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Organic Letters Oct 2013The Pd(II)-catalyzed ortho-C-H trifluoromethylation of benzylamines has been achieved utilizing an electrophilic CF3 reagent. Additives, such as H2O and Ag2O, were found...
The Pd(II)-catalyzed ortho-C-H trifluoromethylation of benzylamines has been achieved utilizing an electrophilic CF3 reagent. Additives, such as H2O and Ag2O, were found to be crucial for obtaining good yields. This protocol will be useful in medicinal chemistry for the preparation of ortho-trifluoromethyl-substituted benzylamines.
Topics: Benzylamines; Catalysis; Methylation; Molecular Structure; Organometallic Compounds; Palladium; Stereoisomerism
PubMed: 24098966
DOI: 10.1021/ol402471y -
Molecules (Basel, Switzerland) Nov 202117β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in...
17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC 17β-HSD3 inhibitors were discovered using -(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (). The most potent compounds have IC values of approximately 75 nM. Compound , -[2-(1-Acetylpiperidin-4-ylamino)benzyl]--[2-(4-chlorophenoxy)phenyl]acetamide, has an IC of 76 nM, while compound , -(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC of 74 nM. Racemic -allyl derivative (IC of 520 nM) was easily formed from in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the -(+)-enantiomer () was active with an IC of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.
Topics: 17-Hydroxysteroid Dehydrogenases; Benzylamines; Cell Line, Tumor; Crystallography, X-Ray; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Male; Molecular Docking Simulation; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Testosterone
PubMed: 34885749
DOI: 10.3390/molecules26237166 -
Angewandte Chemie (International Ed. in... Apr 2017Meta-C-H functionalization of benzylamines has been developed using a Pd /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO Me)...
Meta-C-H functionalization of benzylamines has been developed using a Pd /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.
Topics: Amination; Benzylamines; Catalysis; Halogenation; Ligands; Palladium; Pyridones
PubMed: 28371173
DOI: 10.1002/anie.201701803 -
Journal of Medicinal Chemistry Sep 1984The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are...
The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (19, MIC 10.2 micrograms/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 micrograms/mL), and N-butyl-3,5-difluorobenzylamine (103, MIC 6.4 micrograms/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combinations of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.
Topics: Amines; Antitubercular Agents; Benzylamines; Mycobacterium; Mycobacterium tuberculosis; Structure-Activity Relationship
PubMed: 6433022
DOI: 10.1021/jm00375a005 -
Journal of the American Chemical Society Jun 2016A Pd(II)-catalyzed enantioselective C-H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic...
A Pd(II)-catalyzed enantioselective C-H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive molecules.
Topics: Amino Acids; Benzylamines; Catalysis; Cross-Linking Reagents; Drug Design; Hydroxamic Acids; Kinetics; Ligands; Molecular Structure; Palladium; Stereoisomerism
PubMed: 27249208
DOI: 10.1021/jacs.6b04660 -
Drugs of Today (Barcelona, Spain : 1998) Nov 2015Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine.... (Review)
Review
Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine. Therefore, an individually different pronounced heterogeneity of motor and nonmotor symptoms characterizes each Parkinson's disease patient. Ideal candidates for the balance of these neurotransmitter deficits are compounds like safinamide with broad mechanisms of action such as reversible monoamine oxidase type B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release. Safinamide is administered one time daily with oral doses ranging from 50 to 100 mg. Safinamide was well tolerated and safe, ameliorated motor symptoms when combined with dopamine agonist only or additional levodopa in clinical trials. Safinamide is a novel instrument for the drug therapy of Parkinson's disease with better safety and tolerability particularly concerning diarrhea than inhibitors of catechol-O-methyltransferase, like entacapone, according to an indirect comparison within a meta-analysis with entacapone.
Topics: Alanine; Animals; Benzylamines; Humans; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Parkinson Disease
PubMed: 26744740
DOI: 10.1358/dot.2015.51.11.2414529 -
Biochemistry Aug 2007Structure-activity correlations have been employed previously in the mechanistic interpretation of TTQ-dependent amine dehydrogenases using a series of para-substituted...
Structure-activity correlations have been employed previously in the mechanistic interpretation of TTQ-dependent amine dehydrogenases using a series of para-substituted benzylamines. However, by combining the use of kinetic isotope effects (KIEs) and crystallographic analysis, in conjunction with structure-reactivity correlation studies, we show that para-substituted benzylamines are poor reactivity probes for TTQ-dependent aromatic amine dehydrogenase (AADH). Stopped-flow kinetic studies of the reductive half-reaction, with para-substituted benzylamines and their dideuterated counterparts, demonstrate that C-H or C-D bond breakage is not fully rate limiting (KIEs approximately unity). Contrary to previous reports, Hammett plots exhibit a poor correlation of structure-reactivity data with electronic substituent effects for para-substituted benzylamines and phenylethylamines. Crystallographic studies of enzyme-substrate complexes reveal that the observed structure-reactivity correlations are not attributed to distinct binding modes for para-substituted benzylamines in the active site, although two binding sites for p-nitrobenzylamine are identified. We identify structural rearrangements, prior to the H-transfer step, which are likely to limit the rate of TTQ reduction by benzylamines. This work emphasizes (i) the need for caution when applying structure-activity correlations to enzyme-catalyzed reactions and (ii) the added benefit of using both isotope effects and structural analysis, in conjunction with structure-reactivity relationships, to study chemical steps in enzyme reaction cycles.
Topics: Benzylamines; Catalysis; Crystallography, X-Ray; Deuterium; Hydrogen Bonding; Isotope Labeling; Kinetics; Oxidoreductases Acting on CH-NH Group Donors; Phenethylamines; Quantitative Structure-Activity Relationship
PubMed: 17636875
DOI: 10.1021/bi7007239 -
Organic Letters Jan 2016Photosensitive C70 was used for the catalytic oxidation of benzylamines to the corresponding imines. The advantages of using C70 compared to C60 or other commonly used...
Photosensitive C70 was used for the catalytic oxidation of benzylamines to the corresponding imines. The advantages of using C70 compared to C60 or other commonly used photosensitizers such as tetraphenylporphyrin (TPP) are (1) faster reaction rates, especially under lower energy of light sources, (2) clean reactions with simple workup without chromatography, and (3) lower catalyst loadings. The reactions were suitable for various benzylamine derivatives. Subsequent nucleophilic additions to the imines were successfully carried out on substituted products. Quenching experiments in the presence of DABCO and benzoquinone implicate the involvement of the singlet oxygen ((1)O2) and the superoxide radical anion (O2(•-)) as important reactive species in the oxidation.
Topics: Benzylamines; Catalysis; Fullerenes; Imines; Magnetic Resonance Spectroscopy; Molecular Structure; Oxidation-Reduction; Photochemical Processes; Photosensitizing Agents; Porphyrins; Singlet Oxygen; Superoxides
PubMed: 26700114
DOI: 10.1021/acs.orglett.5b03194 -
Expert Opinion on Drug Metabolism &... Jul 2008Butenafine hydrochloride, a benzylamine derivative, exhibits potent fungicidal activity particularly against dermatophytes, aspergilli, dimorphic and dematiaceous fungi. (Review)
Review
BACKGROUND
Butenafine hydrochloride, a benzylamine derivative, exhibits potent fungicidal activity particularly against dermatophytes, aspergilli, dimorphic and dematiaceous fungi.
OBJECTIVE
To review pharmacokinetics, mechanism of actions and clinical efficacy of butenafine against various dermatophytic and other superficial fungal infections.
METHODS
Medline search was made using keyword butenafine. All English language articles were considered for this review. For inclusion in clinical efficacy section when ever available randomized controlled trials were considered a priority over other trials.
RESULTS/CONCLUSIONS
The drug has excellent penetration into the epidermis and a prolonged retention time following topical application, conferring residual therapeutic activity after treatment cessation. Butenafine possess anti-inflammatory activity too. Topical butenafine 1% cream has been reported to be efficacious for tinea pedis, tinea corporis and tinea cruris in many randomized clinical trials when used for shorter duration. Its efficacy against pityriasis versicolor, seborrheic dermatitis and as anticandidal agent is not yet fully established.
Topics: Animals; Antifungal Agents; Benzylamines; Clinical Trials as Topic; Dermatomycoses; Humans; Naphthalenes
PubMed: 18624686
DOI: 10.1517/17425255.4.7.999 -
The Journal of Organic Chemistry Jan 2015A novel and efficient synthetic method for o-fluorobenzylamines via palladium catalyst using an easily accessible oxalyl amide as directing group has been developed. The...
A novel and efficient synthetic method for o-fluorobenzylamines via palladium catalyst using an easily accessible oxalyl amide as directing group has been developed. The cheap N-fluorobenzenesulfonimide could be used as an effective [F+] source and t-amyl-OH as the solvent with Pd(OAc)2 as catalyst. Selective mono- or difluorination of oxalyl amide-protected benzylamine derivatives were achieved by modifying the reaction conditions, which presented an efficient method for the preparation of ortho-fluorinated benzylamines.
Topics: Amides; Benzylamines; Catalysis; Hydrocarbons, Fluorinated; Hydrogen Bonding; Molecular Structure; Palladium
PubMed: 25490600
DOI: 10.1021/jo502365b