Med Chem Res
DOI 10.1007/s00044-012-0101-3
REVIEW ARTICLE
Quinolone derivatives as antitubercular drugs
Mohammad Asif • Anees A. Siddiqui •
Asif Husain
Received: 3 January 2012 / Accepted: 15 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract New chemotherapeutic drugs are the need to
improve tuberculosis (TB) control particularly due to the
emergence of multidrug-resistant strains and extensively
drug-resistant strains of TB. These antitubercular com-
pounds have different chemical moieties in their structure.
Quinolones are generally used against many Gram-positive
and Gram-negative bacteria. They are also active against
atypical mycobacteria. Some quinolones (ciprofloxacin,
levofloxacin, etc.) inhibit strains of Mycobacterium tuber-
culosis at concentrations \2.0 lg/mL. Fluoroquinolones
are an important recent addition to the drugs available for
TB, especially for strains that are resistant to first-line
agents. The present review provides an overview of the
drugs that are being used have quinolone moieties in TB
treatment.
Keywords Tuberculosis
Chemotherapeutic agents

Multidrug-resistant
Quinolones
Introduction
Mycobacterium tuberculosis, the leading causative agent of
tuberculosis (TB), is responsible for the morbidity and
mortality of a large population worldwide. The organism
infects about 32 % of the world’s population. According to
M. Asif (&)
Department of Pharmacy, Guru Ram Das (PG) Institute
of Management and Technology, 214-Rajpur Road,
Dehradun 248009, Uttarakhand, India
e-mail: aasif321@gmail.com
A. A. Siddiqui
A. Husain
Faculty of Pharmacy, Jamia Hamdard University,
New Delhi, India
MEDICINAL
CHEMISTRY
RESEARCH
a WHO report, by 2020 AD nearly one billion more people
will be infected, 200 million people will get sick and 70
million will die from TB if proper steps are not taken to
control it (WHO, 2004; Dye et al., 1999). The main
obstacles to the global control of the disease are the HIV
epidemic that has dramatically increased risk for devel-
oping active TB, the increasing emergence of multidrug-
resistant-TB (MDR-TB) and the recalcitrance of persistent
infections to treatment with conventional antituberculosis
drugs (Corbett et al., 2003; Gomez and McKinney, 2004;
Smith et al., 2003). The situation is exacerbated by the
increasing emergence of extensively drug-resistant (XDR)-
TB (CDC, 2006). XDR-TB is characterized by resistance to
at least the two first-line drugs rifampicin (RIF) and current
chemotherapy for TB largely relies on drugs that inhibit
bacterial metabolism with a heavy emphasis on inhibitors
of the cell wall synthesis (Zhang, 2005).
According to their mode of action, first- and second-line
TB drugs can be grouped as cell wall inhibitors [isoniazid
(INH), ethambutol, ethionamide, cycloserine], nucleic acid
synthesis inhibitors (RIF, quinolones), protein synthesis
inhibitors (streptomycin, kanamycin) and inhibitors of
membrane energy metabolism (pyrazinamide) (Al-Deeb
and Alafeefy, 2008; Trivedi et al., 2008; Islam et al., 2008).
Existing TB drugs are, therefore, only able to target actively
growing bacteria through the inhibition of cell processes
such as cell wall biogenesis and DNA replication. This
implies that current TB chemotherapy is characterized by an
efficient bactericidal activity but an extremely weak steril-
izing activity, defined as the ability to kill the slowly
growing or slowly metabolizing bacteria that persist after the
growing INH and additionally to a fluoroquinolone and an
injectable drug (kanamycin, amikacin, or capreomycin)
among the second-line drugs (Kaufmann et al., 2005;
Grosset and Ji, 1998; Hirata et al., 1995). The extensive
123
 Med Chem Res

H 3C
O NH NH 2 O
N NH
HO
NH 2 OH
NH

N N CH 3

Isoniazid Pyrazinamide Ethambutol

NH

H 2N NH
CH3 CH3
HO OH
HO

OH H 2N NH OH
AcO O
CH3
O R O
O
H 3 CO OH OH CH3
H 3C H
H 3C H 3C
HOH 2 C HO O
N
O
O N
OH
O N HO
CH3 O R HO
NHCH 3

R = CH 3 Rifampicin R = CHO Streptomycin R = CH 2 CH(CH 3 ) 2 Rifabutin

R = CH 2 OH dihydrostreptomycin R= Rifapentine
Fig. 1 Structures of first-line antitubercular agents

resistance makes this form of TB particularly cumbersome
to treat with available drugs. The current situation clearly
demonstrates the need for a re-evaluation of our approach to
treating TB (Figs. 1, 2, 3, 4, 5).
Drug development for TB and other neglected diseases
has been at a virtual standstill for decades, but increased
awareness and advocacy in recent years have led to new
initiatives in TB drug development. MDR-TB and
XDRTB are even more complex and expensive to treat,
and in developing countries treatment is limited to a few
projects with limited numbers of patients. The main cri-
teria established by the TB alliance to select drug candi-
dates for further development are shortening of the current
treatment, activity against MDR-TB and XDRTB, and
lack of interactions with antiretroviral drugs represent.
There are a sufficient number of promising compounds in
the TB pipeline for a broadly effective new treatment
combination to be developed. Whilst analogues and
derivatives are far quicker to develop, they may be subject
to cross-resistance, as has been the case with the new
quinolones (Russell, 2001; Shafii et al., 2008; Sirgel et al.,
2000; Snider, 1994; Sun and Zhang, 1999; Temple and
Nahata, 1999).
New drugs are needed for TB chemotherapy
To shorten the total duration of treatment and/or signifi-
cantly reduce the number of doses needed to be taken under
DOT, improve the treatment of MDR-TB and provide a
more effective treatment of latent TB infection shortening
of the current treatment, activity against MDR-TB. In order
to shorten the development time for a new regimen, TB
alliance is working on both identifying individual novel
compounds and developing new drug combinations. In
order to analyse, drug candidates are currently grouped in
two main categories: novel chemical entities and com-
pounds originating from existing families of drugs, where
innovative chemistry is used to optimize the compounds
(Primm et al., 2000; Rattan et al., 1998; Reynolds et al.,
1999; Wayne and Sohaskey, 2001; Weil, 1994; Yew et al.,
1990).
Compounds originating from quinolone family of drugs
Nalidixic acid, the first antibacterial quinolone, was intro-
duced in 1963. It is not fluorinated and is excreted too

123
Med Chem Res

NH 2
HO OH HO
NH2 O O
H
H 2N N NH2
O NH N
O NH OH OH O H
O NH HN
H
OH O H 2N NH N O
O
NH 2 CH 3 H
H 2N O
O
HN H 2N
H 2N NH
OH
OH H 2N N O

Amikacin Capreomycin

Cylcoserine
H 2N
O

NH2
HN
HO O HN
H H
OH
N
HN N OH HO
HO O H HO
HO O OH
O N N O
H H H 2N O
OH HO NH 2
O HO
O
O
NH2
NH 2
H 2N H2 N

Viomycin Kanamycin
Fig. 2 Structures of different antibiotics (second-line drugs)

rapidly to be useful for systemic infections. Oxolinic acid
and cinoxacin are similar in structure and function to
nalidixic acid. Their mechanism of action is the same as
that of the fluoroquinolones. These agents were useful only
for the treatment of urinary tract infections and are rarely
used now, having been made obsolete by the more effica-
cious fluorinated quinolones. The important quinolones are
synthetic fluorinated analogs of nalidixic acid. They are
active against a variety of Gram-positive and Gram-nega-
tive bacteria. Quinolones block bacterial DNA synthesis by
inhibiting bacterial topoisomerase-II (DNA gyrase) and
topoisomerase-IV. Inhibition of DNA gyrase prevents the
relaxation of positively supercoiled DNA that is required
for normal transcription and replication. Inhibition of
topoisomerase-IV interferes with separation of replicated
chromosomal DNA into the respective daughter cells dur-
ing cell division (Alangaden and Lerner, 1997; Flamm
et al., 1995). Fluorinated derivatives (ciprofloxacin, levo-
floxacin, etc.) have greatly improved antibacterial activity.
Some quinolones such as ciprofloxacin and levofloxacin
inhibit strains of M. tuberculosis at concentrations \2 lg/
mL. They are also active against atypical mycobacteria.
Ofloxacin was used in the past, but levofloxacin is
preferred because it is the L-isomer of ofloxacin (racemic
mixture). Levofloxacin tends to be slightly more active in
vitro than ciprofloxacin against M. tuberculosis; cipro-
floxacin is slightly more active against atypical mycobac-
teria. Serum concentrations of 2–4 and 4–8 lg/mL are
achieved with standard oral doses of ciprofloxacin and
levofloxacin, respectively. Fluoroquinolones are important
drugs for TB, especially for strains that are resistant to first-
line agents. Resistance, which may result from any one of
several single point mutations in the gyrase A subunit,
develops rapidly if a fluoroquinolone is used as a single
agent; thus, the drug must be used in combination with two
or more other active agents. The standard dosage of cip-
rofloxacin is 750 mg orally twice a day and levofloxacin is
500–750 mg as a single daily dose (Garay, 2004; Hong
Kong Chest Service/British Medical Research Council
1992; Nikonenko et al., 2004).
Quinolones as antibacterial and antitubercular agents
The narrow antibacterial spectrum of nalidixic acid (lim-
ited to Enterobacteriaceae) was first expanded through

123
 Med Chem Res

O F COOH O
F COOH F COOH
H
N N
H 3C
N N OCH 3 N N
N N H HN OCH 3
H 3C H

Ciprofloxacin Moxifloxacin R/S: Gatifloxacin

NH2 O O
O
F COOH F COOH
F COOH
H 3C H 3C
N N N N
N N HN F HN C 2H5
N O
H3C CH3 CH3 CH3

R/S : Ofloxacin Sparfloxacin Enofloxacin

S : Levofloxacin

O
F COOH

H N
F
H2N
H

Trovafloxacin

Fig. 3 Structures of different fluoroquinolones (second-line drugs)

N COOH
S NH2
S NH2 OH

N S

CH3
N S NH2 N CH3

Ethionamide Thioridazine p -Aminosalicylic acid Prothionamide

Fig. 4 Structures of different second-line drugs

drugs such as norfloxacin, pefloxacin, ofloxacin and cip-
rofloxacin to improve the utility for treating Gram-negative
bacterial infections. These were followed by drugs, e.g.
temafloxacin, sparfloxacin, grepafloxacin and gatifloxacin
(GTF), which, whilst maintaining Gram-negative activity,
had additional effects on Gram-positive microbes. More
recently, the bacterial profile of the quinolones has been
enlarged again by such drugs as clinafloxacin, trovafloxa-
cin, gemifloxacin and moxifloxacin (MXF) to encompass
anaerobic bacteria. In general, these drugs are well toler-
ated (Stahlmann and Lode, 1999) but, in some cases, side
effects have been sufficiently severe to cause withdrawal
from the market (grepafloxacin—cardiotoxicity; trova-
floxacin—hepatotoxicity). In line with the expanding

123
Med Chem Res
H 3C
O
O
H 3C
CH 3
CH 3
H 3C
HO O O
OH
O H 3C
O CH 3
CH 3 CH 3
O OH
HO
Clarithromycin
Fig. 5 Structures of drugs for HIV/TB
indications for the quinolones, a number of these com-
pounds have shown promise for the treatment of myco-
bacterial infections. Ciprofloxacin and ofloxacin are
currently finding utility as second-line or alternative TB
drugs. However, resistance to these drugs develops quickly
when used as single agent treatments or as add-ons to other
drugs which are already failing (Sullivan et al., 1995).
Consequently, in seeking to evaluate the potential of the
latest generation of quinolones as TB treatments, the issue
of cross-resistance to the existing drugs needs to be
addressed—possibly by pursuing compounds inherently
more bactericidal than ofloxacin and ciprofloxacin. A fur-
ther advance would be to select quinolones with increased
half lives to facilitate once-daily dosing.
Several newer quinolones have improved activity
against Gram-positive cocci. Methicillin-susceptible strains
of S. aureus are generally susceptible to these fluoroquin-
olones, but methicillin-resistant strains of staphylococci are
often resistant. Streptococci and enterococci tend to be less
susceptible than staphylococci, and efficacy in infections
caused by these organisms is limited. Ciprofloxacin is the
most active agent of this group against Gram negatives,
P. aeruginosa in particular. Levofloxacin, the L-isomer of
ofloxacin and twice as potent, has superior activity against
Gram-positive organisms, including Streptococcus pneu-
moniae. GTF, MXF, sparfloxacin and trovafloxacin com-
prise a third group of fluoroquinolones with improved
activity against Gram-positive organisms, particularly
S. pneumoniae and to some extent staphylococci. Fluoro-
quinolones also are active against agents of atypical
pneumonia (e.g. mycoplasmas and chlamydiae) and against
intracellular pathogens such as legionella species and some
mycobacteria, including M. tuberculosis and M. avium
complex. MXF and trovafloxacin, in addition to enhanced
Gram-positive activity, also have good activity where other
fluoroquinolones lack against anaerobic bacteria (Bagchi
et al., 2007; Daffe et al., 2007; Flynn and Chan, 2001;
H 3C
O
CH 3
OH N
CH 3
O NH NH 2
S N
S
H 3C
Thioacetazone
Glickman et al., 2006; Global Alliance for TB Drug
development, 2001; Herbert et al., 1996).
Fluoroquinolones
Fluoroquinolones were introduced into clinical practice in
the 1980s. Characterized by broadspectrum antimicrobial
activity, they are recommended and widely used for the
treatment of bacterial infection of the respiratory, gastro-
intestinal and urinary tracts. Fluoroquinolones have also
been found to have activity against M. tuberculosis
(Grosset, 1992) and are currently part of the recommended
regimen as second-line drugs. Since fluoroquinolones share
the same molecular targets, it is highly probable that they
will trigger the same mechanisms of resistance. Indeed,
cross-resistance has been reported within the fluoroquino-
lone class such that reduced susceptibility to one fluoro-
quinolones likely confers reduced susceptibility to all
fluoroquinolones (Alangaden et al., 1995; Ruiz-Serrano
et al., 2000; Ginsburg et al., 2003a). The major concern is
that widespread use of fluoroquinolones for treatment of
other bacterial infections may select for resistant strains of
M. tuberculosis. Fluoroquinolones susceptibility is not
routinely assessed in clinical isolates of tubercle bacilli, so
there is not much information available about the preva-
lence of fluoroquinolone resistance in M. tuberculosis. In a
study, among referral samples isolates, resistance to cip-
rofloxacin was assessed and was found to occur in 1.8 % of
isolates. Of those, 75.8 % were also MDR. They concluded
that despite the widespread use of fluoroquinolones for
treatment of common bacterial infection, resistance to
fluoroquinolones remains rare and occurs mainly in MDR
strains (Bozeman et al., 2005).
In contrast, the incidence of M. tuberculosis fluoro-
quinolone resistance in a small sample of patients with
newly diagnosed TB was found to be high among patients
with prior fluoroquinolone exposure. Cross-resistance was
123

observed among the different fluoroquinolones tested
(ofloxacin, levofloxacin, GTF, MXF and ciprofloxacin)
(Ginsburg et al., 2003b). In the Philippines, where fluoro-
quinolone use is poorly controlled, among 117 TB patients,
fluoroquinolone resistance occurred in 53.4 % of those
with M. tuberculosis resistant to four or five drugs, in
23.3 % with resistance to three drugs and in 18.2 % with
resistance to two drugs. Because of the high prevalence of
TB in the Philippines, fluoroquinolones are not included in
the clinical practice guidelines for the treatment of com-
munity-acquired pneumonia. In conclusion, there are rea-
sons for concerns about the rapid development of
resistance particularly when fluoroquinolones are admin-
istered as the only active agent in a failing multidrug
regimen. Moreover, the risk of selecting fluoroquinolone-
resistant M. tuberculosis strains, by empirically treating
with fluoroquinolones other presumed infections before a
diagnosis of TB is established, is of great concern. For this
reason, some investigators in the TB field argue that the use
of fluoroquinolones might be better reserved for specific
serious infection such as fluoroquinolones act by inhibiting
DNA topoisomerase-IV and DNA gyrase, enzymes that
control DNA topology and are vital for cellular processes
that involve duplex DNA, namely replication, recombina-
tion and transcription (Lewin et al., 1991; Willmott et al.,
1994). By inhibiting these enzymes, fluoroquinolones
block DNA replication and induce DNA damage, trigger-
ing a set of still poorly defined events, which result in
eventual cell death. Fluoroquinolone-dependent inhibition
of RNA synthesis, and as a consequence protein synthesis,
is also thought to contribute to the bactericidal activity of
this class of drugs (Lewin et al., 1991; Willmott et al.,
1994). Unlike most other bacterial species, M. tuberculosis
lacks genes encoding for topoisomerase-IV as revealed by
the full genome sequence. Therefore, the main molecular
target for fluoroquinolones in M. tuberculosis is the DNA
gyrase (Onodera et al., 2001; Aubry et al., 2004). Con-
sistently, resistance to fluoroquinolones in clinical isolates
of M. tuberculosis occurs primarily due to mutations in the
quinolone resistance-determining region (QRDR) of the
gyrA gene, which encodes for the A subunit of DNA
gyrase (Sullivan et al., 1995; Kocagoz et al., 1996). Other
mechanisms, such as mutations in the B subunit of DNA
gyrase, decreased cell permeability to the drug, and an
active drug efflux pump mechanism could also be involved
in triggering resistance. In particular, the expression or
overexpression of energy-dependent efflux pumps that can
actively remove antibacterial agents from the cell has been
shown to play a role in determination of fluoroquinolone
resistance (Li et al., 2004; Zhanel et al., 2004; Brenwald
et al., 1998) TB rather than becoming the workhorse of
antimicrobial treatment; however, given the current wide-
spread use of quinolones this might not be realistic. Later,
123
Med Chem Res
the interest on fluoroquinolones as antituberculosis agent
has focused on the new fluoroquinolones MXF and GTF.
Despite a lack of a comprehensive work comparing the
activities of old and new classes of fluoroquinolones in
M. tuberculosis, what can be inferred from published
results is that MXF and GTF are characterized by a higher
activity against M. tuberculosis in vitro when compared
to the old fluoroquinolones ofloxacin and ciprofloxacin
(Hu et al., 2003; Paramasivan et al., 2005; Rodriguez et al.,
2001; Sulochana et al., 2005). These new compounds are
currently taken in consideration as antituberculosis first-
line drugs.
Quinolones PD 161148 and CS-940
The title compounds, despite obvious structural similari-
ties, were synthesized (Biedenbach et al., 1995). Both have
been selected on the basis of their potent broadspectrum
activity against Gram-negative, Gram-positive and anaer-
obic bacteria, and have been tested against a variety of
mycobacteria in comparison to other quinolones. Unfor-
tunately, since these studies were conducted by two dif-
ferent groups, no comparative data between the two
compounds are available. CS-940 was screened against 100
clinical isolates of M. tuberculosis and, along with spar-
floxacin, was found to be have an average IC50 of
0.25–0.5 lg/mL and to be more potent than ofloxacin,
ciprofloxacin and balofloxacin (IC50s of 0.5–2.0 lg/mL),
with norfloxacin (IC50s of 8–16 mcg/mL) being the least
active. PD 161148 was also tested against various clinical
isolates of M. tuberculosis where it was compared with the
desmethoxy analogue and ciprofloxacin and found to be
some three- to fourfold more active. Against ciprofloxacin-
resistant strains, the presence of the C-8 methoxy group
in PD 161148 enhanced lethality. Both PD 161148 and
CS-940 are amongst the most active of all third-generation
quinolones but unfortunately there are no in vivo TB data
in the public domain which would allow the two com-
pounds to be further separated. Structural considerations
do, however, suggest that, of the two, PD 161148, which
contains only one fluorine atom, might be less expensive to
manufacture and have a lower propensity to induce
phototoxicity.
Sitafloxacin
The Daiichi quinolone sitafloxacin (DU-6859a) has out-
standing activity against a broad range of bacteria. When
compared to a number of other quinolones–ciprofloxacin,
trovafloxacin, clinafloxacin, levofloxacin, GTF and MXF–
sitafloxacin was the most active against 3,344 Gram-
positive cocci and 406 anaerobes, and against 5,046
Gram-negative bacteria it either equalled or bettered
Med Chem Res
clinafloxacin. The mechanistic basis for this potency is
believed to reside with sitafloxacin’s ability to equally
inhibit both DNA gyrase and topoisomerase-IV, and its
IC50s against these enzymes were amongst the lowest of
the quinolones (Onodera et al., 2001). Sitafloxacin was
equipotent with GTF and sparfloxacin, and more active
than levofloxacin and ofloxacin, when tested against
M. tuberculosis—minimal inhibitory concentrations
(MICs) at which 90 % of strains of M. tuberculosis
inhibited (MIC90s) were *0.2 lg/mL. No data appear to
have been published for the activity of the compound
against M. tuberculosis in vivo. In clinical studies of sita-
floxacin in healthy volunteers oral bioavailability was at
least 70 %; it was well tolerated with no serious adverse
effects and the elimination half life was 4.4–5 h. The latter
parameter casts some doubt upon a once per day dosing
schedule for this drug. However, a study in which the
postantibiotic effect was determined for sitafloxacin (and
several other quinolones) against various bacteria con-
cluded that this factor would permit dosing on a once every
24 h basis (Houston and Jones, 1994).
Gemifloxacin
Gemifloxacin is another quinolone for the treatment of
respiratory infections (ID Weekly Highlights, 2000). In
healthy volunteers, oral bioavailability is approximately
70 %, it is well tolerated and has a mean elimination half
life of 7.4 h. These characteristics, coupled with its potent
antibacterial activity, suggest its suitability for a once-
daily dosing regimen. Data on the antituberculosis
potential of gemifloxacin appear to be limited to a report
comparing its activity to five other quinolones against 250
clinical isolates of M. tuberculosis susceptible or resistant
to first-line antituberculosis drugs. In these assays, gemi-
floxacin showed a MIC90 value of 8 lg/mL, compared
with 1 lg/mL for levofloxacin, trovafloxacin and grepa-
floxacin (Ruiz-Serrano et al., 2000). Extrapolating these
data to serum concentrations seen in healthy volunteers
suggests that, even at the highest non-toxic dose tested
(800 mg), gemifloxacin would not be effective for TB
treatment.
T-3811ME
T-3811ME is unique amongst the other broadspectrum
quinolones featured in this report in that it lacks the pres-
ence of a fluorine atom at the 6-position of the ring. Since
the synthesis of norfloxacin, virtually all the quinolones of
interest have contained this structural feature. However, the
Toyama compound shows similar broadspectrum and
potent activity against bacteria as the best of the fluoro-
quinolones. Against ten strains of M. tuberculosis,
T-3811ME has an MIC90 value of 0.0625 lg/mL when
compared with ciprofloxacin and levofloxacin, and more
active than trovafloxacin. No other TB-relevant data appear
to have been published but the compound is being
advanced for other bacterial indications.
Gatifloxacin
GTF has been found to have in vitro and in vivo bacteri-
cidal activity against M. tuberculosis (Hu et al., 2003;
Alvirez-Freites et al., 2002). In an in vitro study using
stationary-phase mycobacterial culture, GTF (4 lg/mL)
showed the highest bactericidal activity during the first
2 days but not thereafter (Paramasivan et al., 2005). Sim-
ilar results were obtained when GTF was used in combi-
nation with INH or RIF: GTF was able to slightly increase
the bactericidal activity of INH or RIF only during the first
2 days (Paramasivan et al., 2005). This is in contrast with
other studies showing that GTF and MXF had similar
bactericidal activity on a stationary-phase culture of
M. tuberculosis and comparable to the bactericidal activity
of RIF (Hu et al., 2003; Lenaerts et al., 2005). One paper
reported that when tested in mice in combination with
ethionamide and pyrazinamide (high doses: 450 mg/kg,
5 days/week) GTF was able to clear the lungs of infected
animals after 2 months of treatment (Cynamon and Skla-
ney 2003). Thus, currently available data on GTF do not
support the hypothesis that introduction of GTF in first-line
regimen will impressively contribute to shorten TB treat-
ment. Further investigation should be addressed to properly
assess the activity of GTF in vitro and in mouse models.
Nevertheless, GTF is currently in Clinical Trials. The aim
of the trial is to evaluate the efficacy and safety of a
4 months GTF-containing regimen for the treatment of
pulmonary TB.
Moxifloxacin
MXF is the most promising of the new fluoroquinolones
being tested against M. tuberculosis. In vitro, MXF
appeared to kill a subpopulation of tubercle bacilli whereas
RIF could not, i.e. RIF-tolerant persisters, while the older
fluoroquinolones, ciprofloxacin and ofloxacin did not have
any significant bactericidal effect on the same subpopula-
tion (Hu et al., 2003). One possibility is that MXF inter-
feres with protein synthesis in slowly metabolizing bacteria
through a mechanism that differs from that used by RIF.
However, the molecular mechanisms beyond such a bac-
tericidal activity still await further characterization. In
mouse models, the activity of MXF against tubercle bacilli
was comparable to that of INH (Miyazaki et al., 1999).
Moreover, when used in combination with MXF and
123

pyrazinamide, MXF has been reported to kill the bacilli
more effectively than the INH ? RIF ? pyrazinamide
combination. Indeed, cultures from lungs of mice treated
with RIF–MXF–pyrazinamide for 2 months followed by
RIF–MXF resulted negative upon 4 months of treatment,
while mice that received RIF–INH–pyrazinamide/RIF–
INH showed MXF appears to be a poor substrate for efflux
pumps in other pathogens such as S. pneumonia. This
might be due to the bulky C-7 substituent that characterizes
this compound. In contrast, older and more hydrophilic
fluoroquinolones such as ciprofloxacin are more suscepti-
ble to be actively exported outside the bacterial cell
(Daporta et al., 2004; Coyle et al., 2001; Pestova et al.,
2000). In vitro, MXF inhibitory activity of DNA gyrase is
higher than ofloxacin but comparable to ciprofloxacin
(Aubry et al., 2004). In S. pneumoniae, MXF maintained
clinically useful level of activity against bacterial strains
that bore mutations in the QRDR region of gyrA genes,
suggesting that MXF could target other key domains in the
DNA gyrase enzyme (Pestova et al., 2000), complete cul-
ture conversion after 6 months of treatment (Nuermberger
et al., 2004a). Furthermore, no relapse was observed in
mice treated for at least 4 months with the combination of
RIF–MXF–pyrazinamide, while mice treated with RIF–
INH–pyrazinamide required 6 months of treatment before
no relapse could be detected (Nuermberger et al., 2004a,
b). The authors explain the better activity of the RIF–
MXF–pyrazinamide combination over the RIF–INH–pyr-
azinamide combination as the consequence of a possible
synergism in the antituberculosis activity of the three drugs
RIF, MXF and pyrazinamide. Alternatively, substitution of
MXF with INH in the standard regimen could relieve a
possible antagonism among the currently used drugs
(Grosset et al., 1992).
The Bayer quinolone MXF (BAY12-8039) (Barman
Balfour and Lamb, 2000) is the newest member of this
fourth-generation class of antibiotic to progress through
the clinical pipeline. It has recently been launched in
Germany (1999) for the treatment of respiratory tract
infections (ID Weekly Highlights, 2000), and wider reg-
istration is now being sought. In November 1999, the US
(FDA) advisory panel recommended MXF for approval
for skin and soft tissue infections, acute sinusitis, com-
munity-acquired pneumonia and acute exacerbation and
chronic bronchitis. Because other quinolones have been
associated with cardiac QT prolongation or arrhythmia,
the final approval will be based on assessment of safety
considerations. However, in the period 1999–2000, 1.2
million patients in Germany were treated with the drug
and no ventricular arrhythmia attributable to QT prolon-
gation was observed (ID Weekly Highlights, 2000). The
drug has been shown to be active against M. tuberculosis
123
Med Chem Res
in vitro and in vivo in various test systems (Miyazaki
et al., 1999). Against M. tuberculosis CSU93, a highly
virulent, recently isolated clinical strain, the MIC of MXF
was 0.25 lg/mL. Oral administration of drug to mice at
100 mg/kg produced peak serum concentration of 7.8 lg/
mL within 0.25 h of dosing. On this basis, mice were
infected with a sublethal inoculum of M. tuberculosis
CSU93 and then treated with MXF at 100 mg/kg/day for
8 weeks. In other studies in M. tuberculosis H37Rv-
infected mice, orally administered moxidectin at 100 mg/
kg/day given six times weekly was as bactericidal as INH
at 25 mg/kg over a similar dosing schedule. It was also
demonstrated that 8 weeks of treatment with MXF
(100 mg/kg/day) or with MXF ? INH (100 and 25 mg/
kg/day, respectively) sterilized the lungs in seven of eight
and in eight of eight mice, respectively (Miyazaki et al.,
1999). Interestingly, surviving bacilli isolated from ani-
mals infected with a high-titre inoculums and treated for
7 weeks with low-dose MXF (20 mg/kg/day) did not show
any marked resistance to the drug. Furthermore, the
elimination half life of the drug in man, mean value 12 h
(Sullivan et al., 1995) (compare INH 1–2 h) supports the
possibility of once-a-day treatment.
To summarize, results obtained so far in in vitro and in
vivo studies suggest that MXF might be a promising can-
didate drug to shorten TB treatment. At the molecular
levels, the reason for its improved efficiency is mainly a
consequence of its poor susceptibility to active efflux that
ensures the maintenance of high intracellular concentra-
tion. Shortening of therapy in mouse models seems to be
mainly due to a released of antagonism among the drugs in
the regimen. There is a possibility that MXF might be
active against slowly metabolizing bacteria by inhibiting
DNA transcription and, consequently, mRNA and protein
synthesis, therefore having a mild sterilizing activity.
However, this still needs to be rigorously proven. As far as
emergence of resistance is concerned, in vitro studies in
S. pneumoniae revealed that MXF, used at concentration
above the MIC, is less prone to select first-step mutants
when compared to the fluoroquinolone sparfloxacin.
However, MXF monotherapy in mice models showed that
resistance to MXF might rapidly emerge (Ginsburg et al.,
2005). MXF is currently in Phase II Clinical Trials. A trial
substituting ethambutol with MXF during intensive phase
(TBTC 27) was initiated before above cited animal studies
had been conducted and showed no advantage over eth-
ambutol. Preliminary results of this study have been pub-
lished and showed that MXF-containing regimen did not
present increased sterilizing activity over the standard
regimen. However, MXF-containing regimen did show
increased activity at earlier time points (Burman et al.,
2006).
Med Chem Res
Mefloquine and analogues
The antimalarial drug mefloquine (a 4-aminoquinoline
methanol), and several analogues, have been reported to
have activity against a variety of bacteria including
Mycobacterium (Kunin and Ellis, 2000). From a series of
quinoline methanols obtained from WRAIR, two com-
pounds, WR-3016 and WR-3017, showed potent inhibitory
activity in vitro in the M. avium complex-1 (MAC) assay
with MIC50 values of 1 and 2 lg/mL, respectively, com-
pared to 16 lg/mL for mefloquine. However, these two
compounds were not as active as the parent drug in an in
vivo MAC assay. There is also interest in the antituber-
culosis properties of the mefloquine analogue desbutyl-
halofantrine. This compound is in development for its
antimalarial properties with the apparent advantage over
123

the parent drug halofantrine of lower cardiotoxicity. In
clinical trials, sufficient blood levels were reached to sug-
gest that it would be effective in TB patients.
Non-fluorinated quinolones (NFQ)
Recently, a series of 8-methoxy NFQs have been developed.
NFQs lack a 6-fluorine in their quinolone nucleus differen-
tiating them from fluorinated quinolones such as GTF and
MXF. NFQs target a broadspectrum of bacteria and they
seem to act preferentially through inhibition of DNA gyrase.
NFQs are currently being tested against M. tuberculosis.
Diarylquinoline TMC207
Diarylquinoline TMC207 is an extremely promising mem-
ber of a new class of antimycobacterial agents. To date, 20
molecules of the diarylquinoline series have been shown to
have a MIC below 0.5 lg/mL against M. tuberculosis
H37Rv. Antimicrobial activity was confirmed in vivo for
three of these compounds. The most active compound of the
class is TMC207 and its spectrum is unique in its specificity
to mycobacteria. The target and mechanism of action of
diarylquinoline TMC207 is different from those of other
antituberculosis agents implying low probability of cross-
resistance with existing TB drugs. This is further suggested
by the fact that diarylquinoline TMC207 is able to inhibit
bacterial growth when tested on MDR-TB isolates. Diaryl-
quinoline TMC207 seems to act by inhibiting the ATP
synthase (Petrella et al., 2006), leading to ATP depletion and
pH imbalance. This new antimycobacterial compound has
potent early bactericidal activity in the non-established
infection murine mouse model, matching or exceeding that
of INH. Moreover, diarylquinoline TMC207 has potent late
bactericidal activity in the established infection in murine
TB model. Substitution of RIF, INH or pyrazinamide with
diarylquinoline TMC207 accelerated activity leading to
complete culture conversion after 2 months of treatment
in some combinations. In particular, the diarylquinoline–
INH–pyrazinamide and diarylquinoline–RIF–pyrazinamide
combinations cleared the lungs of TB in all the mice after
2 months. Diarylquinoline TMC207 has also been tested in
various combinations with the second-line drugs like ami-
kacin, pyrazinamide, MXF and ethionamide in mice
123
Med Chem Res
infected with the drug-susceptible virulent M. tuberculosis
strain H37Rv. Diarylquinoline-containing regimen were
more active than the current recommended regimen for
MDR-TB amikacin–pyrazinamide–MXF–ethionamide. A
thorough assessment of diarylquinoline activity against
MDR-TB in vivo would, however, require testing of animal
models infected with MDR bacterial strains rather than with
drug-susceptible strains. Pharmacokinetic and pharmaco-
dynamic studies in mice showed long plasma half-life, high
tissue penetration and long tissue half-life. These are all
attributes that are valuable for treatment of chronic infec-
tions and may also be important for development of simpler
dosing regimens. Diarylquinoline TMC207 has sterilizing
activity in vivo. Studies in mice also showed potential
reduction of treatment duration. Diarylquinoline TMC207 is
in clinical trials.
Discussion
The current molecules in this series will mainly be selected
for further development on the basis of broadspectrum
antimicrobial efficacy in short-term treatment regimens.
However, for TB chemotherapy it would be beneficial to
progress representatives of the series which have a more
selective action on mycobacteria at the expense of other
microbes. This would help avoid the undesirable effect of
severely depleting the beneficial gut fauna. Another
approach to identifying a more appropriate antituberculosis
quinolone would be to select those members of the series
concentrating in lung tissues. It would be highly desirable
to compare all potential candidates for further progression
in a standard series of tests, e.g. efficacy, ADME, toxicity
studies in mice, in vitro tests in quinolone-sensitive and
quinolone-resistant strains of M. tuberculosis. The side
effects of the quinolones, particularly the newer fluoro-
quinolones (Bertino and Fish. 2000), are phototoxicity,
neurotoxicity and drug–drug interactions (possibly caused
by the affinity of these compounds for cytochrome P450).
Less frequently observed problems include renal, hepatic
and cardiac toxicity. Since the treatment regimens for TB
therapy are likely to be longer than for most other bacterial
diseases, it is a cause of some concern that these toxicities
might occur more frequently and blight a drug marketed for
both TB and more commercially attractive diseases. Con-
sequently, the selection of a mycobacterial disease-specific
drug is attractive despite the additional costs of developing
this as a new chemical entity. During quinolone therapy,
resistant organisms emerge with a frequency, especially
among staphylococci and pseudomonas. Resistance is due
to one or more point mutations in the quinolone-binding
region of the target enzyme or to a change in the perme-
ability of the organism. DNA gyrase is the primary target
Med Chem Res
in E. coli, with single-step mutants exhibiting amino acid
substitution in the A subunit of gyrase. Topoisomerase-IV
is a secondary target in E. coli that is altered in mutants
expressing higher levels of resistance. In staphylococci and
streptococci, the situation is reversed: topoisomerase-IV is
usually the primary target, and gyrase is the secondary
target. Resistance to one fluoroquinolone, particularly if of
high level, generally confers cross-resistance to all other
members of this class. With the increasing use of fluoro-
quinolones for a variety of infections, including respiratory
tract infections, fluoroquinolone resistance has emerged
among strains of S. pneumonia (Klemens et al., 1993; Koga
et al., 2004; Manabe and Bishai, 2000).
After administration, the quinolones are well absorbed
and distributed widely in body fluids and tissues. The
flouroquinolones are relatively long half-lives of levoflox-
acin, MXF, sparfloxacin and trovafloxacin permit once-
daily dosing. Alatrofloxacin is the inactive, prodrug form
of trovafloxacin for parenteral administration. It is rapidly
converted to the active compound. Concentrations in
prostate, kidney, neutrophils and macrophages exceed
serum concentrations. Most fluoroquinolones are elimi-
nated by renal mechanisms, either tubular secretion or
glomerular filtration. Non-renally cleared fluoroquinolones
are contraindicated in patients with hepatic failure. Fluo-
roquinolones are effective mainly in urinary tract infections
even when caused by MDR bacteria, e.g. pseudomonas.
These agents are also effective for bacterial diarrhea caused
by shigella, salmonella, toxigenic E. coli, or campylobac-
ter. Fluoroquinolones (except norfloxacin) have been
employed in infections of soft tissues, bones and joints and
in intra-abdominal and respiratory tract infections, includ-
ing those caused by MDR organisms such as pseudomonas
and enterobacter. Ciprofloxacin and ofloxacin are effective
for gonococcal infection, including disseminated disease,
and ofloxacin is effective for chlamydial urethritis or cer-
vicitis. Ciprofloxacin is a second-line agent for legionel-
losis. Ciprofloxacin or levofloxacin is occasionally used for
treatment of TB and atypical mycobacterial infections.
They may be suitable for eradication of meningococci from
carriers or for prophylaxis of infection in neutropenic
patients. However, levofloxacin, GTF and MXF with their
enhanced grampositive activity and activity against atypi-
cal pneumonia agents (e.g. chlamydia, mycoplasma, and
legionella) are likely to be effective and used increasingly
for treatment of upper and lower respiratory tract infec-
tions. Fluoroquinolones are extremely well tolerated. The
most common effects are nausea, vomiting and diarrhea.
Occasionally, headache, dizziness, insomnia, skin rash or
abnormal liver function tests develop. Trovafloxacin has
been associated with acute hepatitis and hepatic failure,
which has led to its restricted indications. Photosensitivity
has been reported with lomefloxacin and pefloxacin.
Ideally, these agents should be avoided or used with cau-
tion in patients GTF has been associated with hypergly-
cemia in diabetic patients and with hypoglycemia in
patients also receiving oral hypoglycemic agents. Fluoro-
quinolones may damage growing cartilage and cause an
arthropathy. Thus, they are not routinely recommended for
use in patients under 18 years of age (Kamal et al., 2008).
Conclusion
The opportunistic TB infection due to AIDs and emergence
of drug-resistant TB strains has made its chemotherapeutic
strategies increasingly ineffective (Somoskovi et al., 2001).
Traditionally, it has relied heavily on a limited number of
drugs such as INH, RIF, ethambutol, streptomycin, ethi-
onamide, pyrazinamide, etc. (Khasnobis et al., 2002).
However, many of these drugs have different disadvan-
tages such as prolonged treatment schedules, host toxicity,
ineffectiveness against resistant strains, etc. This has
motivated for the search of new chemical prototypes
capable of rapid mycobactericidal action with shortened
duration of therapy, reduced toxicity and enhanced activity
against drug-resistant strains and also against the latent
bacteria for its control (Jones et al., 2000; Pasqualoto and
Ferreira, 2001; Teodori et al., 2002; Frieden, et al., 2003;
Smith et al., 2004). In spite of the availability of various
chemotherapeutic agents, TB remains a leading infectious
killer worldwide. This is mainly due to the lack of new
drugs, particularly for effective treatment against the
spread of MDR and XDR strains (Murugasu-Oei and Dick,
2000; O’Brien and Nunn, 2001). Therefore, there is an
urgent need for the development of new antituberculosis
drugs with lesser side effects, improved pharmacokinetic
properties to be effective against both the Gram-positive
and Gram-negative bacteria including the resistant strains.
More importantly, the newly developed drugs are required
to reduce the overall duration of treatment. It is also
important to note that while we pursue the development of
new drugs based on inhibition of bacterial targets. In recent
years, efforts are being made to develop new molecules
based on different scaffolds that act on a number of drug
targets. Hence, new molecules that are active against cell
wall targets could provide valuable therapeutic options for
the therapeutic application including drug resistance. It was
also recommended that the family of antibacterial quino-
lones be further studied in the discovery research phase in
an attempt to identify molecules with greater antitubercu-
losis potential than current candidates which have been
discussed specifically in this report.
Concerning drugs, it is crucial that act through novel
mechanisms which are able to target novel molecular tar-
gets, to avoid cross-resistance with drugs currently in use.
123

These candidate drugs have been shown to be active
against MDR-TB strains in vitro and therefore have the
potential to be effective against MDR-TB in human
patients. There is an urgent need for innovative thinking in
the field of clinical trials for new TB drugs, to speed up the
development of these new drugs and accelerate their
delivery to patients. A major limitation currently is the
difficulty of diagnosing patients with TB. This problem is
even more acute in the case of XDR-TB because the dis-
ease is so rapidly fatal that most patients will die before the
results of their diagnosis are available. Rapid, reliable and
field adapted diagnostic tools for TB and drug-resistant
forms of TB are an integral part of treatment strategies and
urgently need to be developed. The aim is to synthesize and
evaluate novel and more effective quinolone compounds
that could shorten first-line treatment. To date, various
compounds have been synthesized and tested for their
antituberculosis activity. Current work is focused on the
modification of a position which influences activity, phar-
macokinetics and safety profile. The lead compounds
identified so far showed better activity than GTF and MXF.
Acknowledgments The authors are thankful to Guru Ram Das (Post
Graduate) Institute of Management & Technology, Dehradun, India
for the technical support.
References
Alangaden GJ, Lerner SA (1997) The clinical use of fluoroquinolones
for the treatment of mycobacterial diseases. Clin Infect Dis
25:1213–1221
Alangaden GJ, Manavathu EK, Vakulenko SB, Zvonok NM, Lerner
SA (1995) Characterization of fluoroquinolone-resistant mutant
strains of Mycobacterium tuberculosis selected in the laboratory
and isolated from patients. Antimicrob Agents Chemother 39:
1700–1703
Al-Deeb AO, Alafeefy AM (2008) Synthesis of some new
3H-quinazolin-4-one derivatives as potential antitubercular
agents. World Appl Sci J 5(1):94–99
Alvirez-Freites EJ, Carter JL, Cynamon MH (2002) In vitro and in
vivo activities of gatifloxacin against Mycobacterium tubercu-
losis. Antimicrob Agents Chemother 46:1022–1025
Aubry A, Pan XS, Fisher LM, Jarlier V, Cambau E (2004)
Mycobacterium tuberculosis DNA gyrase: interaction with
quinolones and correlation with antimycobacterial drug activity.
Antimicrob Agents Chemother 48:1281–1288
Bagchi MC, Mills D, Basak SC (2007) Quantitative structure–activity
relationship (QSAR) studies of quinolone antibacterials against
M. fortuitum and M. smegmatis using theoretical molecular
descriptors. J Mol Model 13:111–120
Barman Balfour JA, Lamb HM (2000) Moxifloxacin. A review of its
clinical potential in the management of community-acquired
respiratory tract infections. Drugs 59(1):115–139
Bertino J Jr, Fish D (2000) The safety profile of the fluoroquinolones.
Clin Ther 22(7):798–817
Biedenbach DJ, Sutton LD, Jones RN (1995) Antimicrobial activity
of CS-940, a new trifluorinated quinolone. Antimicrob Agents
Chemother 39(10):2325–2330
123
Med Chem Res
Bozeman L, Burman W, Metchock B, Welch L, Weiner M (2005)
Fluoroquinolone susceptibility among Mycobacterium tubercu-
losis isolates from the United States and Canada. Clin Infect Dis
40:386–391
Brenwald NP, Gill MJ, Wise R (1998) Prevalence of a putative efflux
mechanism among fluoroquinolone-resistant clinical isolates of
Streptococcus pneumoniae. Antimicrob Agents Chemother 42:
2032–2035
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher
AW, Choudhri S, Daley CL, Munsiff SS, Zhao Z et al (2006)
Moxifloxacin versus ethambutol in the first 2 months of
treatment for pulmonary tuberculosis. Am J Respir Crit Care
Med 174:331–338
CDC (2006) Emergence of Mycobacterium tuberculosis with exten-
sive resistance to second-line drugs—worldwide, 2000–2004.
MMWR Morb Mortal Wkly Rep 55:301–305
Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione
MC, Dye C (2003) The growing burden of tuberculosis: global
trends and interactions with the HIV epidemic. Arch Intern Med
163:1009–1021
Coyle EA, Kaatz GW, Rybak MJ (2001) Activities of newer
fluoroquinolones against ciprofloxacin-resistant Streptococcus
pneumoniae. Antimicrob Agents Chemother 45:1654–1659
Cynamon MH, Sklaney M (2003) Gatifloxacin and ethionamide as the
foundation for therapy of tuberculosis. Antimicrob Agents
Chemother 47:2442–2444
Daffe M, Brennan PJ, Mcneil M (2007) Predominant structural
features of the cell wall arabinogalactan of Mycobacterium
tuberculosis as revealed through characterization. J Med Chem
50:2492
Daporta MT, Munoz Bellido JL, Guirao GY, Hernandez MS, Garcia-
Rodriguez JA (2004) In vitro activity of older and newer
fluoroquinolones against efflux-mediated high level ciprofloxa-
cinresistant Streptococcus pneumoniae. Int J Antimicrob Agents
24:185–187
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC (1999) Global
burden of tuberculosis: estimated incidence, prevalence, and
mortality by country. JAMA 282:677–686
Flamm RK, Vojtko C, Chu DT, Li Q, Beyer J, Hensey D, Ramer N,
Clement JJ, Tanaka SK (1995) In vitro evaluation of ABT-719, a
novel DNA gyrase inhibitor. Antimicrob Agents Chemother
39:964–970
Flynn JL, Chan J (2001) Tuberculosis: latency and reactivation. Infect
Immun 69:4195–4201
Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C (2003)
Tuberculosis. Lancet 362:887–899
Garay SM (2004) Pulmonary tuberculosis. In: Rom WN, Garay SM
(eds) Tuberculosis. Lippincott Williams & Wilkins, Philadel-
phia, pp 345–394
Ginsburg AS, Grosset JH, Bishai WR (2003a) Fluoroquinolones,
tuberculosis, and resistance. Lancet Infect Dis 3:432–442
Ginsburg AS, Hooper N, Parrish N, Dooley KE, Dorman SE, Booth J,
Diener-West M, Merz WG, Bishai WR, Sterling TR (2003b)
Fluoroquinolone resistance in patients with newly diagnosed
tuberculosis. Clin Infect Dis 37:1448–1452
Ginsburg AS, Sun R, Calamita H, Scott CP, Bishai WR, Grosset JH
(2005) Emergence of fluoroquinolone resistance in Mycobacte-
rium tuberculosis during continuously dosed moxifloxacin
monotherapy in a mouse model. Antimicrob Agents Chemother
49:3977–3979
Glickman SW, Rasiel EB, Hamilton CD, Kubataev A, Schulman KA
(2006) Medicine. A portfolio model of drug development for
tuberculosis. Science 311:1246–1247
Global Alliance for TB Drug Development (2001) Tuberculosis.
Scientific blue print for tuberculosis drug development. Tuber-
culosis (Edinb) 81(Suppl 1):1–52
Med Chem Res
Gomez JE, McKinney JD (2004) M. tuberculosis persistence, latency,
and drug tolerance. Tuberculosis (Edinb) 84:29–44
Grosset JH (1992) Treatment of tuberculosis in HIV infection. Tuber
Lung Dis 73:378–383
Grosset J, Ji B (1998) Experimental chemotherapy of mycobacterial
diseases. In: Gangadharam PRJ, Jenkins PA (eds) Mycobacteria,
II chemotherapy. Chapman & Hall, New York, pp 51–97
Grosset J, Truffot-Pernot C, Lacroix C, Ji B (1992) Antagonism
between isoniazid and the combination pyrazinamide–rifampin
against tuberculosis infection in mice. Antimicrob Agents
Chemother 36:548–551
Herbert D, Paramasivan CN, Venkatesan P, Kubendiran G, Prabhakar
R, Mitchison DA (1996) Bactericidal action of ofloxacin,
sulbactam-ampicillin, rifampin, and isoniazid on logarithmic
and stationary-phase cultures of Mycobacterium tuberculosis.
Antimicrob Agents Chemother 40:2296–2299
ID Weekly Highlights (2000) Moxifloxacin: a new antimicrobial
agent. Presented at the 40th CAAC Meeting, Toronto, and
September 17–20, 2000. Reported by Pireh D, October, 32–33
Hirata T, Saito H, Tomioka H, Sato K, Jidoi J, Hosoe K, Hidaka T
(1995) In vitro and in vivo activities of the benzoxazinorifamy-
cin KRM-1648 against Mycobacterium tuberculosis. Antimicrob
Agents Chemother 39:2295–2303
Hong Kong Chest Service/British Medical Research Council (1992)
A controlled study of rifabutin and an uncontrolled study of
ofloxacin in the retreatment of patients with pulmonary tuber-
culosis resistant to isoniazid, streptomycin and rifampicin. Tuber
Lung Dis 73:59–67
Houston AK, Jones RN (1994) Postantibiotic effect of DU-6859a and
levofloxacin as compared with ofloxacin. Diagn Microbiol Infect
Dis 18(1):57–59
Hu Y, Coates AR, Mitchison DA (2003) Sterilizing activities of
fluoroquinolones against rifampin-tolerant populations of Myco-
bacterium tuberculosis. Antimicrob Agents Chemother 47:653–657
Islam M, Siddiqui AA, Rajesh R (2008) Synthesis, antitubercular,
antifungal and antibacterial activities of 6-substituted phenyl-
2-(3ı́-substituted phenyl pyridazin-6ı́-yl)-2,3,4,5-tetrahydropyri-
dazin-3-one. Acta Pol Pharm 65(3):353–362
Jones PB, Parrish NM, Houston TA, Stapon A, Bansal NP, Dick JD,
Townsend CA (2000) A new class of antituberculosis agents.
J Med Chem 43:3304–3314
Kamal A, Azeeza S, Malik MS, Shaik AA, Rao MV (2008) Efforts
towards the development of new antitubercular agents: potential
for thiolactomycin based compounds. J Pharm Pharmaceut Sci
11(2):56s–80s
Kaufmann SH, Cole ST, Mizrahi V, Rubin E, Nathan C (2005)
Mycobacterium tuberculosis and the host response. J Exp Med
201:1693–1697
Khasnobis S, Escuyer VE, Chatterjee D (2002) Emerging therapeutic
targets in tuberculosis: post genomic era. Expert Opin Ther Targ
6:21–40
Klemens SP, DeStefano MS, Cynamon MH (1993) Therapy of
multidrug-resistant tuberculosis: lessons from studies with mice.
Antimicrob Agents Chemother 37:2344–2347
Kocagoz T, Hackbarth CJ, Unsal I, Rosenberg EY, Nikaido H,
Chambers HF (1996) Gyrase mutations in laboratory-selected,
fluoroquinoloneresistant mutants of Mycobacterium tuberculosis
H37Ra. Antimicrob Agents Chemother 40:1768–1774
Koga T, Fukuoka T, Doi N, Harasaki T, Inoue H, Hotoda H, Kakuta M,
Muramatsu Y, Yamamura N, Hoshi M, Hirota T (2004) Activity
of capuramycin analogues against Mycobacterium tuberculosis
Mycobacterium avium and Mycobacterium intracellulare in vitro
and in vivo. J Antimicrob Chemother 54:755–760
Kunin CM, Ellis WY (2000) Antimicrobial activities of mefloquine
and a series of related compounds. Antimicrob Agents Chemo-
ther 44(4):848–852
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK,
Tompkins NM, Rose JD, Reynolds RC, Orme IM (2005)
Preclinical testing of the nitroimidazopyran PA-824 for activity
against Mycobacterium tuberculosis in a series of in vitro and in
vivo models. Antimicrob Agents Chemother 49:2294–2301
Lewin CS, Howard BM, Smith JT (1991) 4-Quinolone interactions
with gyrase subunit B inhibitors. J Med Microbiol 35:358–362
Li XZ, Zhang L, Nikaido H (2004) Efflux pump-mediated intrinsic
drug resistance in Mycobacterium smegmatis. Antimicrob
Agents Chemother 48:2415–2423
Manabe YC, Bishai WR (2000) Latent Mycobacterium tuberculosis-
persistence, patience, and winning by waiting. Nat Med 6:1327–
1329
Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR (1999)
Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is
active in a mouse model of tuberculosis. Antimicrob Agents
Chemother 43:85–89
Murugasu-Oei B, Dick T (2000) Bactericidal activity of nitrofurans
against growing and dormant Mycobacterium bovis BCG.
J Antimicrob Chemother 46:917–919
Nikonenko BV, Samala R, Einck L, Nacy CA (2004) Rapid, simple in
vivo screen for new drugs active against Mycobacterium
tuberculosis. Antimicrob Agents Chemother 48:4550–4555
Nuermberger EL, Yoshimatsu T, Tyagi S, O’Brien RJ, Vernon AN,
Chaisson RE, Bishai WR, Grosset JH (2004a) Moxifloxacin-
containing regimen greatly reduces time to culture conversion in
murine tuberculosis. Am J Respir Crit Care Med 169:421–426
Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I,
O’Brien RJ, Vernon AA, Chaisson RE, Bishai WR, Grosset JH
(2004b) Moxifloxacin-containing regimens of reduced duration
produce a stable cure in murine tuberculosis. Am J Respir Crit
Care Med 170:1131–1134
O’Brien RJ, Nunn PP (2001) The need for new drugs against
tuberculosis. Obstacles, opportunities, and next steps. Am J
Respir Crit Care Med 163:1055–1058
Onodera Y, Tanaka M, Sato K (2001) Inhibitory activity of
quinolones against DNA gyrase of Mycobacterium tuberculosis.
J Antimicrob Chemother 47:447–450
Paramasivan CN, Sulochana S, Kubendiran G, Venkatesan P,
Mitchison DA (2005) Bactericidal action of gatifloxacin, rifam-
pin, and isoniazid on logarithmic- and stationary-phase cultures
of Mycobacterium tuberculosis. Antimicrob Agents Chemother
49:627–631
Pasqualoto KFM, Ferreira EI (2001) An approach for the rational
design of new antituberculosis agents. Curr Drug Targets 2:
427–437
Pestova E, Millichap JJ, Noskin GA, Peterson LR (2000) Intracellular
targets of moxifloxacin: a comparison with other fluoroquino-
lones. J Antimicrob Chemother 45:583–590
Petrella S, Cambau E, Chauffour A, Andries K, Jarlier V, Sougakoff
W (2006) Genetic basis for natural and acquired resistance to the
diarylquinoline R207910 in mycobacteria. Antimicrob Agents
Chemother 50:2853–2856
Primm TP, Andersen SJ, Mizrahi V, Avarbock D, Rubin H, Barry CE
III (2000) The stringent response of Mycobacterium tuberculosis
is required for long-term survival. J Bacteriol 182:4889–4898
Rattan A, Kalia A, Ahmad N (1998) Multidrug-resistant Mycobac-
terium tuberculosis: molecular perspectives. Emerg Infect Dis
4(2):195–209
Reynolds RC, Bansal N, Rose J, Friedrich J, Suling WJ, Maddry JA
(1999) Ethambutol–sugar hybrids as potential inhibitors of
mycobacterial cell-wall biosynthesis. Carbohydr Res 317:164–
179
Rodriguez JC, Ruiz M, Climent A, Royo G (2001) In vitro activity of
four fluoroquinolones against Mycobacterium tuberculosis. Int J
Antimicrob Agents 17:229–231
123

Ruiz-Serrano MJ, Alcala L, Martinez L, Diaz M, Marin M, Gonzalez-
Abad MJ, Bouza E (2000) In vitro activities of six fluoroquino-
lones against 250 clinical isolates of Mycobacterium tuberculosis
susceptible or resistant to first-line antituberculosis drugs. Anti-
microb Agents Chemother 44:2567–2568
Russell DG (2001) Mycobacterium tuberculosis: here today, and here
tomorrow. Nat Rev Mol Cell Biol 2:569–577
Shafii B, Amini M, Akbarzadeh T, Shafiee A (2008) Synthesis and
antitubercular activity of N3,N5-diaryl-4-(5-arylisoxazol-3-yl)-
1,4-dihydropyridine-3,5-dicarboxamide. J Sci 19(4):323–328
Sirgel FA, Donald PR, Odhiambo J, Githui W, Umapathy KC,
Paramasivan CN, Tam CM, Kam KM, Lam CW, Sole KM,
Mitchison DA (2000) A multicentre study of the early bacteri-
cidal activity of anti-tuberculosis drugs. J Antimicrob Chemother
45:859–870
Smith CV, Huang CC, Miczak A, Russell DG, Sacchettini JC, Honer
zu Bentrup K (2003) Biochemical and structural studies of
malate synthase from Mycobacterium tuberculosis. J Biol Chem
278:1735–1743
Smith CV, Sharma V, Sacchettini JC (2004) TB drug discovery:
addressing issues of persistence and resistance. Tuberculosis
84:45–55
Snider DE (1994) Tuberculosis: the world situation. History of the
disease and efforts to combat it. In: Porter JDH, McAdam KPWJ
(eds) Tuberculosis: back to the future. Wiley, New York,
pp 14–31
Somoskovi A, Parsons LM, Salfinger M (2001) The molecular basis
of resistance to isoniazid, rifampin, and pyrazinamide in
Mycobacterium tuberculosis. Respir Res 2:164–168
Stahlmann R, Lode H (1999) Toxicity of quinolones. Drugs 58(Suppl
2):37–42
Sullivan EA, Kreiswirth BN, Palumbo L, Kapur V, Musser JM,
Ebrahimzadeh A, Frieden TR (1995) Emergence of fluoroqui-
nolone-resistant tuberculosis in New York City. Lancet 345:
1148–1150
123
Med Chem Res
Sulochana S, Rahman F, Paramasivan CN (2005) In vitro activity of
fluoroquinolones against Mycobacterium tuberculosis. J Chemo-
ther 17:169–173
Sun Z, Zhang Y (1999) Antituberculosis activity of certain antifungal
and antihelmintic drugs. Tuber Lung Dis 79:319–320
Temple ME, Nahata MC (1999) Rifapentine: its role in the treatment
of tuberculosis. Ann Pharmacother 33(11):1202–1210
Teodori E, Dei S, Scapecchi S, Gualtieri F (2002) The medicinal
chemistry of multidrug resistance (MDR) reversing drugs. Il
Farmaco\ 57:385–415
Trivedi AR, Siddiqui AB, Shah VH (2008) Design, synthesis,
characterization and antitubercular activity of some 2-heterocy-
cle-substituted phenothiazines. ARKIVOC ii:210–217
Wayne LG, Sohaskey CD (2001) Non replicating persistence of
Mycobacterium tuberculosis. Annu Rev Microbiol 55:139–163
Weil DEC (1994) Drug supply: meeting a global need. In: McAdam
KPWJ, Porter JDH (eds) Tuberculosis: back to the future. Wiley,
New York, pp 123–143
WHO (2004) Tuberculosis Fact Sheet. http://www.who.int/media
centre/factsheets/fs104/en/
Willmott CJ, Critchlow SE, Eperon IC, Maxwell A (1994) The
complex of DNA gyrase and quinolone drugs with DNA forms a
barrier to transcription by RNA polymerase. J Mol Biol
242:351–363
Yew WW, Kwan SY, Ma WK, Lui KS, Suen HC (1990) Ofloxacin
therapy of Mycobacterium fortuitum infection: further experi-
ence. J Antimicrob Chemother 25:880–881
Zhanel GG, Hoban DJ, Schurek K, Karlowsky JA (2004) Role of
efflux mechanisms on fluoroquinolone resistance in Streptococ-
cus pneumoniae and Pseudomonas aeruginosa. Int J Antimicrob
Agents 24:529–535
Zhang Y (2005) The magic bullets and tuberculosis drug targets.
Annu Rev Pharmacol Toxicol 45:529–564