Hydroxylamine Chemistry. IV. O-Aralkylhydroxylamines

El, Schumann; Rv, Heinzelman; Me, Greig; Veldkamp, W.

doi:10.1021/jm00333a017

Cited by 22 publications

(8 citation statements)

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“…Synthesis of 9 was accomplished by following a published procedure which involved a reaction between diphenylbenzhydryl chloride and N-hydroxyphthalimide to produce intermediate pthalimide 8, which on hydrolysis with hydrazine in ethanol furnished O-aralkylhydroxylamine 9. 40 The other intermediate 12 was made from the known ester 10 by reducing it to alcohol 11, which was followed by oxidation under Swern oxidation condition to aldehyde 12. 41 Finally, the target compound 13 was made by reacting amine 9 and aldehyde 12 under a modified reductive amination condition in good yield.…”

Section: Chemistrymentioning

confidence: 99%

Structure−Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters

et al. 2001

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In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our previously developed DAT-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, was the basis for our current structure-activity relationship (SAR) studies exploring the significance of the contribution of the benzhydryl O- and N-atoms in these molecules in interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-atom to an adjacent position, and in one other occasion converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also evaluated the important contribution of the piperidine N-atom to binding by altering its pK(a) value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On the other hand, an enhanced interaction with the SERT was observed when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC(50)) = 19.7, SERT (IC(50)) = 137 nM, NET (IC(50)) = 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for the transporter. The presence of a powerful electron-withdrawing cyano group in compound 5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC(50)) = 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the dopamine reuptake inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. In drug-discrimination studies these selected compounds incompletely generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from vehicle.

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Section: Chemistrymentioning

confidence: 99%

Structure−Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters

et al. 2001

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“…Reaction of hydroxylamine hydrochloride, Omethylhydroxylamine hydrochloride or O-benzylhydroxylamine hydrochloride with a-bromo-2acetylfuran (3) in methanol at room temperature afforded compounds 5a, 5b and 7, respectively (Schumann et al 1964;Schaefer & Mangold 1982). Reaction of quinolones 1, 2 with a-bromo-2-acetylfuran (3) or a-bromo-2-acetylfuran oximes (5a±b and 7) without protection of the 3-carboxylic acid of quinolones (Kondo et al 1986) in the presence of sodium bicarbonate in dimethylformamide (DMF) at room temperature yielded ketones 4a±b and oximes 6a±d and 8a±b, respectively (Figure 1).…”

Section: Chemical Proceduresmentioning

confidence: 99%

Synthesis and In-vitro Antibacterial Activity of New <I>N</I>-Substituted Piperazinyl Quinolones

Foroumadi¹,

Emami²,

Haghighat³

et al. 1999

Pharmacy and Pharmacology Communications

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A series of N-[2-(2-furyl)-2-oxoethyl], N-[2-hydroxyimino-2-(2-furyl)ethyl], N-[2-(2furyl)-2-methoxyiminoethyl] and N-[2-(2-furyl)-2-phenylmethoxyiminoethyl] piperazinyl quinolones were synthesized and evaluated for in-vitro antibacterial activity.Compounds with a 2-(2-furyl)-2-oxoethyl group attached to the piperazine ring had similar antibacterial activity to the reference drugs, nor¯oxacin and cipro¯oxacin, against staphylococci, but signi®cantly decreased activity against Gram-negative bacteria. If the hydrogen of oxime was replaced with a methyl or benzyl group, in-vitro antibacterial activity decreased against Gram-negative bacteria, but activity was similar against staphylococci.Generally, cipro¯oxacin derivatives were more active than nor¯oxacin derivatives.

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“…Chemical procedures a-Bromo-2-acetylthiophene (2) was prepared by bromination of 2-acetylthiophene (1) (Mullen et al 1988). Reaction of the 2 with hydroxylamine hydrochloride, O-methylhydroxylamine hydrochloride or O-benzylhydroxylamine hydrochloride in methanol at room temperature (Schumann et al 1964;Schaefer & Mongold 1982) gave the intermediate compounds 7a±c in good yields. Reaction of quinolones (3, 4 or 5) with a-bromo-2-acetylthiophene (2) or a-bromo-2-acetylthiophenoximes (7a±c) without protection of the 3-carboxylic acid group of the quinolones (Kondo et al 1986) in the presence of sodium bicarbonate in dimethylformamide (DMF) at room temperature afforded ketones 6a±c and oximes 8a±i respectively ( Figure 1).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and In-vitro Antibacterial Activity of <I>N</I>-Piperazinyl Quinolone Derivatives with a 2-Thienyl Group

Mirzaei¹,

Foroumadi²

2000

Pharmacy and Pharmacology Communications

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Novel N‐substituted piperazinyl quinolones have been synthesized by reaction of piperazinyl quinolones with α‐bromo‐2‐acetylthiophene or α‐bromo‐2‐acetylthiophene oximes and evaluated for in‐vitro antibacterial activity. Compounds with a [2‐oxo‐2‐(2‐thienyl)ethyl] group had antibacterial activity against Gram‐positive and Gram‐negative bacteria similar to that of reference drugs, ciprofloxacin, norfloxacin and enoxacin. The oximes were almost as potent as the corresponding ketones against staphylococci but less active against Gram‐negative bacteria. Replacement of the hydrogen of the oxime with a methyl group resulted in greater antibacterial activity against both Gram‐positive and Gram‐negative bacteria, with minimum inhibitory concentrations (MIC) ranging from 0.0075 to 0.5 μg mL−1; this potency was greater than that of the reference compounds. The antibacterial activity of the O‐benzyloxime derivatives was lower. Ciprofloxacin derivatives were usually more active than norfloxacin or enoxacin derivatives.

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Hydroxylamine Chemistry. IV. O-Aralkylhydroxylamines

Cited by 22 publications

References 1 publication

Structure−Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters

Structure−Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters

Synthesis and In-vitro Antibacterial Activity of New <I>N</I>-Substituted Piperazinyl Quinolones

Synthesis and In-vitro Antibacterial Activity of <I>N</I>-Piperazinyl Quinolone Derivatives with a 2-Thienyl Group

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