24
CHAPTER 1 A micro review on fluoroquinolones, hetero ring fused quinolones and benzimidazoles
CHAPTER 1
A micro review on fluoroquinolones, hetero ring fused quinolones and
benzimidazoles
Chapter 1 Introduction
1
1.1.0 Quinolones:
1.1.1 Introduction:
The German bacteriologist Paul Ehrlich and his student Sahachiro Hata developed Salvarsan
in 1910 for the treatment of Syphilis, and this was the first synthetic chemotherapeutic agent.
Alexander Fleming isolated Penicillin in 1929 which was the world first antibiotic from
penicillium notatum. At the same time the first sulfa drug was synthesised, and Streptomycin
(an antituberculosis agent), Tetracycline and other antibiotics with excellent antimicrobial
efficacy were found one after another.
After a gap of 30-40 years quinolones were found as new class of compounds widely
prescribed for the treatment of infections in humans. Currently quinolones are the most
interesting group of antibacterial drugs made a major impact on the field of antimicrobial
chemotherapy with broad spectrum of activity.
Structurally, the quinolones consist of 1-substituted-1, 4-dihydro-4-oxo pyridine-3-carboxylic
moiety A combined with an aromatic ring B fused at the 5-and 6-positions.
The first lead structure 7-chloro-1-ethyl-1, 4-dihydro-4-oxo-3-quinolin carboxylic acid1 was
discovered accidentally as a by-product which is a regio isomer of ethyl-7-chloro-4-hydroxy-
3-quinoline carboxylate (Chloroquine intermediate).
The evolution of quinolones started from the discovery of Nalidixic acid in 1962 by George
Lescher as a part of his antimalarial program.2 Fluoroquinolones became neglected group of
antimicrobials till 1970s to early 1980s. Latter they have dominated the market as most
potent antimicrobial agents.
Chapter 1 Introduction
2
A series of rather more potent agents were introduced such as Oxolinic acid,3 more effective
against both Gram positive and Gram negative than Nalidixic acid, Piromidic acid4 was
relatively similar to Nalidixic acid in its spectrum and applications, Pipemidic acid5 has
broader antimicrobial spectrum than Nalidixic acid, Cinoxacin6 has a cinnoline ring rather
than a pyridone ring and it was a bio ester of Oxolinic acid, it has negligible activity against
Gram positive microorganism.
1.1.2 Fluoroquinolones.
In 1978’s Norfloxacin was discovered in Japan and changed the level of enthusiasm towards
Quinolones. It was a better choice than previous agents against gram negative and gram
positive activity. Norfloxacin had a longer half life than earlier compounds (3-4 h), less
protein binding (50%) and improved gram negative activity.7 The addition of a fluorine atom
at 6th position of quinolone resulted 10 fold increase in gyrase inhibition and upto 100 fold
improvement in MIC.
Recently, more focus was given for the synthesis of quinolones, and as on today over 10,000
molecules have been patented. Most important among the fluoroquinolones was
Ciprofloxacin.8 Ciprofloxacin, not only possesses significant anti gram negative and gram
positive activity but also active clinically against Anaerobes, Pseudomonad’s, Enterobacter,
Chlamydia, Rickettsiae and also active against P. aeruginosa and Acinetobacter spp. It is
very active against Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp.,
including β-lactamase producing strains of Neisseria gonorrhoeae. Subsequently several
Chapter 1 Introduction
3
fluoroquinolones entered with fluorine and piperazinyl moieties at 6 and 7 positions namely
Pefloxacin and Ofloxacin,9 revolutionized the chemistry of fluoroquinolones.10,11
N
OCOOH
NEtHN
Norf loxacin
N
OCOOH
NMeN
Ofloxacin
F
N
OCOOH
NHN
Ciprof loxacin
F
N
OCOOH
NEtMeN
Pefloxacin
F
F
OHMe
In continuation of the search for new fluoroquinolones, Levofloxacin was synthesized and
patented by Daiichi Seiyaku Co., Ltd., Tokyo, Japan in 1987. After thorough clinical trials it
was introduced into the market as an anti bacterial drug with trade name of Cravit® in 1993.
Levofloxacin is the optical isomer of Ofloxacin and found to be high potent drug than
Ofloxacin, Ciprofloxacin and other antibacterial agents.12 Levofloxacin also acts against most
strains of bacterial pathogens for respiratory, urinary tract, gastrointestinal, and abdominal
infections. Thiadiazole and benzotriazole tagged Levofloxacin (1, 2) derivatives are also very
active against various bacterial strains. These two derivatives are low potent than
Levofloxacin and more active than Ofloxacin.13
N
OCOOH
NMeN
Levofloxacin
F
ON
O
NMeN
F
OMe
N
O
NMeN
F
O
Me
Me
NH
O
S
NNNH2
Levofloxacin-1
NH
ON N
N
Levofloxacin-2
Chapter 1 Introduction
4
The scientists continued their efforts towards developing more potent fluoroquinolones for
multi drug resistant gram-positive bacteria during the past decade. As a result of these efforts
Gatifloxacin,14 Moxifloxacin,15 Trovafloxacin16 and Gemifloxacin17 drugs were made
commercially available in the market. Gatifloxacin and Moxifloxacin in particular are being
used for the treatment of community-acquired pneumonia caused by streptococcus
pneumonia, including PRSP.
1.1.3 Hetero ring fused fluoroquinolones:
The antibacterial activity of 4-quinolones depends on the nature of peripheral substituent’s
and their spatial arrangements. Hetero ring fused quinolones between N-1 to C-2 positions
with dihydro thiazole and benzothiazoles18-20 showed good anti bacterial activity against
various bacterial strains but no clinical study on these compounds were reported. Though the
carboxylic acid group at C-3 position is essential for antibacterial activity, the replacement of
-COOH group by isothiazolo ring between 2 and 3 positions was found to be more active
than Ciprofloxacin in vitro studies. 21
Chapter 1 Introduction
5
The furan fused quinolones at 6, 7 and 7, 8 positions of quinolones also showed promising
activity.
The hetero ring fused tri and tetra cyclic fluoroquinolones showed excellent activity against
various bacterial strains.22, 23 Ofloxacin is one of the prominent members of benzoxazine 1, 8
bridged quinolones and well accepted in clinical practice.24 Other 1, 8 -bridged fluoro
quinolone derivatives also showing good antibacterial activity.
Chapter 1 Introduction
6
1.1.4 Classification of quinolone antibiotics:
Quinolone antibiotics are broadly classified into four generations based on their antibacterial
spectrum as indicated below.
Classification Agents Antimicrobial spectrum General clinical indications
First
generation
Nalidixic acid
(NegGram)
Gram-negative organisms (but
not Pseudomonas species)
Uncomplicated urinary tract
infections
Cinoxacin
(Cinobac)
Second
generation
Norfloxacin
(Noroxin)
Gram-negative organisms
(including Pseudomonas
species), some gram-positive
organisms (including
Staphylococcus aureus but not
Streptococcus pneumoniae) and
some atypical pathogens
Uncomplicated and
complicated urinary tract
infections and pyelonephritis,
sexually transmitted diseases,
prostatitis, skin and soft
tissue infections
Lomefloxacin
(Maxaquin)
Enoxacin
(Penetrex)
Ofloxacin
(Floxin)
Ciprofloxacin
(Cipro)
Third
generation
Levofloxacin
(Levaquin)
Same as for second-generation
agents plus expanded gram-
positive coverage (Penicillin-
sensitive and penicillin-resistant
Acute exacerbations of
chronic bronchitis,
community-acquired
pneumonia
Sparfloxacin
(Zagam)
Chapter 1 Introduction
7
Gatifloxacin
(Tequin)
S. pneumoniae) and expanded
activity against atypical
pathogens Moxifloxacin
(Avelox)
Fourth
generation
Trovafloxacin
(Trovan)
Same as for third-generation
agents plus broad anaerobic
coverage
Same as for first-, second-
and third-generation agents
(excluding complicated
urinary tract infections and
pyelonephritis) plus intra-
abdominal infections,
nosocomial pneumonia,
pelvic infections
___________________________________________________________________________
1.1.5 Preparation of fluoroquinolones:
General methods of preparation of quinolones are briefly outlined below.
a) Gould-Jacobs method:
3-Chloro-4-fluoro aniline was reacted with diethyl 2-(ethoxymethylene) malonate to give
diethyl 2-((3-chloro-4-fluorophenylamino) methylene) malonate. The latter on cyclisation at
250 oC (in high boiling non-polar solvent; diphenyl ether) furnished 4-hydroxyquinoline. The
alkylation of hydroxyquinolines with alkyl halide followed by hydrolysis of ester afforded N-
alkyl quinolone-3-carboxylic acid derivative. The reaction of a secondary amine with N-alkyl
quinolone produced 6-fluoro-7-secondary aminoquinolone. This method is commercially
applicable for the synthesis of Norfloxacin25 and their derivatives.
Chapter 1 Introduction
8
b) Ullmann-type cyclisation:
2, 4-Dichloro-5-fluoro-benzoyl chloride was reacted with magnesium salt of diethyl malonate
gave diethyl 2-(2, 4-dichloro-5-fluoro-benzoyl)propanedioate. The latter compound in p-
toluenesulfonic acid and water at refluxing temperature furnished ethyl 3-(2, 4-dichloro-5-
fluoro-phenyl)-3-oxo-propanoate. The keto ester on heating with triethyl ortho formate in
acetic anhydride afforded ethyl (Z)-2-(2, 4-dichloro-5-fluoro-benzoyl)-3-ethoxy-prop-2-
enoate. The latter on condensation with cyclopropyl amine in ethanol gave ethyl 7-chloro-1-
cyclopropyl-6-fluoro-4-oxo-quinoline-3-carboxylate. The amino compound was treated with
sodium hydride and DMF to produce cyclized product quinolone which was further
hydrolyzed using sodium hydroxide-water in refluxing dioxane to give 7-chloro-1-
cyclopropyl-6-fluoro-4-oxo-quinoline-3-carboxylic acid. The final step involves reacting
quinolone carboxylic acid with piperazine in dimethylsulfoxide at higher temperature to
afford 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid also called as Ciprofloxacin.26 This method is very useful for the synthesis of
Ciprofloxacin, Tosufloxacin and Trovafloxacin type of N-1 cyclopropyl and N-1 aryl
substitution fluoroquinolones.
Chapter 1 Introduction
9
c) Preparation of 6-membered hetero ring fused quinolones:
Levofloxacin: Levofloxacin27 was launched in 1993 by Daichii pharmaceutical industry in
Japan with trade name of Cravit®, as the world’s first optical active antibacterial quinolone.
Chapter 1 Introduction
10
d) 7, 8 and 1, 8 imidazo fused quinolones preparation:
3-Chloro-4-fluro aniline was reacted with diethyl 2-(ethoxymethylene) malonate to give
diethyl 2-((3-chloro-4-fluorophenylamino) methylene) malonate. The latter on cyclisation at
250 oC (in high boiling non-polar solvent; diphenyl ether) furnished hydroxyquinoline. Then
nitration of hydroxyquinoline with H2SO4/HNO3 mixture afforded ethyl 7-chloro-6-fluoro-4-
hydroxy-8-nitroquinoline-3-carboxylate and replacement of the chlorine atom with
methylamine afforded 6-fluoro-4-hydroxy-N-methyl-7-(methylamino)-8-nitroquinoline-3-
carboxamide. The nitro group was converted into amine in the presence of Pd/C-H2 furnished
8-amino-6-fluoro-4-hydroxy-N-methyl-7-(methylamino)quinoline-3-carboxamide, and this
diaminoquinoline was reacted with aldehyde gave two products which are 7, 8 imidazo fused
quinolines and 1, 8 imidazo fused quinolones.28
Chapter 1 Introduction
11
NH2
F
Cl
F
Cl NH
O
O
OO
N
OH
O
OF
Cl
N
OH
O
OF
ClNO2
N
OH
NH
OMeF
NH NO2
Me
N
OH
NH
OMeF
NH NH2
MeN
OH
NH
OMeF
N
O
NH
OMeF
NN
Me
RN
NH
Me
R
a) EMME,130 oC, 2 h; b) PhOPh, 250 oC, 1 h; c) HNO3 + H2SO4, 5 h; d) Me-NH2, 30 oC,
48 h; e) Pd / C, H2 gas, RT; f) R-CHO, AcOH, 100 oC, 3.5 h.
a b
c
de
f
1.1.6 Fluoroquinolones, their mechanism of action:
Topoisomerase enzymes are important to DNA replication process.29 Bacterial cells have two
essential topoisomerases which are gyrase and topoisomerase IV. DNA is normally
maintained in a super coiled state and in the replication process DNA must be uncoiled,
which can lead to links and breaks throughout the stand. Bacterial DNA gyrase
(topoisomerase-ІІ) breaks to the DNA stands, separates them and reseals the DNA stands in
the DNA replication process. Fluoroquinolones can damage to the DNA gyrase, as a result
leads to the DNA destruction.30, 31 Mammalian species also depend on topoisomerase for
DNA replication, but fluoroquinolones have a greater selectivity for bacterial DNA gyrase
than for mammalian DNA gyrase.
In addition to DNA gyrase fluoroquinolones have a secondary target topoisomerase-ІV.32
This enzyme mediates relaxation of DNA was involved in the unliking of daughter
chromosomes after replication. Disturbance of the action of this enzyme allows the bacterial
DNA to be trapped after replication, leading to cell death. Inhibition of DNA gyrase was
primarily associated with gram negative bacteria, where as inhibition of topoisomerase-ІV
targets gram-positive bacteria.
Chapter 1 Introduction
12
1.1.7 Fluoroquinolones pharmacological aspects:
Fluoroquinolones have the favourable pharmacokinetics compare to the other antibacterial
agents. The primary advantages of quinolones are the good oral bioavailability and the
protein binding in human ranges from 30-100% and 14-32% respectively. Fluoroquinolones
can also be administered intravenously so that they are readily distributed to tissues and
penetrate well into cell and body fluids. Ciprofloxacin, Pefloxacin and Ofloxacin are also
available in the form of intravenous formulations also.
The fluoroquinolones are used for the treatment of complicated and uncomplicated urinary
tract infections and some drugs are used for the administration of gastrointestinal infections
due to their activity against gram-negative bacteria, particularly multiple resistant Shigella
spp, and Salmonella spp. Newer fluoroquinolones are highly useful for the treatment of
various bacterial infections like intra-abdominal infections, nosocomial pneumonia and pelvic
infections.
Fluoroquinolones distribution is very interesting into respiratory tract tissues and fluids, due
to their activity against common respiratory pathogens. These interesting characters may be
useful for the future role in the treatment of bacterial meningitis.33, 34
1.1.8 Fluoroquinolones resistance:
Fluoroquinolone resistance has increased significantly over the past decade, exceeding 25%
resistance in outpatient E. coli samples in some areas. The resistance rate to either
Ciprofloxacin or to Levofloxacin increased from 2.8% (1998–2003) to 11.8% (2004–2007) in
Taiwan and about 25% of healthy individuals living in Barcelona were found to be
intestinally colonized with quinolone-resistant E. coli.
Exposure to antibiotics and incomplete suppression of bystander bacteria can lead to
resistance; this may lead to a poor response to antimicrobial therapy during the next
exposure. Quinolones are showing resistant against gram-positive and gram-negative
bacteria.35 This resistance appears to be the result of one of three mechanisms: alterations in
the quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability or
the development of efflux mechanisms. An intensive research was under progress worldwide
to get new class of fluoroquinolones to overcome the resistance problem.
Chapter 1 Introduction
13
1.2.0 Benzimidazoles:
The development of antimicrobial agents to treat infections has been one of the most
important medical accomplishments of the past century. Despite significant progress in
antimicrobial therapy, infectious diseases caused by bacteria and fungi remain a major
worldwide health problem due to the rapid development of resistance to the existing
antimicrobial drugs. The increased use of antibacterial and antifungal drugs in recent years
has resulted in the development of resistance to these agents36-38 and possible microbial
implications for morbidity, mortality and health care costs have become a serious fear. Even
though, there are large numbers of antimicrobial drugs available for medical use, there will
always be a vital need to discover new agents due to antimicrobial.39, 40
The benzimidazole ring is an important pharmacophore in modern drug discovery and their
synthesis remains a main focus of medicinal research. The benzimidazole ring system as a
nucleus from which to develop potential chemotherapeutic agents was established in 1950s
when it was found as an integral part of the structure vitamin B12.41, 42 The discovery of
thiabendazole43 in 1961 further spurred chemists around the world to design and synthesize
several thousands of benzimidazole molecules for anthelmintic activity and they are very
important intermediates in organic reactions. 44
1.2.1 Importance of benzimidazole derivatives:
a) Antiulcer agents:
The presence of acid is a fundamental factor in the pathogenesis of gastric and duodenal
ulcers, reflux-oesophagitis and nonsteroidal anti-inflammatory drug-induced lesions.45 In
human body many tissues are responsible for the imbalance between aggressive factors (like
acid, pepsin, H. pylori infection) and local mucosa defense (secretion of bicarbonates, mucus
and prostaglandin) results in acid-peptic and duodenal ulcer, gastroesophageal reflux disease,
Zolinger-ellision syndrome and gastritis. This disease seems to have very prominent share in
health disorder in current scenario of globalization.
Chapter 1 Introduction
14
b) Antipsychotic agents:
Benzimidazoles containing piperdinyl moiety46 are useful as antipsychotic agents and as
analgesic.
Chapter 1 Introduction
15
c) Antihelmintic drugs:
Benzimidazoles are most promising drugs as antihelmintic agents. Thiabendazole and
mebendazole are highly effective as broad-spectrum antihelmintic agents. They are used for
the treatment of nematode infestations and treatment of proto myxzoa infestations.
Albendazole is effective against roundworms, tapeworm and flukes of domestic animals and
human.
d) Antimicrobial and fungicidal drugs:
Infectious diseases have been serious and growing threatens to human health during the past
few decades. Several research groups are working in this direction with a focus to prepare or
invent new class of drugs which can withstand to bacterial resistance strains. Fluconazole is
the first line of triazole based antifungal drug recommended by WHO duo to its
pharmacokinetics characteristics. Tri halogen benzimidazoles exhibited the most potent
antibacterial activity with MIC 3.12 μg/ml against S. aureus.47 Number of benzimidazole
derivatives have commercial application for fungal infections.
N
N
NH
NNH
OMeO
ONH
Me
Cl
Benomyl Chlormidazole
F
F
NOH
N
NN
NN
Fluconazole
e) Anti hypertensive drugs:
Benzimidazoles are considered as promising as anti hypertensive drugs.48 Adimol is an anti
hypertensive agent which acts as anon selective α1-, α2-, β-adrenergic receptor antagonist.
Azilsartan medoxomil and Candesartan are acts as angiotension-ІІ receptor antagonist, which
are benzimidazole nucleus containing compounds.
Chapter 1 Introduction
16
NH
NO
HN
OHO
Adimolol
N
NO
O
NHN
NN
HO
Candesartan
f) Anti-inflammatory drugs:
Some of the benzimidazole derivatives act as anti inflammatory agents, like VUF-6002 a
potent and selective antagonist at the histamine H4 receptor.49 It has anti-inflammatory and
analgesic effects in animal studies of acute inflammation.50
g) Antidiabetic drugs:
Rivoglitazone is a thiazolidine dione which contain benzimidazole nucleus was under the
research for the use in the treatment of type-ІІ diabetes.51
Chapter 1 Introduction
17
h) Antiviral drugs:
Maribavir is an oral anti viral drug which is the benzimidazole derivative; it is used for the
prevention and treatment of human cytomeglo virus (HCMV) disease in hematopoietic stem
cell/ bone marrow transplant patients. The mechanism by which inhibits HCMV replication is
by inhibition of an HCMV encoded protein kinase enzyme called UL97 or pUL.52
1.2.2 Importance of imidazole ring:
● Imidazoles are playing key role as synthons or as end products in medicinal chemistry.
● Imidazoles are forming hydrogen bonds with targets which is very important for drugs.
● Fusing or tagging of these imidazoles, the size variations of quinolones are very small.
● Imidazoles may be increasing lipophilicity of the drugs due to their hydrogen bonds.
1.3.0 Importance of trifluoromethyl group:
● Electro negativity of trifluoromethyl group is intermediate between Cl and F.53
● Lipophilicity parameters of CF3 group are more than Cl and F.
● Trifluoromethyl group increases the lipophilicity and drug stability.
● Fluorinated derivates often exhibit improved bioavailability.
● Increased lipophilicity leading to a smaller effective dose.54
Chapter 1 Introduction
18
1.4.0 Current strategies:
The major problem in the recent times was the resistance of bacterial strains towards certain
fluoroquinolones and other antibacterial agents across the world. In order to meet this
problem several strategies were planned to synthesize new class of compounds such as
combination of two active pharmacophores to make the hybrid molecules or fusion of two
active ring systems to make hetero ring fused bioactive molecules. The hybrid molecules
concept was first adopted by Lescher55 and his co-workers for antimalarial activity with an
idea that presence of two pharmacophores in single molecule may enhance the activity. Other
strategy was to prepare hetero ring fused quinolones such as isothiazolo fused, furon fused,
imidazole fused fluoroquinolones at 1, 2 or 2, 3 or 5, 6 or 1, 8 positions of quinolones moiety.
In some cases enhanced activity was found than the standard Ciprofloxacin.
1.5.0 Present work:
Present work has been designed for the preparation of novel imidazo fused quinolones and
evaluation of their activity was conveniently divided in to 6 chapters:
Chapter 1: This chapter describes a micro review of various antibacterial drugs, discovery
and antibacterial activity of quinolones, fluoroquinolones and hetero ring fused quinolones,
mechanism of action, pharmacological aspects of fluoroquinolones. It also covers the
introduction about the benzimidazoles and their medicinal importance.
Chapter 2: The second chapter deals with the preparation of benzimidazoles, separation and
characterisation of positional isomers of 1-alkyl-2-perfluoroalkyl-5 or 6-substituted
benzimidazoles. Experimental procedures adopted for the above compounds. The activity
studies are included in chapter-6.
Chapter 3: Chapter three describes the synthesis of imidazole ring fused quinolones, and
their characterisation, influencing factors for formation of angular (5, 6-imidazo fused) form
of imidazo fused quinolones. Experimental procedures adopted for the imidazofused
quinolone derivatives. The activity data was included in chapter-6.
Chapter 4: This chapter deals with the importance of amide bond in medicinal research,
preparation of imidazo fused quinolone carboxamides and preparation of linear (6, 7-imidazo
Chapter 1 Introduction
19
fused) form of imidazo fused quinolone and it’s characterization. Experimental procedures
are also included. The activity data of compounds are included in chapter-6.
Chapter 5: The method development for the N-alkylation of amines using alcohols as
alkylating agents, mechanistic aspects are described. Environmentally benign method for the
preparation of benzimidazoles and experimental procedures were described.
Chapter 6: This chapter covers the introduction about the anti bacterial agents, evaluation of
the compounds synthesized in chapter-2, chapter-3 and chapter-4 for their anti bacterial
activity, supporting data by molecular modelling studies.
1.6.0 References & notes:
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1358-1363.
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564.
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Chapter 1 Introduction
20
14. M. Hosaka, T. Yosue, H. Fukuda, H. Tomizawa, K. Hirai. Antimicrob. Agents
Chemother., 1992, 36, 2108-2117.
15. U. Peterson, K.D. Bremm, A. Dalhoff, R. Endermann, W. Healmann, A. Krebs, T.
Schenke. New Orleans, L.A, 1996; Abstract F1.
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Castaldi, S. A. Miller. Anaheim., CA 1992, Abstract 751.
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Kand Tsudo. US Patent 4 426 381, 1984
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Chemother., Houston, 1989, Abst. 1250.
23. J. Nakano, T. Hirose, K. Yamamoto, K. Shibamori, M. Fujita, M. Kataoka, H. Okada,
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1358-1363.
26. K. H. Grohe and J. Zeiler., (Bayer A.-G.), DE 3,142,854 Al.
27. Lester A. Mitscher, Padam N. Sharma, Daniel T. W. Chu, Linus L. Shen, Andre G.
Pernet. J. Med. Chem., 1987, 30 (12), 2283-2286
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Kishore, U.S.N. Murthy, B. Ravi, B. Ashok Kumar, T, Parthasarathy. Eur J. Med.
Chem., 2009, 44, 1570-1578.
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30. D M. Boothe. antibiotic drugs, W B Saunders., 2001, 162-166.
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32. E. L. Zechiedrich, W. R. Cozzarelli. Genes Dev., 1995, 9, 2859-2869,
Chapter 1 Introduction
21
33. K. W. Garey, G. W. Amsden, Trovafloxacin: an overview. Pharmacotherapy, 1999,
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Antimicrob Chemother., 1997, 39 (suppl B), 1-14.
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