14451-85-5Relevant academic research and scientific papers
Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues
Kolocouris, Antonios,Spearpoint, Philip,Martin, Stephen R.,Hay, Alan J.,Lopez-Querol, Marta,Sureda, Francesc X.,Padalko, Elizaveta,Neyts, Johan,De Clercq, Erik
, p. 6156 - 6160 (2008)
The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2′-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.
Approaches to primary tert-alkyl amines as building blocks
Tzitzoglaki, Christina,Drakopoulos, Antonios,Konstantinidi, Athina,Stylianakis, Ioannis,Stampolaki, Marianna,Kolocouris, Antonios
, (2019/07/10)
Primary tert-alkyl amines include analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a difficult problem. Four synthetic procedures, some of which have been previously reported for the synthesis of amines with primary (RCH2NH2) or secondary (RR'CHNH2) alkyl and/or aryl groups, were tested for the synthesis of primary tert-alkyl amines (RR′R″CNH2) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO)4 or CeCl3. These synthetic routes are unexplored for primary tert-alkyl amines. Studies on the synthetic routes for primary tert-alkyl amines are currently lacking. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the most general and applicable also for compounds bearing bulky adducts.
Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A
Kolocouris, Antonios,Tzitzoglaki, Christina,Johnson, F. Brent,Zell, Roland,Wright, Anna K.,Cross, Timothy A.,Tietjen, Ian,Fedida, David,Busath, David D.
, p. 4629 - 4639 (2014/07/07)
A series of 2-adamantanamines with alkyl adducts of various lengths were examined for efficacy against strains of influenza A including those having an S31N mutation in M2 proton channel that confer resistance to amantadine and rimantadine. The addition of as little as one CH2 group to the methyl adduct of the amantadine/rimantadine analogue, 2-methyl-2-aminoadamantane, led to activity in vitro against two M2 S31N viruses A/Calif/07/2009 (H1N1) and A/PR/8/34 (H1N1) but not to a third A/WS/33 (H1N1). Solid state NMR of the transmembrane domain (TMD) with a site mutation corresponding to S31N shows evidence of drug binding. But electrophysiology using the full length S31N M2 protein in HEK cells showed no blockade. A wild type strain, A/Hong Kong/1/68 (H3N2) developed resistance to representative drugs within one passage with mutations in M2 TMD, but A/Calif/07/2009 S31N was slow (>8 passages) to develop resistance in vitro, and the resistant virus had no mutations in M2 TMD. The results indicate that 2-alkyl-2-aminoadamantane derivatives with sufficient adducts can persistently block p2009 influenza A in vitro through an alternative mechanism. The observations of an HA1 mutation, N160D, near the sialic acid binding site in both 6-resistant A/Calif/07/2009(H1N1) and the broadly resistant A/WS/33(H1N1) and of an HA1 mutation, I325S, in the 6-resistant virus at a cell-culture stable site suggest that the drugs tested here may block infection by direct binding near these critical sites for virus entry to the host cell.
13C, 1H Spin-Spin Coupling. X - Norbornane: A Reinvestigation of the Karplus Curve for 3J(13C, 1H)
Aydin, Rafet,Guenther, Harald
, p. 448 - 457 (2007/10/02)
13C, 1H spin-spin coupling constants over one, two and three bonds were measured from the 100 MHz 13C NMR spectra of deuteriated isotopomers of norbornane-d1 (1) and fenchane-2-d1 (2) and also of a number of monodeuteriated alkyl-substituted adamantanes.The magnitudes of the corresponding J(13C, 1H) values derived from these data by application of the well known relationship J(X, 1H) = 6.5144J(X, 2H) are discussed with respect to the structural data for the hydrocarbons, which were taken from force field calculations with the Allinger MM2 method.In particular, the dihedral angle dependence and the Karplus curve for 3J(13C, 1H) are investigated.Coupling constants calculated by the FP-INDO method are compared with the experimental data, and the effect of substitution by additional CC bonds in α-, β- and γ-positions of the 13C-α-C-β-C-γ-H bond fragment is elucidated.If substituent effects that arise through branching and methyl substitution in 1 and 2 are taken into account for dihedral angles Φ > 90 deg, one derives 3J(13C, 1H) = 4.50 - 0.87 cos Φ + 4.03 cos 2Φ with J(0 deg) = 7.7, J(60 deg) = 2.0 and J(180 deg) = 9.4 Hz.
