| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 7, Number 6, July 2010
Contents
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Abstracts i-iv
Editor’s
Choice
Synthesis and Evaluation of Estradiol Derivatives
as Anti-Breast Cancer Agents Pp. 389-394
J.S. Cooperwood, J. Edwards, M. Musa, D. Simmons, A.D.
Mian, K.-K. Park and Z. Wan
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Self-Organizing Molecular Field Analysis on Pyridazine
Analogues as Protein Tyrosine Phosphatase 1B (PTP 1B) Inhibitors
Pp. 395-401
S. Thareja, S. Aggarwal, T.R. Bhardwaj and M.
Kumar
[Abstract] [Purchase
Article]
Evaluation of Novel 7-(hetero)aryl-substituted
Pyrazolo[1, 5-a] pyrimidines as Phosphodiesterase-4
Inhibitors Pp. 402-408
A. Kodimuthali, R. Gupta, K.V.L. Parsa, P.L. Prasunamba
and M. Pal
[Abstract] [Purchase
Article]
Assessing Drugs for their Cardio-Toxicity
Pp. 409-414
A. Rayan, M. Falah, J. Raiyn, H. Mawassi and
N.-E. Raiyn
[Abstract] [Purchase
Article]
Design, Synthesis and Biological Evaluation
of Benzopyran Derivatives as KATP
Channel Openers Pp. 415-420
J. Zhou, H. Qian, H. Zhang, H. Gao, W. Huang, X. Zhu,
S. Ni and C. Zhang
[Abstract] [Purchase
Article]
Design and Synthesis of Novel 1,3-Dioxane-2-Carboxylic
Acid Derivatives as PPARα/γ
Dual Agonists Pp. 421-429
H. Pingali, M. Jain, S. Shah, P. Makadia,
P. Zaware, J. Jamili, K.V.V.M. Sairam, P. Patil, D. Suthar,
S. Giri, H. Patel and P. Patel
[Abstract] [Purchase
Article]
Pyrrole-Based Hydrazones Synthesized
and Evaluated In Vitro as Potential Tuberculostatics
Pp. 430-437
A. Bijev and M. Georgieva
[Abstract] [Purchase
Article]
Application of Molecular Topology to the Search of
Novel NSAIDs: Experimental Validation of Activity
Pp. 438-445
M. Galvez-Llompart, R.M. Giner, M.C. Recio, S. Candeletti
and R. Garcia-Domenech
[Abstract] [Purchase
Article]
Synthesis and Biological Evaluation
of Novel Bioisosteric Analogues of DimebonTM
Pp. 446-451
A.V. Ivachtchenko, E.B. Frolov, O.D. Mitkin, S.E. Tkachenko
and A. Khvat
[Abstract] [Purchase
Article]
New Limonene-Hybrid Derivatives with
Anti-T. cruzi Activity Pp. 452-460
G. Álvarez, A. Gerpe, D. Benitez, F. Garibotto,
S. Zacchino, C.S. Graebin, R.G. da Rosa, V.L. Eifler-Lima,
M. González and H. Cerecetto
[Abstract] [Purchase
Article]
Design, Synthesis and 3-D Characterization
of 1-Benzenesulfonyl 1,2,3,4-Tetrahydroquinolines
as Lead Scaffold for Antiparasitic Drug Pp. 461-470
R.J. Pagliero, A.B. Pierini, R. Brun and M.R.
Mazzieri
[Abstract] [Purchase
Article]
Synthesis and Anticoccidial Activity
of 3-(2-(1-methoxynaphthalen 2-yl)-2-oxoethyl) Quinazolinone
Derivatives Pp. 471-475
Y. Zhang, G. Chen, Y. Weng, R. Li, Y. Wang and
Y. Wang
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Article]
Abstracts
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Synthesis and Evaluation of Estradiol
Derivatives as Anti-Breast Cancer Agents
J.S. Cooperwood, J. Edwards, M. Musa, D. Simmons, A.D.
Mian, K.-K. Park and Z. Wan
3-N-alkyloxyestradiol derivatives were synthesized,
characterized and tested for activity in MCF-7 human breast
cancer cells. Among the compounds, the diisopropyl and piperidinyl
derivatives were found to be more active than 4-hydroxytamoxifen
(HO-Tam), the active metabolite of tamoxifen based upon IC50
values. The IC50s were correlated
with structures using molecular modeling.
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Self-Organizing Molecular Field Analysis on Pyridazine
Analogues as Protein Tyrosine Phosphatase 1B (PTP 1B) Inhibitors
S. Thareja, S. Aggarwal, T.R. Bhardwaj and M.
Kumar
A 3D-QSAR study has been performed using Self-organizing
molecular field analysis (SOMFA) on a novel class of pyridazine
analogues as non-competitive and reversible inhibitors of
PTP 1B. SOMFA is a novel 3D-QSAR methodology, similar to both
comparative molecular field analysis (CoMFA) and molecular
similarity studies. SOMFA studies have been performed to correlate
chemical structures of pyridazine analogues with their observed
PTP 1B inhibitory activity. The master grid obtained for the
various SOMFA models indicates electrostatic and shape potential
contributions. These can be mapped back onto the structural
features relating to trends in activities of the molecules.
On the basis of the spatial arrangement of the various shape
and electrostatic potential contributions, new inhibitors
of PTP 1B can be designed with improved spectrum of activity
for the management of type 2 diabetes.
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Evaluation of Novel 7-(hetero)aryl-substituted
Pyrazolo[1, 5-a] pyrimidines as Phosphodiesterase-4
Inhibitors
A. Kodimuthali, R. Gupta, K.V.L. Parsa, P.L. Prasunamba
and M. Pal
A novel series of 7-(hetero)aryl substituted-pyrazolopyrimidines,
prepared via an AlCl3
induced C-C bond forming reaction of 7-chloro-5-phenyl-pyrazolo[1,5-a]pyrimidine
with arenes and heteroarenes have been investigated as PDE4
inhibitors. Among all the compounds tested the 7-indolyl substituted
pyrazolopyrimidine showed good inhibition of PDE 4 in
vitro.
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Assessing Drugs for their Cardio-Toxicity
A. Rayan, M. Falah, J. Raiyn, H. Mawassi and
N.-E. Raiyn
Drug-induced long QT syndrome (LQTS) that may
lead to sudden cardiac death has become one of the key reasons
for which some drugs fail to enter market, while others have
been withdrawn from the market. Early identification of chemical
entities causing LQTS is of extreme importance relevant to
the production of safer drugs as well as to the direct reduction
of attrition rate in drug development. In the present study,
we have employed fourteen classification methods to develop
a prediction model for cardio-toxicity. The analyses have
been carried out on 127 drugs inducing LQTS and 250 cardio-safe
drugs. These compounds have been randomly divided into two
sets, namely a training set (consisting of 2/3) and a test
set (consisting of 1/3). CONCLUSIONS: When models from different
algorithms are combined using the proposed method, quality
compared to the individual models is consistently and significantly
improved in both training and test sets. The accuracy of our
approach has 10-25% improvement over the best result obtained
by individual classification techniques. The proposed strategy
could be employed to infer cardio-toxicity or -safety for
current and potential drugs. Certainly, it will also have
important impact on decision making in the fields of screening
molecules for drug development, biological activity, and other
applications as well.
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Design, Synthesis and Biological Evaluation
of Benzopyran Derivatives as KATP
Channel Openers
J. Zhou, H. Qian, H. Zhang, H. Gao, W. Huang, X. Zhu,
S. Ni and C. Zhang
In order to complete the SAR and discover new
potent and selective PCOs, some changes were made to the C-4
and C-2 substitutions of cromakalim. A series of 4 -amino
acid substituted -2, 2-dialkylchromans structurally related
to cromakalim were synthesized and evaluated, as ATP-sensitive
potassium channel openers (8a-l). Preliminary
biological tests suggested that these compounds exhibited
potent to mild relaxation activity of the KCl-contracted rat
aortic strips. Compounds 8b (IC50
=0.25μM),
8f (IC50
=6.44μM)
and 8j (IC50
=8.65μM)
exhibited commendable opening activity of potassium channels.
In addition to anti-hypertension, these compounds can also
be considered as lead candidates for the further development
of myocardial antiischemic drugs.
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Design and Synthesis of Novel 1,3-Dioxane-2-Carboxylic
Acid Derivatives as PPARα/γ
Dual Agonists
H. Pingali, M. Jain, S. Shah, P. Makadia,
P. Zaware, J. Jamili, K.V.V.M. Sairam, P. Patil, D. Suthar,
S. Giri, H. Patel and P. Patel
1,3-dioxane carboxylic acid derivatives were
prepared based on our previous studies directed towards identifying
novel pharmacophore for the development of PPAR α/γ
dual agonists. Based on the typical topology of PPAR agonists
we focused our design approach on modifying lipophilic tail
and prepared a series of compounds by replacing the oxazole
moiety of our previously reported compound with optimized
lipophilic groups. Compound 8a was found
to be a weak PPAR activator but exhibited potent hypolipidemic
and anti-hyperglycemic activities in vivo due to
superior bioavailability, whereas 8f exhibited
potent in vitro and invivo effects. The
activity of 8f is further supported by molecular
docking study.
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Pyrrole-Based Hydrazones Synthesized
and Evaluated In Vitro as Potential Tuberculostatics
A. Bijev and M. Georgieva
Twelve pyrrole hydrazones were synthesized and evaluated in
vitro as inhibitors of Mycobacterium tuberculosis
H37Rv with IC50 and IC90
to 5.92 µg/ml and 9.37 µg/ml respectively. The
most active 12d (ethyl 5-(4-chlorophenyl)-2-methyl-1-(4-(2-((5-nitrofuran-2-yl)methylene)hydrazinyl)-4-oxobutyl)-1H-pyrrole-3-carboxylate)
has IC90 value of 9.372 µg/ml. The derived second order
QSAR model favors moderate molecular surfaces in a combination
with electron-accepting substituents in the aromatic hydrazone
moiety.
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Application of Molecular Topology to the Search of
Novel NSAIDs: Experimental Validation of Activity
M. Galvez-Llompart, R.M. Giner, M.C. Recio, S. Candeletti
and R. Garcia-Domenech
A topological-mathematical model obtained by
linear discriminant analysis has been used to the search of
new nonsteroidal antinflammatory drugs (NSAIDs). After carrying
out an in silico screening based on such a model,
on the Aldrich database, new structures potentially active
were selected. Among these structures stand fourteen compounds,
from which only one had been previously recorded as NSAID
in the literature. The experimental tests performed on the
remaining substances demonstrated that several compounds showed
either in vitro or in vivo or both activity.
Moreover, four compounds, namely 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea,
4,6-dichloro-2-methylthio-5-phenylpyrimi-dine, 2-chloro-2',6'-acetoxylidide
and trans-1,3-diphenyl-2-propen-1-ol, showed a significant
in vivo antinflammatory activity as compared to the
reference drug (indomethacin). These results reinforce the
role of Molecular Topology as a useful tool for drug discovery.
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Synthesis and Biological Evaluation
of Novel Bioisosteric Analogues of DimebonTM
A.V. Ivachtchenko, E.B. Frolov, O.D. Mitkin, S.E. Tkachenko
and A. Khvat
In the present paper, we describe the synthesis
and biological evaluation for a series of novel 6,9-disubstituted
2-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indoles.
These compounds represent unique bioisosteric analogues of
DimebonTM
with promising biological activity against a panel of various
targets including some GPCR family members.
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New Limonene-Hybrid Derivatives with
Anti-T. cruzi Activity
G. Álvarez, A. Gerpe, D. Benitez, F. Garibotto,
S. Zacchino, C.S. Graebin, R.G. da Rosa, V.L. Eifler-Lima,
M. González and H. Cerecetto
The development of hybrid compounds containing
limonene- and recognized anti-T. cruzi-heterocycle-frameworks
is described. The six new compounds displayed broad antitrypanosomal
activities having 5-nitrofuran and 5-nitroindazole derivatives,
the best profiles. In addition, a 5-nitroindazole derivative
evaluated against a panel of fungi exhibited relevant activities.
Knowing that free-radical-production operates as one of the
mechanisms of action on these heterocycles, we studied a potential
extra-mechanism, membrane-sterols changes. Non-relevant T.
cruzi squalene accumulation was observed for any of the
tested hybrid-limonene derivatives.
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Design, Synthesis and 3-D Characterization
of 1- Benzenesulfonyl-1,2,3,4-Tetrahydroquinolines
as Lead Scaffold for Antiparasitic Drug
R.J. Pagliero, A.B. Pierini, R. Brun and M.R.
Mazzieri
Ten 1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline
(BSTHQ) were synthesized and characterized and their antiprotozoal
activities were investigated. This small library was designed
by combining two chemical moieties that are known to be biologically
active by itself. The BS group seems to be favorable for the
antiparasitic activity, since the derivatives presented lower
IC50 value than the precursor
heterocycle. Most compounds were moderately active against
T cruzi, but 3 showed a promising IC50
value (9.76µM) with low cytotoxicity (L6). Also, 3,
6 and 9 showed interesting activity
and reasonable selectivity against P. falciparum.
These derivatives are considered as lead scaffolds and merit
further exploration through structure optimization.
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Synthesis and Anticoccidial Activity
of 3-(2-(1-methoxynaphthalen-2-yl)-2-oxoethyl) Quinazolinone
Derivatives
Y. Zhang, G. Chen, Y. Weng, R. Li, Y. Wang and
Y. Wang
A series of 3-(2-(1-methoxynaphthalen-2-yl)-2-oxoethyl) quinazolinone
derivatives (8a-k) were designed and synthesized.
Their anticoccidial activities were evaluated against Eimeria
tenella in vivo. The results indicated that
compounds 8a, 8b and 8e
exhibited anticoccidial activity against Eimeria tenella
in the chicken’s diet with a dose of 18 mg/Kg.
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