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Umesh Shiroya., et al. / International Journal of Advances in Pharmaceutical Research
IJAPR
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Review Article
ISSN: 2230 – 7583
DNA-GYRASE: A POTENTIAL AND EMERGING TARGET FOR FINDING NOVEL ANTI-BACTERIAL
AGENTS
Umesh Shiroya * , Amit Poshiya, Anand Patel, Ankit Parikh, Sanjay Patel
Department of Pharmaceutical Chemistry, L.B.Rao Institute of Pharmaceutical Education and Research, Bethak
Road, Khambhat-388620, Gujarat, India
Received on 22 – 06 - 2011 Revised on 21 – 07- 2011 Accepted on 12 – 08 – 201
ABSTRACT
DNA-gyrase has drawn much attention as selected target for finding potent anti-bacterial agents against multi-drug
resistant strains. DNA-gyrase, a typical of type-II topoisomerase, has been known to cause DNA replication,
transcription and recombination. DNA-gyrase catalyzes the ATP-dependent introduction of negative supercoils into
bacterial DNA as well as the decatenation and unknotting of DNA. The DNA-gyrase enzyme consists of two
subunits, A and B, of molecular mass 97 and 90 kDa, respectively, with the active enzyme being an A 2 B 2 complex.
The A subunit of DNA gyrase is involved in DNA breakage and reunion while the B subunit catalyzes the
hydrolysis of ATP. In view of the existing literature, it is evident that the emergence of bacterial resistance to most
of the antibacterials used clinically represents a major challenge in today’s antibiotic research, outweighing the task
to develop drugs of higher potency, expanded spectrum of activity, and improved safety profile.
Key Words: DNA-gyrase, Type-II Topoisomerase, Multi-drug resistant strains.
INTRODUCTION
DNA gyrase is an A 2 B 2 holoenzyme that
mediates various reactions essential for the bacterial
cell, e.g. the introduction of negative superhelical
turns into bacterias circular DNA. The increasing use
of anti-bacterial agents such as beta-lactams,
macrolides, vancomycin or quinolones has resulted in
the emergence of multi-drug resistant pathogens,
especially gram-positive bacteria. i Widespread
emergence of bacterial resistance to present drugs
represents a serious problem in treatment of bacterial
infections. Modern approaches toward development
of new potential inhibitors are based on knowledge of
structure and function of proteins specific to bacteria.
One of them is DNA gyrase, a characteristic and
essential bacterial enzyme whose inactivation leads
to bacterial death. 2
* For correspondence
Umeshkumar Chaturbhai Shiroya
Tel.: +91 9033109108
E-mail: u_shiroya@yahoo.com
DNA-gyrase has drawn much attention as selected
target for finding potent anti-bacterial agents against
multi-drug resistant strains such as methicillinresistant
Staphylococcus aureus (MRSA),
vancomycin-resistant enterococci (VRE), Penicillinresistant
Streptococci pneumonia (PRSP).
Quinolones (e.g. ciprofloxacin) are the only class of
the DNA gyrase inhibitors currently used in clinical
practice. They act by inhibiting the GyrA subunit,
thus interfering with the DNA cleavage and
relegation reactions. The coumarins (e.g. novobiocin)
and cyclo-thialidines, natural antibiotics from the
Streptomyces organisms, are the most studied
inhibitors of the GyrB-subunit. Both classes act as
competitive inhibitors of the ATP-binding site on the
GyrB subunit, thus inhibiting the ATP-dependent
step in the enzyme catalytic cycle. The inhibitory
mechanism has also been characterized with
radiolabelled benzoyl-cyclothialidine and
dihydronovobiocin and by structural analysis. More
recently, GyrB inhibitors from various chemical
classes have been reported including indazole,
pyrazole, benzimidazole, phenol and indolinone. 2
DISCOVERY OF DNA-GYRASE AS AN ANTI-
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BACTERIAL TARGET
The development of chemotherapy during
past 60 years constitute one of most important
therapeutic advances in history of medicine and
antimicrobial drugs are the greatest contribution of
present century to therapeutics. Potential therapeutic
targets are being disclosed with increasing frequency
and the exponential growth will continue during the
next decades. In this situation there is a need for rapid
and effective target validation and for accelerated
lead discovery procedures. Organic chemists are
increasingly directing their attention towards
synthetic aspects of biomolecules and biologically
active compounds, biosynthesized by plants and
animals.
DNA-gyrase, a typical of type-II
topoisomerase, has been known to cause DNA
replication, transcription and recombination. DNAgyrase
catalyzes the ATP-dependent introduction of
negative supercoils into bacterial DNA as well as the
decatenation and unknotting of DNA. The DNAgyrase
enzyme consists of two subunits, A and B, of
molecular mass 97 and 90 kDa, respectively, with the
active enzyme being an A2B2 complex. The A
subunit of DNA gyrase is involved in DNA breakage
and reunion while the B subunit catalyzes the
hydrolysis of ATP. DNA-gyrase is mainly inhibited
by quinolones and coumarins. Some of which are
widely used for the treatment of bacterial infections
diseases. Quinolones, inhibit the DNA breakagereunion
cycle by binding to the subunit A and by
blocking the gyrase-DNA complex while the latter
act on subunit B. In the absence of the ATP, DNA
gyrase catalyzes only the relaxation of supercoiled
DNA but not the introduction of negative supercoils.
Unfortunately multidrug-resistant gram-positive have
started posing serious issues in medical science to
deal with. To overcome the limitations of the known
DNA-gyrase inhibitor, it has become imperative to
identify new class of compounds. 3,4
ANTI-BACTERIAL STUDIES BASED ON
BACTERIAL DNA-GYRASE AS TARGET
ENZYME
A number of studies have carried out for
finding potent anti-bacterial agents targeting bacterial
DNA-gyrase. Mitscher L.A. et.al 5 have reported
synthesis and antimicrobial activity of the
enantiomers of 6-fluoro-7-(1-piperazinyl)-1-(2’-
trans-phenyl-1’-cyclopropyl)-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid (1) as chiral DNAgyrase
inhibitors.
Wentland M.P. et.al 6 have reported
synthesis and bacterial DNA-gyrase inhibitory
properties of a spirocyclopropyl-quinolone
derivatives (2). Rosen T. et.al 7 have reported
synthesis and DNA-gyrase inhibitory activity of 3-
dienoyl tetramic acid derivatives (3). Tetramic acids
were recurrent motif among natural products
originating from a variety of marine and terrestrial
species such as sponges, cyanobacteria, bacteria and
fungi. The ability of various synthetic 3-dienoyl
tetramic acids to inhibit bacterial DNA-gyrase was
investigated. Out of 33 compounds with variances in
the residues at C 5, N and at the terminal C=C bond
those derivatives inhibited supercoiling by DNAgyrase
isolated from E.coli H560, using norfloxacin
as a standard. Kondo H. et.al 8 have reported
synthesis and anti-bacterial activity of thiazolo-,
oxazolo- and imidazolo-[3,2-a][1,8]naphthyridinecarboxylic
acid derivatives (4).
Hubschwerlen C. et.al 9 have reported
design, synthesis and biological activity of pyrimido
[1,6-a]benzimidazoles (5) as novel DNA-gyrase
inhibitors. Jinbo Y. et.al 10 have reported synthesis
and anti-bacterial activity of tetracyclic pyridine
carboxylic acid with a thiazolidine ring, 1,2-dihydro-
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9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-
piperazinyl)-5-oxo-5H-thaizolo[3,2-α]quinoline-4-
carboxylic acid (6) and variants with a nitrogen atom
or carbonyl group in place of the 10-position oxygen
atom and evaluated against gram-positive organisms
and DNA-gyrase of E.coli.
Atarashi S. et.al 11 have reported synthesis
and SAR of 1-(2-fluorocyclopropyl)-3-pyridone
carboxylic acid anti-bacterial agents (7) and
evaluated for their anti-bacterial activity against
gram-positive and gram-negative organisms. Inoue
Y. et.al 12 have reported synthesis and anti-bacterial
activity of thiazolopyrazine-incorporated tetracyclic
quinolone (8) antibacterials. Jinbo Y. et.al 13 have
reported new oxidation method for the synthesis of
4,9b-diaza-8,9b-dihydro-6-fluoro-5-(4-methyl-1-
piperazinyl)-8-oxo-1- thia-1H-cyclopenta[cd]
phenalene-9-carboxylic acid (9), a potent DNAgyrase
inhibitor and exhibited anti-bacterial activity
against gram-positive and gram-negative bacteria.
New oxidation method involved the conversion of
amine to the imine with DMSO activated by
trifluoro-acetic anhydride or oxalyl chloride.
Flamm R.K. et.al 14 have reported in vitro obtained from in-silico screening were evaluated
evaluation of ABT-719, a novel compound of DNAgyrase
inhibitors of 2-pyridones (10). ABT-719 was
against DNA-gyrase. Novel DNA-gyrase inhibitors
were obtained, divided into seven classes.
more active against gram-positive, gram-negative and 1) phenols 2) 2-aminotriazines 3) 4-
anaerobic organisms. Barett D. et.al 15 have reported
aminopyrimidines 4) 2-aminopyrimidines 5)
new synthetic route for synthesis of pyrido[3,2,1-i,j] Pyrrolo-pyrimidines 6) indazoles and 7) 2-
cinnoline ring system (11) of potent DNA-gyrase hydroxymethyl-indoles.
inhibitors. Ohemeng K.A. et.al 16 have reported When the in-silico screening was performed, the
synthesis and inhibitory activity against DNA-gyrase initial data set containing 3,50,000 compounds could be
of a series of diphenic acid mono-hydroxamides (12). reduced to 3000 molecules. Testing these 3000 selected
Molecular diphenic acid monohydroxamides compounds in the DNA gyrase assay provided 150 hits
indicated that they bind to the DNA-DNA gyrase clustered in 14 classes.
complex in similar fashion as quinolone series. Ma Seven classes could be validated as true, novel
Z. et.al 17 have synthesized a series of 4H-4- DNA gyrase inhibitors that act by
oxoquinolizine derivatives (13) with structural binding to the ATP binding site located on subunit B.
modification at C-8 position and evaluated for their LUDI method was used to dock
antimicrobial activity against gram-positive, gramnegative
small needle type molecules into the binding
and anaerobic organisms. Peixoto C. et.al 18 site. Only those molecules were accepted as valid hits that
have synthesized a series of novel isothiochroman in-silico formed both critical H-bond. LUDI search
2,2-dioxide and 1,2-benzoxathin 2,2-dioxide resulted in a list of 200 molecules that were
compounds (14) and evaluated for their DNA-gyrase tested for their DNA-gyrase
inhibitory activity. Boehm H. et.al 19 have reported inhibitory activity. The CATALYST search
combined approach of an in silico screening for required the precise topological
potential low molecular weight inhibitors, a biased definition of essential ligand enzyme interactions,
highthroughput DNA-gyrase screen, validation of the i.e., H-bond donors/acceptors,
screening hits by biophysical methods and a 3D van der-Waals interactions, and excluded volumes.
guided optimization process. Selected compounds The precise positions and types
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Umesh Shiroya., et al. / International Journal of Advances in Pharmaceutical Research
of these key inter-actions were defined in the cyclothialidine-DNA gyrase X-ray
structure using molecular modeling program MOLOC.
Li Q. et.al 20 have reported synthesis and evaluation of 2-pyridones (15) as bacterial topoisomerase
inhibitors. They have synthesized pyrido-pyrimidines, quinolizine and ofloxacin bioisosteres from quinolones,
naphthridones and evaluated in vivo and in vitro. Gray J.L. et.al 21 have reported synthesis and biological activity of
quinolones without the usual 6-fluorine substituent as potent anti bacterial agents. A series of non-fluorinated
analogues of levofloxacin (16) were synthesized and evaluated for its anti-bacterial activity.
Kerns R.J. et.al 22 have reported the
synthesis of symmetric and asymmetric piperazinyl
linked dimers of the fluoroquinolones and evaluated
for its anti-bacterial activity against drug resistant
strains of S.aureus, including strains possessing
resistant due to the NorA multidrug efflux pump and
a mutation in the quinolone resistant determining
region of topoisomerase-IV. Gordeev M.F. et.al 23
have synthesized and evaluated antimicrobial
compounds incorporating oxazolidinone and
quinolone pharmacophore substructures. Selected
compounds showed an improved potency over
linezolid against gram-positive and gram-negative
pathogens and ciprofloxacin resistant S.aureus and
enteroccous faecium strains. The Mechanism of
action for novel oxazolidinone-quinolone hybrid
antimicrobials was consistent with a combination of
protein synthesis and gyrase-A/ topoisomerase-IV
inhibition. Foroumadi A. et.al 24 have synthesized a
series of N-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-
yl] piperazinyl quinolones (17). Hu X.E. et.al 25 have
reported design and synthesis of novel quinolone
anti-bacterial agents bearing (3S)-amino-(4R)-
ethylpiperidines side-chains (18).
Kuramoto Y. et.al 26 have reported novel
anti-bacterial 8-chloroquinolone with a distorted
orientation of the N 1 -(5-amino-2,4-difluorophenyl)
group. They designed m-aminophenyl groups as
novel N-1 substituents of naphthyridones and
quinolones (19a and 19b). Tanitame A. et.al 27 have
reported synthesis and antibacterial activity of novel
and potent DNA gyrase inhibitors with azole ring.
The 4-piperidyl moiety and pyrazole ring in 1-(3-
chloro phenyl)-5-(4-phenoxyphenyl)-3-(4-
piperidyl)pyrazole were transformed to other groups
such as pyrazole, oxazole, and imidazole derivatives
(20a and 20b) and in-vitro antibacterial activity of
synthesized compounds was evaluated against DNA
gyrase, topoisomerase-IV and quinolone resistant
clinical isolates and coumarin resistant laboratory
isolates of gram positive bacteria with MIC values
equivalent to those against susceptible strains.
Tanitame A. et.al 28 have designed and synthesized a
series of novel indazole derivatives (21a and 21b) as
DNA gyrase inhibitors. The selected compounds
were exhibited potent anti-bacterial activity against
gram-positive bacteria including multidrug resistant
strains, Methicillin resistant S.aureus and
Vancomycin resistant Enterococcus. They have also
studied structure -activity relationship. X-ray studies
of indazole analogues with a 24-kDa fragment of
DNA-gyrase B (PDB code: 1EI1) from S.aureus
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revealed that 1) the indazole scaffold forms
postulated H-bond network with Asp-73 and a water
molecule. 2) the ‘X’ moiety stacked on the Glu-50-
Arg-76 salt bridge and ‘Y’ moiety was H-bonded to
Arg-136. 3) The benzyloxy side chain interacts
vander-waals interaction with the lipophillic area
around Ile-94. They also performed molecular
dynamic simulations for 1ns at 298 K using the
software InsightII/Discover 95.0 with cvff field with
each structure along the trajectory path being energyminimized.
Tanitame A. et.al 29 have designed and
synthesized novel 5-vinyl pyrazole analogues (22) by
the decreasing the lipophilicity of the parent
compound, 3-[(3-methoxycarbonyl) cyclohexyl
aminomethyl] indazole derivatives while keeping the
vander-walls interaction with the lipophilic area of
DNA gyrase-B. The selected compounds showed
good anti-bacterial activity against staphylococci and
enterococci including multi drug resistant strains.
Tran T. P. et.al 30 have reported the synthesis and
structure –activity relationship of 3-
hydroxyquinazoline-2,4-dione (23).
Angehrn P. et.al 31 have reported new antibacterial
agents derived from the DNA-gyrase
inhibitor cyclothialidine (24). From variety of
analogues, they have identified pharmacophoric core.
Based on minimal structure requirements, they have
synthesized novel DNA-gyrase inhibitors of
subclasses like bicyclic lactones of different ring
sizes, seco-derivatives lacking the lactone ring.
Tanitame A. et.al 32 have reported synthesis and antibacterial
activity of pyrazole derivatives (25), as
novel potent DNA-gyrase inhibitors and evaluated
against DNA-gyrase and Topoisomerase-IV.
Schechner M. et.al 33 have reported functionality
maps of the ATP binding site of DNA-Gyrase-B and
generation of a consensus model of ligand
binding. Multiple copy-simultaneous search
method was used to construct functionality maps
for functional groups binding in the ATP binding
site of DNA-gyraseB. Calculations were done for
three different conformations of the 24k-Da
subdomain of DNA-gyraseB. A continuum dielectric
model to include solvent effects was used to calculate
the binding free energy for every functional groups.
The affinities for DNA-gyrase-B were measured and
clustered using procedure based on vander-waals
contacts. The results gave consensus maps that
indicate those functional groups binding sites that
were in sensitive to the specific protein conformation.
The maps also demonstrate that functional groups
other than those found in the known ligands may bind
competitively in the binding sites of known ligands.
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Umesh Shiroya., et al. / International Journal of Advances in Pharmaceutical Research
O
R
O
R 1
N
N
H
O
21a
HN
N
N
H
21b
O R 2
HN
N
NH
22
O
O
R 1
R 3
R 2 N O
N
F
OH
O
23
R 3
S
O
R 2
R 1 O
24
HN
R 4
O
R 5
R 1
R 2 N
N
25
NH
Tanitame A. et.al 34 have reported the
synthesis and anti-bacterial activity of a novel series
of 5-[(E)-2-arylvinyl]pyrazole in 1-(3-chlorophenyl)-
3-(4-piperdyl)-5-[(E)-2-(5-chloro-1H-indol-3-
yl)vinyl]pyrazole (26). Oblak M. et.al 35 have
described fragment-based design of potent DNA
gyrase inhibitors, using the tools of virtual screening
and NMR spectroscopy. They identified binding of
two low molecular weight fragments [2-amino
benzimidazole and indolin-2-one] to the 24-kDa N-
terminal fragment of DNA gyrase-B by 15 N HSQC
NMR spectroscopy of isotopically labeled protein.
They have also done in silico optimization of indolin-
2-one that inhibited the DNA gyrase supercoiling
activity led to the discovery of potent DNA-gyrase
inhibitors. Foroumadi A. et.al 36 have synthesized
and evaluated a series of N-[2-(5-bromothiophen-2-
R 1 4-PhCH 2 O-Ph, 4-CH 3 O-Ph,
4-PhO-Ph, 2-Naphthyl
R 2 H, CH 3 , 3-Cl-Ph, PhCH 2
yl)-2-oxoethyl] and N-[2-(5-bromothiophen-2-yl)-2-
oxoiminoethyl] derivatives of piperazinyl quinolones
(27) as DNA gyrase inhibitors for its anti-bacterial
activity. Hansen T.M. et.al 37 have reported synthesis
and antibacterial activity of 5-methoxy and 5-
hydroxy-6-fluoro-1,8-naphthyridone-3-carboxylic
acid derivatives (28).Selected compounds were
evaluated for cell-free bacterial protein synthesis
inhibition and whole cell antibacterial activity. Fecik
R.A. et.al 38 have reported synthesis of 10-fluoro-6-
methyl-6,7-dihydro-9-piperazinyl-2Hbenzo[α]quinolizin-20-one-3-carboxylic
acid (29) as
chiral DNA gyrase inhibitors. Foroumadi A. et.al 39
have synthesized N-(phenethyl) piperazinyl
quinolone derivatives (30) that bear a methoxyimino
substituent and evaluated for its anti-bacterial activity
against gram-positive and gram-negative organisms.
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Grover G. et.al 40 have synthesized a series
of novel nalidixic acid derivatives having
quinazolones moiety (31) and screened for its antibacterial
and antifungal activity. Wiles J.A. et.al 41
have reported synthesis and biological activity of
isothiazolo pyridines (32), as a new class of antibacterial
agents. Tran T.P. et.al 42 have reported
synthesis and structure-activity relationship of 3-
aminoquinazolinediones (33), a new class of bacterial
type-2 topoisomerase inhibitors (DNA gyrase and
topoisomerase-IV) and evaluated for their antibacterial
activity. Dang Z. et.al 43 have reported the
design and synthesis of novel fluoroquinolone antibacterial
agents (34) having substituted piperidine
ring, which bear an oxime substituent and substituted
amino group in the piperidine ring at the C-7
position. Lubbers T. et.al 44 have reported design and
synthesis of a series of novel 2,3-dihydroisoindol-1-
ones derivatives structurally related to cyclothialidine
with DNA-gyrase inhibitory activity against grampositive
bacterial strains, starting from a biased
needle screening hit. Foroumadi A. et.al 45 have
synthesized a series of levofloxacin analogues
carrying a 2-aryl-2-oxoethyl or 2-aryl-2-
oxyiminoethyl moiety attached to the piperazine ring
(35) at C-10 position. Ostrov D.A. et.al 46 have
identified novel targets for drug interaction that differ
from existing drug binding structural pockets in
DNA-gyrase. They have selected novel DNA-gyrase
inhibitors by high-throughput molecular docking by
using DOCK version 5.1.0 and PDB protein structure
1AB4, 1KIJ and 2SPH. The small molecules were
molecularly docked onto two sites of E.coli DNAgyrase
targeting (1) a previously unexploredstructural
pocket formed at the dimer interface of
subunit A and (2) a small region of ATP binding
pocket on subunit B. This approach identified several
small-molecules that inhibited DNA supercoiling
activity of DNA-gyrase of E.coli.
Gradisar H. et.al 47 have determined
catechins inhibit bacterial DNA-gyrase by binding to
the ATP binding site of the gyraseB subunit. Specific
binding to the N-terminal 24-kDa fragment of gyrase-
B subunit of PDB code: 1AJ6, was determined by
fluorescence spectroscopy and confirmed using
heteronuclear 2D-NMR spectroscopy of the EGCG-
15 N-labeled gyrase-B fragment complex. Four
hydroxyl groups of catechins showed hydrogen
bonding with Gly77, Thr165 and Asp73. Liu X.
et.al 48 have synthesized a series of novel 1-(5-
substituted-3-substituted 4,5-dihydropyrazole-1-
yl)ethanone oxime ester derivatives. Hutchings
K.M. et.al 49 have reported synthesis and antibacterial
activity of a novel series of 3-aminoquinazolinediones
(36). The C-7 side-chain SAR against grampositive
and gram-negative organisms was reported.
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O
HN
S
O
32
N
F
N
R 3
R 4
R 5
R 6
33
O
N
N
R 1
H
N
R2
O
F
N N
HN
R 1 NOR 2
34
O
N
OH
O
X
R
N
N
O
F
N
O
O
OH
35
X H, 4-Br, 4-Cl, 4-F, 4-CH 3 O,
2,4-Cl 2 , 4-CH 3
R O, NOH, NO, Benzyl
Liu X. et.al 50 have synthesized a new series
of 2-(1-(2-substituted –phenyl)-5-methyl-oxazol-4-
yl)-3-(2-substituted-phenyl)-4,5-dihydro-1H-pyrazol-
5-yl)substituted- 1,2,3,4-tetrahydroquinoline
derivatives (37). Ramesh E. et.al 51 have synthesized
novel five tetrahydroquinoline annulated
heterocycles, which has been accomplished by
intramolecular imino and bis-imino Diels-alder
reaction. These compounds were evaluated for its anti
bacterial activity against six different strains, 1)
S.aureus 2) E.coli 3) P.aeruginosa 4) K.pneumonia
5) S.typhimurium 6) B.subtillis, using Disc diffusion
assay. Starr J. T. et.al 52 have reported synthesis of a
series of 5-(2-pyrimidinyl)-imidazo[1,2-a] pyridines
(38) targeting the domains of DNA-gyrase and
topoisomerase-IV. Selected compounds were
efficacious in mouse sepsis and lung infection
models.
Siti R.M. et.al 53 have synthesized two
region isomeric citrate-functionalized ciprofloxacin
conjugates (39). Cellular uptake mechanisms were
investigated using wild-type and ompF deletion
strains of E.coli K-12. Chai Y. et.al 54 have
synthesized a series of novel 7-(4-alkoxyimino-3-
amino-3-methyl piperidin1-yl) fluoroquinolone
derivatives (40). Khalil A.M. et.al 55 have synthesized
a series of novel thiazole and thiophene analogues.
Pokrovkaya V. et.al 56 have designed and synthesized
a series of novel hybrid structures containing
fluoroquinolone and aminoglycoside antibiotics
linked via 1,2,3-triazole moiety. Brvar M. et.al 57
have reported in-silico discovery of 2-amino-4-(2,4-
R 1
F
36
N
O
N
O
NH 2
N
R N N 2
N
O
R 3
37
dihydroxyphenyl) thiazole (41) as novel inhibitors of
DNA-gyrase B. Starting the available structural
information on cyclothialidine, an in silico virtual
screening campaign was designed combing molecular
docking calculations using Flexx software and with
three-dimensional structure based pharmacophore
information, a novel class of thiazoles based
inhibitors with low micromolar antigyrase activity
was discovered. In-silico virtual screening campaign
was designed, taking into account the available
structural from information on binding mode of
cyclothialidine into ATP-binding site of gyrase-B.
The main objective of the virtual screening was to
screen the available compound databases to identify
novel low-molecular inhibitors mimicking the
cyclothialidine molecular recognition pattern. They
searched for potential conformational rigid
replacements of the 12-membered lactone ring in
cyclothialidine that would retain the anti-gyrase B
affinity. The 3D-structure based pharmacophore
model was constructed using ligandscout software. In
the constructed pharmacophore model, three
pharmacophoric features (two hydroxyl groups of
resorcinol moiety for H-bonding with Asp-73 and
Val-43 of gyraseB subunit.and H-bond between Asn-
46 and oxygen of the lactone ring) were used.
Hossion A.M.L. et.al 58 have reported design and
synthesis of a series of novel quercetin
diacylglycosides by steglich esterification on the
basis of MRSA strains inhibiting natural compound
kaemferol diacylrhmnoside.
R 1
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Ronkin S.M. et.al 59 have reported design
and synthesis of novel series of substituted 5-(1Hpyrazol-3-yl)
thiazole (42) as inhibitors of bacterial
gyrase. Structure-guided optimization lead to
greater enzymatic potency and moderate
antibacterial potency against E.coli and S.aureus
gyrase-B subunit. Crystallographic data showed that
pyrazole moiety of substituted thiazole analogues
having binding interaction with Asp-81 and
conserved water molecule in S.aureus gyrase-B (PDB
code: 3G75). Gouda M.A. et.al 60 have synthesized a
series of novel thiazole and pyrazole derivatives
based on 4,5,6,7-tetrahydrobenzothiophene moiety.
Bondock S.et.al 61 have synthesized a series of novel
thiazole, thiophene and pyrazole derivatives
containing benzothiazole moiety. Vijesh A.M. et.al 62
have synthesized a series of novel 2,4-disubstituted
thiazole derivatives containing substituted pyrazole
moiety. Thomas S. et.al 63 has reported design and
synthesis of 2-quinolones as anti bacterials and antioxidants.
They have synthesized lead molecules of
the 2-quinolone skeleton (43) for binding to the
bacterial DNA-gyrase subunit A. Docking
simulations and QSAR analysis were performed
using molegro virtual docker and sarchitech
softwares. Based on these, they have synthesized lead
molecules using Conrad limpach synthesis.
CONCLUSION
In view of the existing literature, it is evident that the
emergence of bacterial resistance to most of the
antibacterials used clinically represents a major
challenge in today’s antibiotic research, outweighing
the task to develop drugs of higher potency,
expanded spectrum of activity, and improved safety
profile. Thus, DNA-gyrase has drawn much attention
as selected target for finding potent anti-bacterial
agents against multi-drug resistant strains.
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