| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design
& Discovery
Volume 7, Number 1, January 2010
Contents
Graphical
Abstracts i-v
New Bisquaternary Isoquinolinium Inhibitors of Brain Cholinesterases
– Synthesis and Anticholinesterase Activity Pp.
1-4
J. Binder, M. Paar, D. Jun, M. Pohanka,
M. Hrabinova, V. Opletalova and K. Kuca
[Abstract] [Full Text
Article]
Design, Synthesis, and Biological Evaluation
of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives as Acetylcholinesterase
Inhibitors Pp. 5-8
S.-J. Liu, L. Yang, X.-G. Liu, Y. Luo, Z.-J.
Cao, D.C.C. Wan, H.-Q. Lin and C. Hu
[Abstract] [Full Text
Article]
Synthesis of the Neurotransmitter 4-Aminobutanoic
Acid (GABA) from Diethyl Cyanomalonate Pp.
9-13
M.C. Cook, R.D. Witherell and R.L.
White
[Abstract] [Full Text
Article]
Structure Activity Relationship of Organic
Alcohol and Esters for Antidepressant Like Activity Pp.
14-17
S. Perveen, A. Yasmeen, M.A. Khan, A. Dar,
R. Jafri and A. Ahmed
[Abstract] [Full Text
Article]
Synthesis and Biological Study of 3-Butyl-1-(2,6-dichlorophenyl)-
1H- [1,2,4]triazol-5(4H)-one Derivatives as Anti-hypertension
Drugs Pp. 18-22
Y. Zhang, J. Zhou, W. Pan, X. Wu and
S. Wang
[Abstract] [Full Text
Article]
The Antisense Oligonucleotides Decrease
Expression of the Cellular Prion Pp. 23-26
V.V. Stadnyk, L.A. Izyumova, Y.A. Rzhepetskiy,
C.Y. Mayor and V.V. Vlizlo
[Abstract] [Full Text
Article]
Synthesis and Preliminary Biological
Activity of Some New Pyrazole Derivatives as Acyclonucleoside
Analogues Pp. 27-30
S. Radi, S. Salhi and A. Radi
[Abstract] [Full Text
Article]
Synergistic Combinations of Chitosans
and Antibiotics in Staphylococcus aureus Pp.
31-35
S. Tin, C.S. Lim, M.K. Sakharkar and
K.R. Sakharkar
[Abstract] [Full Text
Article]
Structure Function Relationships of KTS
Disintegrins and Design of Antiangiogenic Drugs Pp.
36-40
O. Kallech-Ziri, J. Luis, Z. Faljoun, J.-M.
Sabatier, M. Lehmann, M. El Ayeb, N. Marrakchi and
E. Loret
[Abstract] [Full Text
Article]
Synthesis and Biological Activity of
New Triazole Compounds Pp. 41-45
H. Al Bay, B. Quaddouri, A. Guaadaoui, R. Touzani,
N.-E. Benchat, A. Hamal, M. Taleb, M. Bellaoui and
S. El Kadiri
[Abstract] [Full Text
Article]
Synthesis and In Vitro Evaluation
of Novel 1, 2, 4-Triazole Derivatives as Antifungal Agents
Pp. 46-49
G.R. Kokil, P.V. Rewatkar, S. Gosain, S.
Aggarwal, A. Verma, A. Kalra and S. Thareja
[Abstract] [Full Text
Article]
Physicochemical Interaction Study of
Non-Steroidal Anti- Inflammatory Drugs with Dimyristoylphosphatidylethanolamine
Liposomes Pp. 50-56
M. Manrique-Moreno, J. Howe, M. Suwalsky,
P. Garidel and K. Brandenburg
[Abstract] [Full Text
Article]
Editor’s
Choice
Homology Modelling of Human E1 Ubiquitin Activating Enzyme
Pp. 57-62
G. Brahemi, A.M. Burger, A.D. Westwell and
A. Brancale
[Abstract] [Full Text
Article]
Preparation of Tiagabine HCl/2-HPβCD
Complex Pellets by Extrusion- Spheronization Using Glycerol
Monostearate as Pellet Aid Pp. 63-69
A. Sughir, M. Lahiani-Skiba and
M. Skiba
[Abstract]
[Full Text
Article]
Abstracts
[Back to top]
[Full Text
Article]
New Bisquaternary Isoquinolinium Inhibitors
of Brain Cholinesterases – Synthesis and Anticholinesterase
Activity
J. Binder, M. Paar, D. Jun, M. Pohanka,
M. Hrabinova, V. Opletalova and K. Kuca
Alzheimer´s disease (AD) is one of the most
discussed diseases of present time. Because of the aging of
our population it is high threat for future. Due to this,
new drugs combating AD are still developed. In this study,
twelve bisquaternary isoquinolinium derivatives differing
in the linker between two heteroarenium rings were synthesized
and tested for their potency to inhibit brain cholinesterases.
According to the obtained in vitro results, the anticholinesterase
activity grew up with the length of the connection chain.
Possible binding to the enzyme cavity was described using
software Autodock. Moreover, LogP and molecular volume of
prepared compounds were predicted. As resulted, the highest
probability of synthesized compounds to penetrate blood-brain
barrier could be expected for the compound with linker having
eight methylenes.
[Back to top]
[Full Text
Article]
Design, Synthesis, and Biological Evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
Derivatives as Acetylcholinesterase Inhibitors
S.-J. Liu, L. Yang, X.-G. Liu, Y. Luo, Z.-J.
Cao, D.C.C. Wan, H.-Q. Lin and C. Hu
The docking study on a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
derivatives with acetylcholinesterase has been demonstrated.
The synthesis and characterization of a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
derivatives were described. All target compounds were evaluated
in vitro for the inhibitory activities against AChE via Ellman
colorimetric assay. Most of the target compounds possessed
anti-acetylcholinesterase activity. The preliminary structure-activity
relationships were discussed.
[Back to top]
[Full Text
Article]
Synthesis of the Neurotransmitter 4-Aminobutanoic Acid (GABA)
from Diethyl Cyanomalonate
M.C. Cook, R.D. Witherell and R.L.
White
GABA was synthesized by deethoxycarbonylation, ester
hydrolysis and nitrile reduction of a highly functionalized
intermediate obtained by alkylation of diethyl cyanomalonate
with ethyl bromoacetate. By judicious employment of D2O
or NaBD4 in one of the three
functional group transformation steps, deuterium was selectively
introduced into each of the three possible sites in GABA.
[Back to top]
[Full Text
Article]
Structure Activity Relationship of Organic Alcohol and Esters
for Antidepressant Like Activity
S. Perveen, A. Yasmeen, M.A. Khan, A. Dar,
R. Jafri and A. Ahmed
The synthesized compounds 1-7 were
evaluated for their antidepressant activity, among which 2-phenylethyl
alcohol 1 and isoamyl phenylacetate 3
showed 43 % and 37 % reduction in immobility time in mice
using forced swim test, thereby, displaying antidepressant-like
activity. Compound 1 and 3
were equipotent and both these compounds were 2x effective
than the standard drug phenelzine. Considering other esters
it appears that a decrease in alkyl chain length or addition
of either NO2 or OH groups
to the phenyl ring caused a marked decline in the antidepressant-like
activity.
[Back to top]
[Full Text
Article]]
Synthesis and Biological Study of 3-Butyl-1-(2,6-dichlorophenyl)-
1H- [1,2,4]triazol-5(4H)-one Derivatives as Anti-hypertension
Drugs
Y. Zhang, J. Zhou, W. Pan, X. Wu and
S. Wang
A series of nitric oxide-donating derivatives of
[1,2,4]triazol-5(4H)-one (9a-f and 15a-f)
as a novel class of angiotensin II receptor AT1
antagonists have been designed and synthesized by coupling
furoxan and nitric oxide with lead compound 1.
The synthesized compounds were evaluated for their antagonism
of AT1 receptor with induced
contraction in the rabbit thoracic aortic ring and the results
showed that compounds 9b, 15b and 15d
exhibited potent antagonistic activity of AT1
receptor. Moreover 9b, 15b, 15d, 15e had
good maximum NO release amount of this series.
[Back to top]
[Full Text
Article]
The Antisense Oligonucleotides Decrease Expression of the
Cellular Prion
V.V. Stadnyk, L.A. Izyumova, Y.A. Rzhepetskiy,
C.Y. Mayor and V.V. Vlizlo
The subject of this work was an inhibition of cellular
prion expression in vitro and in vivo by antisense oligodeoxyribonucleotides,
incorporated into cationic immunoliposomes. It was shown that
asODNs are able to reduce the level of PrPc expression in
vitro and in vivo.
[Back to top]
[Full Text
Article]
Synthesis and Preliminary Biological Activity of Some New
Pyrazole Derivatives as Acyclonucleoside Analogues
S. Radi, S. Salhi and A. Radi
Some novel pyrazole acyclonucleosides were prepared
through binding of pyrazole-3,5-substituted derivatives with
acyclic substituents mimetizing individual fragments of the
ribose ring such as: 1-[(2-hydroxyethoxy) methyl], 1-[4-(hydroxybutyl)],
1-[3-(hydroxypropyl)] and 1-[(2-hydroxyethyl amino) methyl].
Their syntheses were performed from easily accessible starting
materials. The prepared compounds were evaluated for their
antibacterial activity. Structure-activity relationship studies
(SAR) indicate that introduction of modified arm in N1 position
of pyrazole moieties has not any impact on the biolgical activity.
[Back to top]
[Full Text
Article]
Synergistic Combinations of Chitosans and Antibiotics in Staphylococcus
aureus
S. Tin, C.S. Lim, M.K. Sakharkar and
K.R. Sakharkar
This investigation reports on the drug interactions between
chitosans and antibiotics in Staphylococcus aureus.
The combination study shows that chitosan oligosaccharides
have synergistic effect in combination with tetracycline,
ceftriazone and sulfamethoxazole. Also, high molecular weight
chitosan was found to be effective against Staphylococcus
aureus in combination with Sulfamethoxawzole. These results
indicate the potential efficacy of chitosans in combinations
with antibiotics for enhancing total biological activity.
[Back to top]
[Full Text
Article]]
Structure Function Relationships of KTS Disintegrins and Design
of Antiangiogenic Drugs
O. Kallech-Ziri, J. Luis, Z. Faljoun, J.-M.
Sabatier, M. Lehmann, M. El Ayeb, N. Marrakchi and
E. Loret
Disintegrins are natural toxins found in snake venom
having anti angiogenic activity. The KTS disintegrins group
appears to be the most interesting as specific blocking agent
of tumor growth. We report the chemical synthesis of three
KTS disintegrins (Lebestatin, Obtustatin and Viperistatin)
carried out with different substitution. The activity of these
synthetic peptides (41 aa) and native Lebestatin purified
from venom was compared with cell adhesion and migration assays.
Synthetic and native Lebestatin inhibit cell adhesion of PC12
cells at 0.2 nM and integrin-dependent migration of CHO cells
at 1 nM. This study shows that Lebestatin has the highest
activity followed by Obtustatin and then Viperistatin in the
two assays. Circular dichroism spectra of these KTS disintegrins
show that their folding is similar. Molecular modeling shows
that two arginines (8 and 24) and two lysines (21 and 32)
have probably their chemical function interacting with integrins
in protruding from the surface of Lebestatin. This study should
help to design a lead compound to discover a new family of
anti-angiogenic drugs.
[Back to top]
[Full Text
Article]
Synthesis and Biological Activity of New Triazole Compounds
H. Al Bay, B. Quaddouri, A. Guaadaoui, R. Touzani,
N.-E. Benchat, A. Hamal, M. Taleb, M. Bellaoui and
S. El Kadiri
Six new N,N-bis(1,2,4-triazol-1-ylmethyl)amines have
been prepared in one step by condensation of 1-(hydroxymethyl)triazole
with a series of amines. These reactions were carried out
in refluxed CH3CN for 4 hours.
The products were recuperated with excellent and good yields
(75-89.5%). Compounds (3a-f) were screened
for their antifungal activity against the budding yeast
Saccharomyces cerevisiae and their antibacterial activity
against Escherichia coli.
[Back to top]
[Full Text
Article]
Synthesis and In Vitro Evaluation of Novel 1, 2,
4-Triazole Derivatives as Antifungal Agents
G.R. Kokil, P.V. Rewatkar, S. Gosain, S.
Aggarwal, A. Verma, A. Kalra and S. Thareja
Despite the advances in medicine and the emergence of
new antifungal agents, fungal infections remain a significant
cause of morbidity and mortality. Azoles are widely used as
antifungal agents. Azoles interfere with the conversion of
lanosterol to ergosterol by inhibiting a fungal cytochrome
P450enzyme, lanosterol 14α-demethylase.
Resistance to azoles, particularly fluconazole, is emerging
to Candida albicans, after long-term suppressive
therapy. Thus, there is an urgent need for newer potent antifungals
to combat resistance developed against widely used azoles.
In present work, we report synthesis of novel triazole derivatives
of 7-hydroxy-4-methylcoumarin using various substituted aromatic
aldehydes and evaluated for their in vitro fungicidal
activity against Candida albicans at various concentrations
to obtain minimum inhibitory concentration (MIC).
[Back to top]
[Full Text
Article]
Physicochemical Interaction Study of Non-Steroidal Anti- Inflammatory
Drugs with Dimyristoylphosphatidylethanolamine Liposomes
M. Manrique-Moreno, J. Howe, M. Suwalsky,
P. Garidel and K. Brandenburg
The molecular details of the clinical side effects of
nonsteroidal anti-inflammatory drugs are poorly understood.
In order to better understand the molecular basis of these
effects, the interactions of Ibuprofen, Naproxen and Diclofenac
with dimyristoylphosphatidylethanolamine (DMPE) phospholipid
bilayers as model for a cell membrane were performed. By applying
FTIR, data for the headgroup vibrations give no indication
for an essential contribution of this molecular part, in particular
the phosphate bands, in the interaction with the NSAID. In
contrast, the evaluation of lipid vibrational bands of DMPE
indicates a considerable fluidization of its hydrocarbon chains,
being strongest for Diclofenac. Summarizimg the data also
from ITC and DSC experiments, it can be stated that the interaction
is essentially entropy driven.
[Back to top]
[Full Text
Article]
Homology Modelling of Human E1 Ubiquitin Activating Enzyme
G. Brahemi, A.M. Burger, A.D. Westwell and
A. Brancale
Human E1 is a key player in protein ubiquitination, however
the E1 structure is not available. In this paper, we describe
the derivation of a human E1 structure using molecular modelling
based on the crystal structure of S. cerevisiae E1
and M. Musculus E1. Key interactions between our
E1 model and ubiquitin are also discussed.
[Back to top]
[Full Text
Article]
Preparation of Tiagabine HCl/2-HPßCD Complex Pellets
by Extrusion- Spheronization Using Glycerol Monostearate as
Pellet Aid
A. Sughir, M. Lahiani-Skiba and
M. Skiba
Glycerol monostearate was used as a pellet-aid to prepare
tiagabine HCl/2-HPβCD
inclusion complex pellets (an antiepileptic agent partially
included into the 2-HPβCD
cavity to improve its stability). The pellitization of tiagabine
HCl/2-HPβCD
inclusion complex (1:1 stoichiometric composition) using 27.3%
of melted GMS (60°C)
in its liquid form as wetting agent, 30% of microcrystalline
cellulose (pellet-forming agent) and 3% of kollidone-30 (binder)
was studied. Pellitization was prepared using extrusion/spheronization
method. >
80% of pellets, size ranging between 800-1000μm,
were obtained indicating a significant pellet yield. The disintegration
test of the pellets complied with the Eur. Ph. Limit (0.8%).
The TGB pellets formed were better sized and spherically shaped
than when GMS was used in its liquid form. Pellets obtained
using tiagabine HCl/2-HPβCD
inclusion complex after addition of GMS with very little water
content (<
5%) have also a spherical shape, retain their integrity in
dissolution medium, which suggested that coatings will not
burst prematurely due to granule swelling and release their
TGB load rapidly 65-85% in 15min in a phosphate buffered dissolution
medium.
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