicrobial activity of three naturally occurring, low molecular weight, phenols, and their derivatives were evaluated against planktonic and biofilm Staphylococcus epidermidis and Pseudomonas aeruginosa. The structure activity relationships of eugenol, thymol, carvacrol, and their corresponding 2- and 4-allyl, 2-methallyl, and 2- and 4-n-propyl derivatives were evaluated. Allyl derivatives showed a consistent increased potency with both killing and inhibiting planktonic cells but they exhibited a decrease in potency against biofilms. This result underscores the importance of using biofilm assays to develop structure-activity relationships when the end target is biofilm.

8.
Synlett ; 29(2): 181-184, 2018 Jan.
Article in English | MEDLINE | ID: mdl-31068740

ABSTRACT

Metalloamination-alkylation of representative N,N-dimethyl-hydrazinoalkenes has been shown to be effectively catalyzed by CuBr-SMe2, CuCN, and Cul. The current method obviates the use of stoichiometric CuCN(LiCl)2 as a promoter for the electrophilic functionalization event.

9.
J Org Chem ; 81(21): 10160-10164, 2016 11 04.
Article in English | MEDLINE | ID: mdl-27454875

ABSTRACT

Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as reaction participants in metalloamination/cyclization-allylation cascades.

10.
J Org Chem ; 80(20): 9847-55, 2015 Oct 16.
Article in English | MEDLINE | ID: mdl-26360508

ABSTRACT

A concise and highly diastereoselective synthesis of the polyfused tetracyclic cores of the Stemona alkaloids asparagamine A and stemofoline that relies on a 2-propylidine-1,3-(bis)silane bicyclization onto a enantiodefined pyrrolidine 2,5-di(cation) equivalent derived from l-malic acid is reported. A crucial feature of this divergent synthetic approach involves the solvolysis of a transient and highly labile tertiary-propargylic hydroxylactam trifluoroacetate in the strongly ionizing medium 5 M LiClO4/Et2O. The acyliminium ion generated in this manner undergoes stereospecific interception by the aforementioned (bis)silane nucleophile.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Trimethylsilyl Compounds/chemistry , Crystallography, X-Ray , Cyclization , Heterocyclic Compounds, 4 or More Rings/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism
11.
Angew Chem Int Ed Engl ; 53(52): 14352-6, 2014 Dec 22.
Article in English | MEDLINE | ID: mdl-25302713

ABSTRACT

Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N,N-dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines.

12.
PLoS One ; 7(7): e40973, 2012.
Article in English | MEDLINE | ID: mdl-22808288

ABSTRACT

Staphylococcus aureus biofilms are associated with chronic skin infections and are orders of magnitude more resistant to antimicrobials and host responses. S. aureus contains conserved nonribosomal peptide synthetases that produce the cyclic dipeptides tyrvalin and phevalin (aureusimine A and B, respectively). The biological function of these compounds has been speculated to be involved in virulence factor gene expression in S. aureus, protease inhibition in eukaryotic cells, and interspecies bacterial communication. However, the exact biological role of these compounds is unknown. Here, we report that S. aureus biofilms produce greater amounts of phevalin than their planktonic counterparts. Phevalin had no obvious impact on the extracellular metabolome of S. aureus as measured by high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. When administered to human keratinocytes, phevalin had a modest effect on gene expression. However, conditioned medium from S. aureus spiked with phevalin amplified differences in keratinocyte gene expression compared to conditioned medium alone. Phevalin may be exploited as potential biomarker and/or therapeutic target for chronic, S. aureus biofilm-based infections.


Subject(s)
Biofilms/drug effects , Gene Expression Regulation/drug effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Pyrazines/metabolism , Pyrazines/pharmacology , Staphylococcus aureus/physiology , Apoptosis/drug effects , Chromatography, High Pressure Liquid , Culture Media, Conditioned/pharmacology , Extracellular Space/drug effects , Extracellular Space/metabolism , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Metabolome/drug effects , Proteome/metabolism , Pyrazines/chemistry , Staphylococcus aureus/drug effects
13.
Chem Commun (Camb) ; 47(48): 12861-3, 2011 Dec 28.
Article in English | MEDLINE | ID: mdl-22046591

ABSTRACT

Highly diastereoselective bicyclizations of aminodienes catalyzed by chelating diamide complexes of Sc(III) and Y(III) that lead to pyrrolizidines and indolizidines are described. This bis(annulation) procedure has been utilized in a concise synthesis of the pyrrolizidine alkaloid 195F.


Subject(s)
Amides/chemistry , Coordination Complexes/chemistry , Metals/chemistry , Pyrrolizidine Alkaloids/chemical synthesis , Catalysis , Chelating Agents/chemistry , Cyclization , Indolizidines/chemistry , Pyrrolizidine Alkaloids/chemistry , Scandium/chemistry , Stereoisomerism , Yttrium/chemistry
14.
Chem Commun (Camb) ; 47(11): 3281-3, 2011 Mar 21.
Article in English | MEDLINE | ID: mdl-21286619

ABSTRACT

Intermediates easily prepared by partial reduction of various esters with LDBBA as a reducing agent smoothly react with lithium acetylides to give propargyl alcohols, without isolation of partial reduction intermediates, in good yields (73-83%).


Subject(s)
Alkynes/chemistry , Propanols/chemistry , Alkynes/chemical synthesis , Esters , Lithium/chemistry , Oxidation-Reduction , Propanols/chemical synthesis
15.
Org Lett ; 12(19): 4271-3, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20812756

ABSTRACT

A highly diastereoselective binary hydroamination of a 5-amino-1,8-diene containing a 2-(5-ethyl-2-thienyl)ethenyl terminator has been utilized in an efficient synthesis of (±)-xenovenine (1). A pronounced rate enhancement was observed for cyclization onto the 2-(heteroaromatic)ethenyl group in comparison to a simple 1,2-disubstituted alkene.


Subject(s)
Amines/chemistry , Ethylenes/chemistry , Pyrrolizidine Alkaloids/chemical synthesis , Scandium/chemistry , Catalysis , Cyclization , Molecular Structure , Stereoisomerism
16.
Microbiology (Reading) ; 154(Pt 11): 3319-3328, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18957585

ABSTRACT

An endophytic fungus, Gliocladium roseum (NRRL 50072), produced a series of volatile hydrocarbons and hydrocarbon derivatives on an oatmeal-based agar under microaerophilic conditions as analysed by solid-phase micro-extraction (SPME)-GC/MS. As an example, this organism produced an extensive series of the acetic acid esters of straight-chained alkanes including those of pentyl, hexyl, heptyl, octyl, sec-octyl and decyl alcohols. Other hydrocarbons were also produced by this organism, including undecane, 2,6-dimethyl; decane, 3,3,5-trimethyl; cyclohexene, 4-methyl; decane, 3,3,6-trimethyl; and undecane, 4,4-dimethyl. Volatile hydrocarbons were also produced on a cellulose-based medium, including heptane, octane, benzene, and some branched hydrocarbons. An extract of the host plant, Eucryphia cordifolia (ulmo), supported the growth and hydrocarbon production of this fungus. Quantification of volatile organic compounds, as measured by proton transfer mass spectrometry (PTR-MS), indicated a level of organic substances in the order of 80 p.p.m.v. (parts per million by volume) in the air space above the oatmeal agar medium in an 18 day old culture. Scaling the PTR-MS profile the acetic acid heptyl ester was quantified (at 500 p.p.b.v.) and subsequently the amount of each compound in the GC/MS profile could be estimated; all yielded a total value of about 4.0 p.p.m.v. The hydrocarbon profile of G. roseum contains a number of compounds normally associated with diesel fuel and so the volatiles of this fungus have been dubbed 'myco-diesel'. Extraction of liquid cultures of the fungus revealed the presence of numerous fatty acids and other lipids. All of these findings have implications in energy production and utilization.


Subject(s)
Bioelectric Energy Sources/microbiology , Energy-Generating Resources , Gliocladium/metabolism , Hydrocarbons/metabolism , Plants/microbiology , Volatile Organic Compounds/metabolism , Avena/metabolism , Bioelectric Energy Sources/economics , Culture Media/chemistry , Culture Media/metabolism , Energy-Generating Resources/economics , Gliocladium/chemistry , Hydrocarbons/chemistry , Mass Spectrometry , Volatile Organic Compounds/chemistry
17.
FEMS Microbiol Lett ; 283(2): 140-5, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18422630

ABSTRACT

Oidium sp. has been recovered as an endophyte in Terminalia catappa (tropical chestnut) in Costa Rica. The volatile organic compounds (VOCs) of this organism uniquely and primarily consist of esters of propanoic acid, 2-methyl-, butanoic acid, 2-methyl-, and butanoic acid, 3-methyl-. The VOCs of Oidium sp. are slightly inhibitory to many plant pathogenic fungi. Previous work on the VOCs of Muscodor albus demonstrated that besides esters of small organic acids, a small organic acid and a naphthalene derivative were needed to obtain maximum antibiotic activity. Thus, the addition of exogenous volatile compounds such as isobutyric acid and naphthalene, 1,1'-oxybis caused a dramatic synergistic increase in the antibiotic activity of the VOCs of Oidium sp. against Pythium ultimum. In fact, at elevated concentrations, there was not only 100% inhibition of P. ultimum but killing as well. In addition, a coculture of Muscodor vitigenus (making only naphthalene) and Oidium sp. plus isobutyric acid produced an additive antibiosis effect against P. ultimum. The biological implications of multiple volatile compounds acting to bring about antibiosis in nature are discussed.


Subject(s)
Antibiosis , Antifungal Agents/biosynthesis , Antifungal Agents/pharmacology , Ascomycota/physiology , Oils, Volatile/metabolism , Oils, Volatile/pharmacology , Pythium/drug effects , Antifungal Agents/chemistry , Ascomycota/metabolism , Ascomycota/ultrastructure , Drug Synergism , Microscopy, Electron, Scanning , Oils, Volatile/chemistry
18.
Chem Commun (Camb) ; (41): 5205-7, 2005 Nov 07.
Article in English | MEDLINE | ID: mdl-16228036

ABSTRACT

A neutral Zr(IV) complex has been shown to be an effective precatalyst for intramolecular alkene hydroaminations that provide cyclic amines in good to excellent yields.


Subject(s)
Alkenes/chemistry , Organometallic Compounds/chemistry , Phosphines/chemistry , Zirconium/chemistry , Amination , Catalysis , Molecular Conformation , Stereoisomerism
19.
Org Lett ; 7(20): 4391-3, 2005 Sep 29.
Article in English | MEDLINE | ID: mdl-16178541

ABSTRACT

[reaction: see text] Neutral scandium amido complexes are viable catalysts for intramolecular alkene hydroamination. Catalytic activity is strongly coupled to the electronic character of the Sc(III) ligand environment with chelating diamide coordination providing a precatalyst possessing substantially improved activity and superb distereoselectivity in the synthesis of trans-2,5-disubstituted pyrrolidines.


Subject(s)
Alkenes/chemistry , Chelating Agents/chemistry , Diamide/chemistry , Hydrogen/chemistry , Scandium/chemistry , Amination , Catalysis , Molecular Structure
20.
Org Lett ; 7(9): 1737-9, 2005 Apr 28.
Article in English | MEDLINE | ID: mdl-15844894

ABSTRACT

[structure: see text] A yttrium(III) complex derived from proligand 7c has been shown to be a superior catalyst for enantioselective intramolecular alkene hydroaminations that provide cyclic amines with ee's ranging from 69% to 89%.


Subject(s)
Alkenes/chemistry , Organometallic Compounds/chemistry , Sulfhydryl Compounds/chemistry , Yttrium/chemistry , Amination , Catalysis , Indicators and Reagents , Ligands , Molecular Structure , Stereoisomerism
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