Search

In an attempt to synthesize potent blockers of the influenza A M2 S31N proton channel with modifications of amantadine, we used MD simulations and MM-PBSA calculations to project binding modes of compounds 2-5, which are analogues of 1, a dual blocker. Blocking both the S31N mutant and the wild type (WT) M2, 1 is composed of amantadine linked to an aryl head group, (4-methoxy-2-hydroxy)-benzyl. Compound 6, used as control, has an 3-(thiophenyl)isoxazolyl aryl head group, and selectively blocks M2 S31N (but not WT) in an aryl head group “out” (i.e. N-ward) binding orientation. We then tested 1-6 as anti-virals in cell culture and for M2 binding efficacy with electrophysiology (EP). The new molecules 2-5 have a linker between the adamantane and amino group which can be as small as a CMe2 in rimantadine derivative 2, or longer like phenyl in 3. Alternatively, we explored the impact of expanding the diameter of adamantane with diamantyl or triamantyl in 4 and 5, respectively. Antiviral effects against A/WSN/33 and its M2 WT revertant (M2 N31S) were seen for all six compounds except for 5 vs. the native (S31N) virus and (as predicted from previous studies) 6 vs. the WT revertant. Compounds 1-5, projected to bind in a polar head group “in” (C-ward) orientation, strongly block proton currents through M2 WT expressed in voltage-clamped oocytes with fast association rate constants (kon), and slow dissociation rate constants (koff). Surprisingly, 2-5, projected to bind in a polar head group out orientation, do not effectively block M2 S31N-mediated proton currents in EP. The results from MD and MM-PBSA calculations suggested that compounds 2-5 can be fully effective at blocking the M2 channel when present. The low degree of blocking in M2 S31N is due to their kinetics of binding observed in EP, i.e. two orders of magnitude reduction in kon compared to 6, and a fast off rate constant similar to that of 6, which is consistent with steered-MDsimulations. The low kon values can be interpreted from MD simulations, which suggest distortions to V27 cluster of the M2 S31N caused by the longer (even by one methylene) hydrophobic segment from adamantane to aryl head group, appropriate to fit from G34 to V27. The deformations in the N-terminus may be sufficiently energetic for 2-5 (compared to 6) to cause the observed low kon.

Pyrrole is a very important pharmacophoric moiety. It has been widely incorporated into the skeleton of antitumor, anti-inflammatory, antibacterial, antioxidant and antifungal active substances. Access to this key heterocycle by diverse routes is particularly attractive in terms of chemistry, and al-so from the environmental point of view. The present minireview summarizes the reported methods for the preparation of highly substituted pyrrole derivatives based on the one-pot multicomponent reaction of aldehydes, primary amines, and oxalacetate analogues as well as their biology. © 2020 Bentham Science Publishers.

The synthesis and pharmacological evaluation of C1-substituted adamantane hydrazones, their C2-substituted isomers, and C1-substituted adamantane furanoic carboxamides is described. These new adamantane derivatives exhibited an interesting pharmacological profile in terms of trypanocidal activity and selectivity. The most active adduct with the best selectivity in this study was found to be the phenylacetoxy hydrazone 1 b (2-[4-(tricyclo[3.3.1.13,7]dec-1-yl)phenyl]-N′-[(5-nitrofuran-2-yl)methylene]acetohydrazide; EC50=11±0.9 nm, SITb=770). © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

In this work, the synthesis and the pharmacological evaluation of diphenoxyadamantane alkylamines Ia–f and IIa–f is described. The new diphenoxy-substituted adamantanes share structural features present in trypanocidal and antitubercular agents. 1-Methylpiperazine derivative Ia is the most potent against T. brucei compound, whilst its hexylamine congener IIf exhibits a significant antimycobacterial activity. © 2019 Elsevier Ltd

Bone tumours around the elbow are rare. Even nowadays diagnostic dilemmas and delays are common. During recent decades the management and prognosis of patients with elbow bone tumours has improved significantly. Benign tumours can be treated using minimally invasive procedures, whereas malignant ones require a multidisciplinary team approach based on an adjuvant therapeutic regimen of chemotherapy, radiotherapy and limb salvage procedures. This article reviews the most commonly encountered elbow bone tumours and their management. © 2019 The author(s).

A series of fluorine substituted methoxyphenylalkyl amides were prepared with different orientations of the fluorine and methoxy groups with respect to the alkylamide side chain and with alkyl sides of differing lengths (n = 1-3). β-Dimethyl and α-methyl derivatives were also synthesised. The compounds were tested as melatonin agonists and antagonists using the pigment aggregation of Xenopus melanophores as the biological assay. A number of these compounds were potent melatonin agonists, the potency depending on the length of the alkyl chain, the orientation of the methoxy and fluorine substituents, the amide chain length and, for the ethyl side-chain analogues, the presence of β-substituents. © The Royal Society of Chemistry 2019

Organometallic reactions, such as those involving Grignard and organocadmium reagents, are very useful but require prudent laboratory skills. In many papers related to the medicinal chemistry of adamantane derivatives with sigma receptor (σR)-binding affinity and antiproliferative/anticancer activity, organometallics play a crucial role in the synthetic pathways. In this work, the experimental procedures utilizing Grignard and organocadmium reagents are presented in detail, because these techniques are not analyzed and are important in the rational drug design. © Springer Science+Business Media, LLC, part of Springer Nature 2018.

Background: Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines) 1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'-substituded-[4-(1-Adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-Adamantyl)-phenoxy]alkylamines 4a,b. Method: A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating. Results: The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis. Conclusion: The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f,g and 2e,f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring. © 2017 Bentham Science Publishers.

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy. © 2017 by the authors. Licensee MDPI.

Background: In our previous publications we have described the synthesis of aminosubstituded diaryl adamantanes and their pharmacological evaluation in vitro and in vivo against many cancer cell lines. More recently, we have reported the synthesis of mono C2-Aryl substituted aminoadamantane derivatives that have moderate antiproliferative activity at low micromolar IC50 against a panel of four tumor cell lines. Methods: The synthesis and the pharmacological evaluation of 4-(1-Adamantyl) phenylalkylamines 1-4 is described in this work. The new derivatives present an aryl substitution at C-1 adamantane position and diverge from the methylene spacer between the phenyl ring and the amine heterocycle moiety. Results: Piperazines 1a (R:N-H) and 1b (R:N-Me) are more active than piperidine 1c. This difference indicates the importance of the presence of this nitrogen atom in 1a and 1b, which is at a distance of 3 atoms (two carbons and the piperazine nitrogen included) from the benzene ring. Adducts 2a,b are less active than the rest of the products, because neither the R:N-H nitrogen atom (compound 2a) nor the R:N-Me nitrogen (compound 2b) are in an optimum distance from the benzene ring. Derivatives 3a-c are almost as potent as the piperazines 1a and 1b, which means that also in this case, the distance of 2 atoms (PhβCH2αCH2N) is sufficient for antiproliferative activity. Products 4a-c have also significant activity, possibly due to the fact that the benzene moiety is attached to the nitrogen atom via a three methylene linker. Piperidine 4c is the most potent compound, showing that the nitrogen atom of these cyclic amines, which is near to benzene ring, is important for the pharmacological action. Conclusion: The comparison of the pharmacological results of the present work in relation to our previous publication shows that C-1 substitution in adamantane skeleton with aminoaryl or aminoalkyl groups enhances the antiproliferative activity towards to C-2 substitution. Our approach shows that the optimization of the antiproliferative activity is the incorporation of the p-Aminoalkylphenyl side chain at C-1 adamantane position. © 2016 Bentham Science Publishers.

The design and synthesis of 4-(2-adamantyl)phenylalkylamines 1-4 are described and their antiproliferative activity against four different tumor cell lines is reported. © 2015 Bentham Science Publishers.

Previous studies have showed that perceived stress (PS) in patients with multiple sclerosis (MS) constitutes an important factor for disease onset, relapse, symptomatology and psychological adjustment. Objectives: The aim of this pilot cross-sectional study was to examine the role of self-esteem in PS, after controlling for sociodemographical characteristics, depression and personality in MS patients. Methods: Sixty-six relapsing-remitting MS patients (66.67% females, mean age of 40±11.1 years old, mean duration of disease 133.6±128.8 months) were studied. Perceived stress, self-esteem, depression and personality type were assessed using self-administered questionnaires. Hierarchical multivariate regression modelling was used. Results: Higher education and depression and lower self-esteem were independently and significantly associated with increased PS, accounting for 40.5% of its variance. Univariate analyses revealed that low extroversion and openness and higher neurotism were associated with higher PS, although no significant after adjusting for other factors. Discussion: Although our findings need further confirmation, psychological interventions targetting self-esteem are strongly encouraged. © W. S. Maney and Son Ltd 2015.

1-Benzyl-2-aminoadamantanes 2a-c, conformationally constrained aminoadamantanes 3a, b and 4 and diaminoadamantanes derivatives 5a-c, 6a-c were synthesized and tested as antiproliferative agents. The in vitro biological evaluation showed a significant difference in activity between 1-phenyl and 1-benzyl derivatives. © Springer Science+Business Media 2013.

Introduction of the hydrophobic substituents cyclopentyl, cyclohexyl and phenyl into adamantane imidazolines was accomplished with the synthesis of compounds 4. Members of this series were found to display a range of activities against bloodstream forms of Trypanosoma brucei. © The Royal Society of Chemistry 2013.

The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ1, σ2, and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound. © 2012 American Chemical Society.

The synthesis of N-4-[a-(1-adamantyl)benzyl]phenylpiperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ 1, σ 2-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain. © 2012 Elsevier Ltd. All rights reserved.

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6- diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs. © 2012 Bentham Science Publishers.

A series of new 2-[3-(2-alkyloxy-ethyl)-adamantan-1-yl]-ethoxy substituted ether phospholipids was synthesized and their antileishmanial activity was evaluated against Leishmania infantum amastigotes. The majority of the new analogues were significantly less cytotoxic than miltefosine while, antiparasitic activity depended on the length of the 2-alkyloxy substituent. The most potent compounds were 2-[[[3-(2-hexyloxy-ethyl)-adamant-1-yl]-ethoxy] hydroxyphosphinyloxy]ethyl-Ν,Ν,Ν-trimethyl-ammonium inner salt (5b) and 2-[[[3-(2-octyloxy-ethyl)-adamant-1-yl]-ethoxy]hydroxyphosphinyloxy]ethyl- Ν,Ν,Ν-trimethyl-ammonium inner salt (5c). © 2010 Elsevier Ltd. All rights reserved.

(Chemical Equation Presented) Treating African trypanosomiasis: The synthesis and biological evaluation of novel 1-alkyloxy and 1- benzyloxyadamantano 2-guanylhydrazones, their 1-dioxa congeners and two 1-benzyladamantano 2-guanylhydrazones is reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Treatment of piperidine 8 with acetyl chloride or ethyl chloroformate in the presence of triethylamine gave the 2,3-dehydrogenated products 10a and 10b, respectively, together with the expected N-acylpiperidines 9. © 2008 Bentham Science Publishers Ltd.

To develop functionalized adamantanes for treating African trypanosomiasis, we report on the synthesis of new 1-alkyl-2-aminoadamantanes 1a-i, 1-alkyltricyclo[3.3.1.13,7]decan-2-guanylhydrazones 2a-g, and their congeneric thiosemicarbazones 3a,b. The potency of these compounds against Trypanosoma brucei was compared to that of amantadine and rimantadine and found to be substantially higher. The most active analogues, 1c, 1d, 2c, 2g, and 3b, illustrate the synergistic effect of the lipophilic character of the C1 side chain and the C2 functionality on trypanocidal activity. © 2008 American Chemical Society.

New conformationally constrained adamantane 2-oxazoline building blocks 1-4 were synthesized and their antimicrotubule and antitrypanosomal potency was investigated. Although most of the new compounds affect tubulin polymerization, this does not make a major contribution to trypanocidal activity. © 2008 The Japan Institute of Heterocyclic Chemistry.

(Chemical Equation Presented) Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we report on the synthesis of spiro adamantane 2-imidazolines 8a-f and 9a-c, and their congeneric 5-(1-adamantyl)imidazolines 14 and 15. The potency of these compounds against Trypanosoma brucei was compared to that of rimantadine and found, in the case of compound 14e, to be three fold higher. Together with the other active compounds, 14b and 15b, which were equipotent to rimantadine, the new molecules illustrate the synergistic effect of the lipophilic character of adamantane and the C1 amidine functionality on trypanocidal activity.

A novel, miniaturized biosensor system was created by combining the electrophysiological response of immobilized cells with superoxide-sensing technology, optical and fluorescence microscopy. Vero cells were immobilized in a calcium alginate matrix (at a density of 1.7 x 10(6) cells ml(-1)). A 0.5 cm x 0.5 cm piece of cell-containing gel matrix was aseptically adhered on a glass microscope slide with a microfabricated gold electrode array, sealed with a cover slip and provided with Dulbecco’s medium +10% (v/v) fetal calf serum every day by means of a capillary feeding tube. During a culture period of 7 days, the membrane potential of immobilized cells was continuously monitored, while cell division was assayed with an optical microscope. In addition, daily measurements of immobilized cell membrane potential, viability, RNA and calcium concentration, radical oxygen species (ROS) and glutathione accumulation, were conducted by fluorescence microscopy after provision of an appropriate dye. Superoxide accumulation was assayed by covering the electrodes with superoxide dismutase (SOD). Maximum cell membrane potential values and superoxide production were observed upon initiation of cell division. Using the novel biosensor, we were able to correlate seven different cell physiological parameters to each other and formulate a model for ROS-mediated signaling function on cell division and death. In addition, we were able to predict cell proliferation or death by comparing the relative response of the electrophysiological and superoxide sensor during the culture period. (c) 2005 Elsevier B.V. All rights reserved.

2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the α-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus. © 2006 Elsevier Ltd. All rights reserved.

A facile preparation of 2-aminomethyl-2-tricyclo[3.3.1.1 1,7]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[3.3.1. 11,7]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the pentylenetetrazole (PTZ) and semicarbazide (SCZ) induced tonic convulsions and exhibits analgesic activity in the hot plate test on mice. Although its mechanism of action is quite similar to that proposed previously for gabapentin (interaction with the α2δ subunit of the voltage gated Ca2+ channels), further studies were undertaken in order to clarify the precise mechanism of the anticonvulsant and analgesic effects of AdGABA on a molecular level. © 2005 Elsevier Ltd. All rights reserved.

In order to investigate the effect of light on the tissue culture of lavender (Lavandula vera L.) and wall germander (Teucrium chamaedrys L.), leaf explants from greenhouse-grown plants were inoculated on a Murashige and Skoog (MS) medium (1) supplemented with 1 mg L-1 2,4-D and 2 mg L-1 kinetin and incubated either (i) continuously in the darkness for 6 weeks or (ii) first in the darkness for 0-5 weeks and then under illumination (150 μmol m-2 s-1, 16 hour light/8 hour dark photoperiod). Lavender callus growth was improved under increased incubation in darkness while somatic embryogenesis was remarkably reduced under the same conditions. Incubation in darkness did not affect the growth of wall germander cultures, but improved somatic embryogenesis. Moreover, a possible participation of boron in the effect of light on somatic embryogenesis for both species was indicated. © 2002 by The Haworth Press, Inc. All rights reserved.