| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 5, Number 5, July 2008
Contents
QSAR Studies on some Calcium Channel Blockers
Pp. 307-312
M.A. Naik, V.S.A.K. Satuluri and
S.P. Gupta
[Abstract]
Synthesis of N-Benzenesulfonylbenzotriazole Derivatives,
and Evaluation of their Antimicrobial Activity Pp.
313-318
L.Y. Hergert, M.J. Nieto, M.C. Becerra, I. Albesa
and M.R. Mazzieri
[Abstract]
Virtual Screening of the Guanylate Monophosphate
Kinase (GMPK) Family: Investigating the Rules of Ligand Specificity
Pp. 319-326
T.E. Malliavin, H. Munier-Lehman and V.
Stoven
[Abstract]
Antibacterial Pleuromutilin Derivatives based
on Alternate Core Structures: Arigoni and Birch Chemistry
Revisited Pp. 327-331
D.M. Springer, J.T. Goodrich, B.-Y. Luh,
J.J. Bronson, Q. Gao, S. Huang, K. DenBleyker, T.J. Dougherty
and J. Fung-Tomc
[Abstract]
The Interaction of Titanocene Y with Double-Stranded
DNA: A Computational Study Pp. 332-335
M. Tacke
[Abstract]
Structure-Activity Relationship Study of 8-amino-2,8-dideoxy-β
KDO, a Potent CMP-KDO Synthetase Inhibitor Pp. 336-339
H. Adachi, K.-I. Kondo, F. Kojima, Y. Umezawa,
K. Ishino, H. Kunimoto, Y. Nishimura and Y. Akamatsu
[Abstract]
Discovery of AX8312, an N-alkyl-Gly-boro-Pro Derivative
that Accelerates Recovery from Neutropenia in the Mouse
Pp. 340-345
E.C.K. Lin, K.R. Shreder, M.C. Zhang, Y.
Hu, L. Morera, M. Wu, M.S. Wong, L. Ma, D. Chun, S. Corral
and J.W. Kozarich
[Abstract]
Disodium Phosphate of Novel Pyrazole-Linked Norcantharidin
Analogs: Design, Synthesis and their Anticancer Evaluation
Pp. 346-352
L. Deng, B. Yang, Q. He and Y.
Hu
[Abstract]
Synthesis and Biological Evaluation of a New Series
of Benzothiazole- Quinolone Hybrids as Antibacterial Agents
Pp. 353-357
A. Kamal, S.K. Ahmed, M.N.A. Khan, R.V.C.R.N.C.
Shetty, B. Siddhardha and U.S.N. Murty
[Abstract]
Abstracts
[Back to top]
QSAR Studies on some Calcium Channel Blockers
M.A. Naik, V.S.A.K. Satuluri and
S.P. Gupta
Quantitative structure-activity relationship studies
have been made on some calcium channel blockers (CCBs) that
include the most widely studied class of 1,4-dihydropyridines
and two new classes of CCBs, namely benzazepinone analogs
and quinolizidinyl derivatives. In the case of 1,4-dihydropyridines
some simple correlations have been found as compared to those
reported in several earlier studies and in the other two classes
it could be shown that the electronic parameters and the bulk
of the molecules may be important for the activity of the
compounds.
[Back to top]
Synthesis of N-Benzenesulfonylbenzotriazole Derivatives,
and Evaluation of their Antimicrobial Activity
L.Y. Hergert, M.J. Nieto, M.C. Becerra, I. Albesa
and M.R. Mazzieri
A series of benzenesulfonyl compounds, 1a-i,
containing a BZT moiety was synthesized and characterized,
and their antifungal and antibacterial activities were investigated.
Compounds 1a and 1d showed
the highest activity against Escherichia coli ATCC
25922; in addition 1a presented bactericidal
activity against E. coli and Staphylococcus aureus
at 8.6 mM. The ability of 1a to generate
superoxide anion (O2.-) was
measured and it showed more stimuli in S. aureus
compared to sulfathiazole, indicating that 1a can be involved
in oxidative stress of bacteria. None of the compounds inhibited
the growth of the dermatophytes strains at the tested concentration
(250 μg/ml).
[Back to top]
Virtual Screening of the Guanylate Monophosphate
Kinase (GMPK) Family: Investigating the Rules of Ligand Specificity
T.E. Malliavin, H. Munier-Lehman and V.
Stoven
Guanylate kinases (GMPK) from Mycobacterium tuberculosis,
Mus musculus and Saccharomyces cereviae were
submitted to virtual screening in order to determine protein-ligand
interactions specific to M. tuberculosis. The opening
of the cleft between CORE, LID and GMP domains was found to
have a large influence on the established interactions and
on the determination of ligands binding specifically to the
M. tuberculosis GMPK. An extended definition of the active
site pocket, allowing to be more discriminant between Mycobacterium
tuberculosis and M. musculus, is given. A virtual
screening run with the extended pocket definition, was used
to select compounds having high docking scores on M. tuberculosis
GMPK and low ones on M. musculus GMPK. The protein
residues involved in hydrogen bonds with ligands were the
same than in the GMPK-GMP complex, but the chemical functions
of the ligand involved in these hydrogen bonds are often different.
On the other hand, the hydrophobic interactions are different
from the ones observed in the GMPK-GMP structure, and may
be a way to increase the specificity between the M. tuberculosis
and M. musculus GMPKs.
[Back to top]
Antibacterial Pleuromutilin Derivatives based
on Alternate Core Structures: Arigoni and Birch Chemistry
Revisited
D.M. Springer, J.T. Goodrich, B.-Y. Luh,
J.J. Bronson, Q. Gao, S. Huang, K. DenBleyker, T.J. Dougherty
and J. Fung-Tomc
Pleuromutilin derivatives comprised of varied core structures
have been synthesized. Many of the compounds described were
found to have surprisingly good antibacterial activity
in vitro.
[Back to top]
The Interaction of Titanocene Y with Double-Stranded
DNA: A Computational Study
M. Tacke
In a computational study using the force field method
MM+, the known anticancer drug Titanocene Y was reacted with
its biological target, which is believed to be double-stranded
DNA. It was found that after the loss of two chloride ligands,
the substituted titanocene dication conveniently coordinates
strongly to a phosphate group by replacing a counter ion.
In addition, the two p-methoxybenzyl groups have
exactly the right length and flexibility to coordinate to
two sodium counter ions bonded to two neighbouring phosphate
groups, which allows Titanocene Y to become a chelating ligand
strongly bonded to the surface of double-stranded DNA.
[Back to top]
Structure-Activity Relationship Study of 8-amino-2,8-dideoxy-β
KDO, a Potent CMP-KDO Synthetase Inhibitor
H. Adachi, K.-I. Kondo, F. Kojima, Y. Umezawa,
K. Ishino, H. Kunimoto, Y. Nishimura and Y. Akamatsu
8-Amino-2,8-dideoxy-β-KDO
is a well-known inhibitor of CMP-KDO synthetase involved in
the biosynthesis of lipopolysaccharide (LPS), an essential
component of the outer membrane of gram-negative bacteria.
Chemical modification of the hydroxyl groups of 8-amino-2,8-dideoxy-
β-KDO
proved that they play a crucial role in CMP-KDO synthetase
inhibition.
[Back to top]
Discovery of AX8312, an N-alkyl-Gly-boro-Pro Derivative
that Accelerates Recovery from Neutropenia in the Mouse
E.C.K. Lin, K.R. Shreder, M.C. Zhang, Y.
Hu, L. Morera, M. Wu, M.S. Wong, L. Ma, D. Chun, S. Corral
and J.W. Kozarich
A screen of N-alkyl-Gly-boro-Pro DPP inhibitors using
an acute murine model revealed that N-adamantyl and N-cycloalkyl
groups greater in size than cyclobutyl significantly induced
G-CSF. Treatment of neutropenic mice with the most efficacious
compound, AX8312 (N-(1-adamantyl)-Gly-boro-Pro),
resulted in a faster and greater neutrophil recovery versus
vehicle-treated mice.
[Back to top]
Disodium Phosphate of Novel Pyrazole-Linked Norcantharidin
Analogs: Design, Synthesis and their Anticancer Evaluation
L. Deng, B. Yang, Q. He and Y.
Hu
To design and synthesize novel pyrazole-linked norcanthridin
analogs and their disodium phosphates by [3+2]1, 3-dipolar
cycloaddition reaction of norcantharidin derivatives of substituted
aromatic amines with three hydrazines. All analogues have
been screened for their antiproliferative activity in
vitro against a panel of tumor cell lines: KB, SMMC-7721,
SGC7901, ECA109, HO-8910, K562, A549 and MCF-7 producing IC50
values from 0.07 μM
to >100 μM.
Compound 8c showed potency for the treatment
of hepatoma, with IC50 value
to SMMC-7721 cell line comparable to that of norcantharidin.
High potency and selectivity of compound 12
to MCF-7 cell line prove that the phosphorylation of norcantharidin
analogs is an effective way to increase the activity and solubility.
[Back to top]
Synthesis and Biological Evaluation of a New Series
of Benzothiazole- Quinolone Hybrids as Antibacterial Agents
A. Kamal, S.K. Ahmed, M.N.A. Khan, R.V.C.R.N.C.
Shetty, B. Siddhardha and U.S.N. Murty
In an effort to develop new and more effective therapies
to treat bacterial infection, quinolone coupled benzothiazoles
(6a-f) have prepared and evaluated for their
efficacy as antibacterial agents against various Gram-positive
and Gram-negative strains of bacteria. Some of the compounds
from this series exhibited antibacterial activity comparable
to ciprofloxacin.
|
