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PubMed2002

Synthesis and antimicrobial activity of new adamantane derivatives III.

Some novel ester imides synthesised from trimellitic acid anhydride and 1-adamantanol or 2-adamantanol, were tested as antimicrobial compounds. Unfortunately, these agents showed a modest antibacterial activity (MIC > 6 microg/ml). However, a comparison of these N-substituted adamantylester imides with the series published previously, indicated that the incorporation of L-alanine and L-phenylalanine into the phthalimide moiety was the best choice regardless of the series and leads to antimicrobial activity against Staphylococcus aureus strains.

Adamantane↗
PubMed2003

A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-derived zinc-chelating trioxa-adamantane-triol.

The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.

Adamantane↗
PubMed1976

Adamantane and protoadamantanealkanamines as potential anti-Parkinson agents.

The synthesis of 2-halo-1-adamantanemethanamines, 4-protoadamantanemethanamines, and 4-protoadamantaneamines is described. The anti-Parkinson activity of these amines in terms of reversal of reserpine-induced catalepsy in rats has been evaluated and compared with amantadine. 2-Bromo- and 2-chloro-1-adamantanemethanamines are shown to be twice as active as amantadine.

Adamantane↗
PubMed2002

Nanoscale 1,3,5,7-tetrasubstituted adamantanes and p-substituted tetraphenyl-methanes for AFM applications.

[structure: see text] Tetrahedrally shaped nanoscale molecules 18-20 were synthesized from the corresponding tetraiodide by a series of Sonogashira coupling reactions. Three of the sulfur-containing termini are intended for eventual binding to a gold-coated conventional AFM tip, while the fourth terminus scans the sample. AFM images of 19 demonstrate that the molecule is sufficiently large and rigid to be imaged by a conventional AFM tip.

Adamantane↗
PubMed1997

Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

The influenza virus M2 protein, target of the antiviral drugs amantadine and rimantadine, forms a proton channel which functions during virus uncoating and maturation by modifying the pH in virions as well as in trans-Golgi vesicles. We studied the influence of different ionic gradients on the inhibition of the proton translocation activity of isolated, baculovirus-expressed M2 protein reconstituted into liposomes. Two distinct patterns of inhibition were observed. A group of amphiphilic amines including amantadine, cyclooctylamine and rimantadine inhibited M2 effectively in the presence of physiological Na+ concentrations. The 10-fold greater activity of rimantadine over amantadine and the 100-fold stronger effect of cyclooctylamine compared to cyclopentylamine matched the relative activities in influenza virus-infected cells. A completely different inhibitory pattern emerged for the polyamines spermine, spermidine and putrescine. Polyamines have recently been identified as the 'intrinsic' rectifiers of a class of potassium channels and shown to interact with acidic amino acid residues lining and flanking the channel pore. In the presence of a physiological Na+/K+ gradient their minimal inhibitory concentrations for influenza virus M2 protein were 100, 400 and 500 microM, polyamine levels reported to exist in oocytes. In conditions depleted for Na+, polyamines inhibited M2 at concentrations two to three orders of magnitude lower. The data suggest that influenza virus M2 protein possesses a binding site for polyamines, distinct from the amantadine binding site, which is normally masked by Na+ and which could be targeted by selective antiviral inhibitors.

Adamantane↗
PubMedDate not supplied

In vitro antitumor and antimicrobial activities of N-substituents of maleimide by adamantane and diamantane.

New N-1-adamantylcitraconimide (compound 1) and N-1-diamantylcitraconimide (compound 2) were synthesized by reaction of citraconic anhydride with 1-aminoadamantane, and 1-aminodiamantane, respectively, followed by imidization with acetic anhydride and sodium acetate. Compound 1, N-1-adamantylmaleimide (compound 3) and N-1-diamantylmaleimide (compound 4) exhibited strong growth-inhibitory activity against four cancer cell lines (Colo 205, Hep G2, SK-BR-3 and Molt-4). Moreover, compound 1 showed relatively specific cytotoxicity against the test tumor cell lines. Compound 2 exhibited growth inhibitory activity against Colo 205, and SK-BR-3 cells, similar to 5-fluorouracil. It was noted that compound 2 showed relatively low cytotoxicity against Molt-4 cells, approximately 42 times lower than 5-fluorouracil. The N-substituents of imides with adamantly substituents have a more potent antitumor activity than the imides with diamantyl substituents. The imides with methyl substituents (compounds 1 and 2) showed relatively higher selectivity against the tested cancer cell lines than the imides without methyl substituents (compounds 3 and 4). Compounds 3 and 4 show good in vitro activities against Staphylococcus aureus and Trichophyton mentagrophytes. Compound 1 had weak antimicrobial activity against T. mentagrophytes.

Adamantane↗
PubMedDate not supplied

Detection of the production of reactive oxygen species by neutrophils in whole blood: modulation by adamantanes and triggering by Fe(3+)-ions.

Using indicators for the production of reactive oxygen species (ROS) such as the a) OH-radical type (alpha-keto-gamma-methiolbutyric acid, KMB) or b) hypochlorous acid (1-amino-cyclopropyl-1-carboxylic acid, ACC) neutrophil activities can be both quantified and differentiated in whole blood via ethene production. Ethene is trapped in the head space of blood samples incubated in the presence of zymosan and the respective indicators, KMB or ACC. This procedure allows the detection of effects of aminoadamantanes (AAD) such as amantadine or memantine, compounds frequently used for the treatment of Morbus Parkinson and Morbus Alzheimer. In this report we describe the detection of OH.-type oxidants produced by isolated activated neutrophils and whole blood. Immunomodulatory activities of AAD are deduced from the following observations: AAD-stimulated ethene formation from (KMB) as an indicator for production of OH.-type reactive oxygen species by zymosan-stimulated neutrophils ("respiratory burst") is detectable with isolated neutrophils. In whole blood, however, this reaction is only measurable in the presence of Fe-EDTA-complex. Stimulating effects of AAD are observed within a concentration range between 10(-8) and 10(-4) M with a maximum at 1 microM. Ethene release from (ACC) as indicator for the myeloperoxidase reaction after degranulation is not stimulated by AAD but inhibited at concentrations higher than 100 microM. The presented results suggest that submicromolar concentrations of AAD only stimulate the respiratory burst and apparently not degranulation of zymosan-prestimulated polymorphonuclear neutrophils (PMN).

Adamantane↗
PubMedDate not supplied

[The antiparkinson activity of a new adamantane derivative].

The activity of the new original compound--hydrochloride N-2-(adamantyl) hexamethylenimine (code A-7) synthesized at the Institute of Pharmacology, Russian Academy of Medical Sciences, was studied on models of akinetic-rigid and tremor manifestations of the parkinsonian syndrome. A-7 completely relieves the akinetic-rigid manifestations of the syndrome and surpasses mydantan and L-dopa in antagonism with haloperidol and triftazine. Just as L-dopa, cyclodol, and mydantan, A-7 alleviates reserpine-induced oligokinesis and restores body temperature which is lowered by reserpine. A-7 possesses evident antitremor activity which advantageously distinguishes it from mydantan which failed to demonstrate antagonism with arecoline. A-7 is promising for further study as a potential agent for the treatment of parkinsonism.

Adamantane↗
PubMedDate not supplied

[Bis-ammonium adamantane derivatives--novel modulators of polyamine binding sites].

Experiments on intact rats and mice showed that the polyamine agonist spermine and the bis-ammonium adamantyl-containing compounds IEM-1460 and IEM-1754 potentiate the NMDA induced analgesia and convulsions and eliminate the analgesic effects of nicotine and kainate. Arcain, a competitive polyamine antagonist, eliminated (at the same dose) the activating and blocking effects of spermine, IEM-1460 and IEM-1754. In small doses, IEM-1754 (similarly to arcain) removed the analgesic effect of NMDA. It is suggested that IEM-1460 (similarly to spermine) is a polyamine agonist, while IEM-1754 is an antagonist/agonist of the polyamine site of NMDA, AMPA/kainate, and nicotinic receptors. The potentiating activity of IEM-1460 is two orders higher as compared to that of spermine.

Adamantane↗
PubMedDate not supplied

[Pharmacological activity of the new adamantane derivative--potential antiparkinson preparation during subchronic administration].

The effect of a new potential antiparkinsonian drug, N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7), upon some behavioral parameters was studied in rats after subchronic 14-day treatment. Also studied was the effect of abrupt termination of a prolonged (22-day) drug administration. The subchronic treatment with A-7 at a dose of 10, 20, or 40 mg/kg did not produce significant changes in coordination, explorative behavior, muscle tone, and aggression level. At the same time, the 14-day treatment with A-7 at a dose of 10 mg/kg increased the pain threshold; A-7 at a dose of 40 mg/kg (but not 10 or 20 mg/kg) increased the spontaneous motor activity. Upon abrupt termination of the drug administration after a prolonged treatment sensitivity of the test animals with respect to the MFTP neurotoxin as compared to that observed in the non-drug control group.

Adamantane↗
PubMed2001

Synthesis and modulation of cytokine production by two new adamantane substituted acyclic desmuramyldipeptide analogs.

Two new adamantyl-desmuramyldipeptides LK 415 and LK 517 with 1-adamantylcarboxamido moiety as a replacement for muramyldipeptide's N-acetylglucosamine fragment were synthesized. Their efficacy to modulate the production of cytokines was measured in vitro in ionomycin and phorbol-12-myristate-13-acetate (PMA) activated cultures of human peripheral blood mononuclear cells (PBMC), co-incubated with the substances tested. The results were compared with the activity of muramyldipeptide (MDP). All three substances are strong up-regulators of IL-12 synthesis and hence of the IFN gamma synthesis as well. While MDP and LK 415 are relatively ineffective in modulation of IL-2, IL-4 and IL-10 production in vitro, the synthesis of all three cytokines is considerably up-regulated when peripheral blood mononuclear cells are co-incubated with LK 517. It seems likely that the introduction of the diethyl phosphonate moiety into LK 517 is of great importance for the augmented T-cell cytokine production.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMedDate not supplied

[Effect of the potential antiparkinsonian agent adamantane derivative on ion channels of NMDA glutamate receptors].

Interaction of a new potential antiparkinsonian drug, N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7), with NMDA channels in acutely isolated rat hippocampal neuron culture was studied by the whole-cell patch-clamp technique. The currents through the NMDA channels were excited by aspartate (Asp) application in a magnesium-free glycine-containing (3 microM) medium. It was found that A-7 produced a concentration-dependent (IC50 = 11.8 +/- 0.6 microM) NMDA channel blocking. The blocking rate increased with the A-7 concentration, whereas the unblocking was concentration-independent. The degree of blocking was independent of the Asp concentration, but was markedly increased by hyperpolarization of the cell membrane. After Asp washout, A-7 remained trapped in the channel by the activation gate. The channel was unblocked upon the next Asp application. These data is evidence that the antiparkinsonian effect of A-7 is related to the NMDA-channel-blocking activity of the drug.

Adamantane↗