Download reviews - Medicina

REVIEWS
39
Medicina (Kaunas) 2011;47(Suppl 2):39-48
Structure-Activity Relationships of Antituberculins
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
Department of Drug Chemistry, Medical Academy, Lithuanian University of Health Sciences, Lithuania
Key words: tuberculosis; Mycobacterium tuberculosis; antitubercular drugs.
Summary. Tuberculosis caused by Mycobacterium tuberculosis remains the leading cause of
mortality worldwide in the 21st century. The multidrug therapy to treat tuberculosis patients was
introduced more than 50 years ago mainly because of the emergence of drug resistance. The mortality and spread of tuberculosis has been further aggravated because of the synergy of this disease with
HIV. A number of antitubercular drugs are ineffective against this disease because of the development of drug-resistant strains. Unfortunately, most drugs that are used today for the treatment of
tuberculosis were developed 40 or more years ago. Therefore, tuberculosis was the focus of renewed
scientific interest in the last decade. This article provides a brief review of the drugs currently used
in the treatment of tuberculosis and the most advanced compounds undergoing preclinical or clinical
trials. A short description of the mechanisms of their action on related biochemical targets is also
presented.
Introduction
Tuberculosis (TB) is an old disease that is
thought to have evolved sometime between the seventh and sixth millennia BC. In 1882, Robert Koch
discovered the tubercle bacillus Mycobacterium tuberculosis (MTB), the organism that causes TB. TB
remains an important public health problem worldwide and in the European region (Fig. 1). One of
the aims of the World Health Organization (WHO)
is to reduce morbidity rates and death rates caused
by TB in 18 high-priority countries of Eastern Europe. The plan to reach this aim includes 6 targets
for the year 2010 (1):
1. To reach 100% DOTS (directly observed treatment, short-course) population coverage in all
eastern European countries;
2. To increase the detection rate of new infectious
TB cases to at least 73%;
3. To achieve treatment success in at least 85% of
detected new infectious TB cases;
4. To provide treatment according to internationally recommended guidelines in 100% of multidrug-resistant TB cases, both new and previously
treated;
5. To reduce the prevalence of all TB forms to 188
cases per 100 000 population;
6. To decrease the mortality rate of all TB forms to
16 deaths per 100 000 population.
The Deteriorating Situation of TB/HIV
and Multidrug-Resistant TB combination
Coinfection with TB and HIV has been shown
Correspondence to L. Šlepikas, Department of Drug Chemistry, Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus 9, 44307 Kaunas, Lithuania
E-mail: [email protected]
to be a lethal combination. According to the alarming data from the WHO, TB is the leading cause of
mortality in people with HIV. People who are HIVpositive and infected with TB are 20 to 40 times
more likely to develop active TB than people not
infected with HIV. In 2008, 1.8 million people died
from TB including 500 000 people with HIV. Another factor contributing to the rise in TB infections and, consequently, to the increased number
of deaths is the emergence of multidrug resistance
(MDR) (2–4). According to the data collected during the last decade, 5% of all TB cases have MDRTB.
Three treatments used in practice have been at
least partly successful in the control of the illness:
• The sanatorium with fresh air and nutrition (not
discussed in this publication);
• Vaccination;
• Chemotherapy.
Vaccination
Active immunization is one of the most important treatments to control TB, but in most cases, it is
still ineffective today. The bacille Calmette–Guérin
(BCG) vaccine has existed for 80 years and has been
one of the most widely used of all current vaccines.
The impact of BCG vaccination on the transmission of TB is limited, because it does not prevent
primary infection and, more importantly, does not
prevent reactivation of latent pulmonary infection,
the principal source of bacillary spread in the community.
Adresas susirašinėti: L. Šlepikas, LSMU MA Vaistų chemijos
katedra, A. Mickevičiaus 9, 44307 Kaunas
El. paštas: [email protected]
Medicina (Kaunas) 2011;47(Suppl 2)
40
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
Cases per 100 000 Population
80
70
Eastern Europe (18 Countries)
European Region (53 Countries)
EU (With Enlargements)
79
60
50
41
40
30
20
12
10
0
1980
1985
1990
1995
2000
2005
Year
Fig. 1. TB notification rates in the European Region,
1980–2005 (1)
Chemotherapy
Various agents have been discovered for the treatment of tuberculosis since the 1940s when streptomycin and p-aminosalicylic acid were introduced.
The common antitubercular drugs used in treatment
are first-line and second-line drugs. First-line drugs
(isoniazid, rifampicin, ethambutol, and pyrazinamide) have high antitubercular efficiency and low
toxicity compared with second-line drugs (thiacetazone, p-aminosalicylic acid, ethionamide, prothionamide, cycloserine, amikacin, kanamycin, ciprofloxacin, levofloxacin, moxifloxacin, and floxacillin),
which have lower efficiency, and/or higher toxicity.
Many current antitubercular agents interact with the
macromolecules inactivating biosynthesis pathways:
Inhibitors of fatty acid biosynthesis (Fig. 2)
• Isoniazid (INH)
• Pyrazinamide (PZA)
• Ethionamide (ETA)
• Prothionamide (PRO)
Inhibitors of arabinogalactan and peptidoglycan
biosynthesis (Fig. 3)
• Ethambutol (ETH)
• D-Cycloserine (CYS)
Inhibitors of protein synthesis (Fig. 4)
• Streptomycin (STR), kanamycin, amikacin
• Clarithromycin (CLA)
• Linezolid (LIN)
Inhibitors of DNA-based processes (Fig. 5)
• Rifamycins (RPM): rifampicin (RIF), rifapentine
(RIFAP), rifalazil (RIFAL), rifabutin (RIFAB)
• Fluoroquinolones: moxifloxacin (MOXI), ciprofloxacin (CIP), levofloxacin (LEV), ofloxacin
(OFL), gatifloxacin (GATI).
Inhibitors of dihydrofolate reductase or siderophore biosynthesis (Fig. 6):
• p-Aminosalicylic acid (PAS)
According to the latest literature data, apart from
some of the abovementioned targets, which are
still in the process of being established, other potential targets exist: inhibitors of the proton pump
F0F1H+ATPase (5–9); inhibitors of mycobacterial cytochrome P450 monooxygenases (10–14);
FtsZ targeting compounds (15–23); inhibitors of
branched-chain amino acid biosynthesis (24–26),
nucleoside monophosphate kinase inhibitors, pyrimidine or purine nucleoside analogues (27–32);
signaling kinase inhibitors (33–38); and miscellaneous mechanism-based inhibitors (37–41).
Current antitubercular drugs
Isoniazid. INH was first synthesized in 1912 and
for the first time used in clinical practice in 1952.
INH is a prodrug activated by catalase-peroxidase
hemoprotein, KatG. As an inhibitor of fatty acid
biosynthesis, INH inhibits the mycolic acid biosynthesis in MTB by affecting an enzyme mycolate synthetase, unique for MTB. INH is orally active and
exhibits bacteriostatic action on resting bacilli and
is highly active against M. tuberculosis, M. bovis, M.
atricanum, and M. microti. Activity of IHN against
these pathogens is 0.02–0.06 μg/mL (42). The risk
of developing severe hepatitis and liver toxicity is
associated with INH usage. This risk is higher in
patients who take drugs like carbamazepine, phenobarbital, and RIF, abuse alcohol and older people.
Pyrazinamide. An isostere of INH, the synthetic
molecule PZA, was first synthesized in 1936; since
1985, this compound has been the third most important antitubercular drug. The activity of PZA depends on the presence of bacterial amidase, which
Fatty Acid Biosynthesis
Inhibitors
Fig. 2. Drugs acting as inhibitors of fatty acid biosynthesis
Medicina (Kaunas) 2011;47(Suppl 2)
Structure-Activity Relationships of Antituberculins
converts PZA to pyrazinoic acid (POA), the active
anti-TB molecule. The accumulation of POA and
protonated POA lowers the intracellular pH to a
suboptimal level that may inactivate many pathways
including fatty acid synthase and membrane transport function. However, it is widely accepted that
POA may not have a specific target, but rather that
cellular acidification causes the inhibition of major
processes. In vitro activity of PZA against MTB is
6–50 μg/mL at pH 5.5; MIC90 at pH 5.5 is 50 μg/
mL, at pH 5.8 is 100 μg/mL, and at pH 5.95 is 200
μg/mL (43). The primary adverse effect of PZA is a
hepatic reaction. Hepatotoxicity is dose related and
may appear at any time during drug therapy. PZA is
contraindicated in persons with severe liver damage
or with acute gout.
Ethionamide and Prothionamide. The mode of action of the activated form of ETA is via inhibition
of the inhA gene product enoyl-ACP reductase. In
vitro activity of ETA and PRO against MTB H37Rv
is 0.25 μg/mL and ~0.5 μg/mL, respectively(42).
ETA is active against M. tuberculosis, M. bovis, and
M. smegmatis. ETA is also active against M. leprae.
PRO is active against mycobacterial species including M. leprae and M. avium (44). It was found that
PRO killed M. leprae more quickly than ETA did
(45). The most common side effects are nausea,
vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight
loss. PRO should be avoided during pregnancy or
in women of childbearing potential. Hepatotoxic effects of ETA are common and occur at a fairly high
rate although they tend to be less serious than those
of the related drug PRO. The most common adverse
reactions of ETA and PRO are dose-related gastrointestinal disturbances, anorexia, excessive salivation,
metallic taste, nausea, vomiting, abdominal pain,
and diarrhea. Disturbances of the central nervous
system (CNS) include depression, anxiety, psychosis, headache, postural hypotension, and asthenia.
41
Arabingalactan and
Peptidoglycan Biosynthesis
Inhibitors
Fig. 3. Drugs acting as inhibitors of arabingalactan
and peptidoglycan biosynthesis
Ethambutol. ETH is a synthetic amino alcohol
first used in the treatment of TB in 1966. ETH inhibits arabinosyl transferases involved in cell wall
biosynthesis. ETH is effective against actively growing MTB microorganisms. Nearly all strains of M.
tuberculosis, M. kansasii, and M. avium are sensitive
to ETH. In vitro potency against MTB H37Rv is 0.5
μg/mL (S,S form is 600 times more active than R,R)
(42). Optic neuropathy and occasional hepatotoxicity
are common. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association
with ETH therapy may be characterized by one or
more of the following events: decreased visual acuity,
scotoma, color blindness, and/or visual defect.
D-Cycloserine. CYS is an analogue of the amino
acid D-alanine. CYS inhibits alanine racemase (Alr,
converts L-alanine to D-alanine) and D-alanine ligase
(Ddl), which synthesize the pentapeptide core using
D-alanine; both enzymes are essential in the synthesis
of peptidoglycan and, consequently, in cell wall biosynthesis and maintenance. CYS is a broad-spectrum
antibiotic, which inhibits MTB at concentrations of
5–20 μg/mL (42). CNS toxicity is dose-related and
shows neuropsychiatric effects like drowsiness and
slurred speech. Symptoms of CYS overdose are generally neuropsychiatric and include convulsions, seizures, slurred speech, paralysis, and unconsciousness.
Inhibitors of Protein
Synthesis
Fig. 4. Drugs acting as inhibitors of protein synthesis
Medicina (Kaunas) 2011;47(Suppl 2)
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
42
Rifapentine
Rifalazin
Rifampicin
Rifabutin
Inhibitors
of DNA-Based Processes
Ciprofloxacin
Gatifloxacin
R/S: Ofloxacin
S: Levofloxacin
Moxifloxacin
Fig. 5. Drugs acting as inhibitors of DNA-based processes
Inhibitors of
Dihydrofolate Reductase
or Siderophore
Biosynthesis
p-Aminosalycilic Acid
Fig. 6. Drug acting as inhibitors of dihydrofolate reductase
or siderophore biosynthesis
Streptomycin. The chemotherapy with STR introduced in 1946 by its combination with others anti-TB agents, such as p-aminosalicylic acid and isoniazid. STR was the first aminoglycoside antibiotic
isolated from Streptomyces griseus. It inhibits protein synthesis by binding tightly to the conserved
A site of 16S rRNA in the 30S ribosomal subunit,
and its use can lead to the selection of overlapping
cross-resistant MTB strains (46). Streptomycin is
active against MTB H37Rv (MIC, 1 μg/mL) and a
number of clinical M. tuberculosis strains including
an MDR strain with resistance to INH and RIF (42).
Moreover, STR is least toxic in the aminoglycoside
class. Many toxic effects appear on the peripheral
and central nervous system; the frequency of neurotoxic reactions (cochlear and vestibular dysfunction,
optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy) increases in patients
with impaired renal function or prerenal azotemia.
Accordingly, STR is contraindicated in patients with
renal impairment. Aminoglycosides remain important drugs for treating diseases caused by MTB,
but they are no longer first-line drugs because the
growing resistance is unacceptably rapid.
Clarithromycin. CLA, a macrolide antibiotic
similar to erythromycin and azithromycin, binds to
the 50S ribosomal subunit resulting in inhibition of
protein synthesis (47). In vitro potency against MTB
H37Rv is 8 μg/mL at pH 7.4 (42). MIC against a
panel of clinical MTB isolates is 1.3–10 μg/mL
compared with >10 μg/mL for erythromycin. CLA
has relatively poor in vitro activity against M. tuberculosis, but has better activity against M. avium
(MIC90, 8 μg/mL) and M. kansasii (MIC90, ≤0.5 μg/
mL). CLA is 8 to 32 times more active than erythromycin against M. avium (42). CLA should not be
used during pregnancy due to adverse effects seen
in fetal development in monkeys, rats, and mice.
The most common adverse effects are gastrointestinal (diarrhea, vomiting, abdominal pain, and nausea); headache and rash are common as well.
Linezolid. LIN is the first in a new class of oxazolidinone antibiotics and inhibits protein synthesis.
LIN binds to 23S rRNA inhibiting translation in the
Medicina (Kaunas) 2011;47(Suppl 2)
Structure-Activity Relationships of Antituberculins
early phase and preventing the proper binding of
formyl-methionine tRNA. In vitro potency against
MTB H37Rv is 0.25 μg/mL. LIN is active against
MDR M. tuberculosis strains (48). LIN causes reversible myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) in
patients especially when the drug is administered
for prolonged periods. The most common adverse
events in patients treated with LIN were diarrhea,
headache, and nausea.
Rifamycins. RPMs are a group of semisynthetic
antibiotics of rifamycin B isolated from Streptomyces mediterrani. This class of drugs inhibits bacterial RNA synthesis by binding to the β subunit of
the DNA-dependent polymerase and has no effect
on mammalian enzymes. The lipophilic properties
of the molecule are important for binding of the
drug to the polymerase and helping the drug in its
transport across the mycobacterial cell wall. RPM is
bactericidal with a very broad spectrum of activities
against most gram-positive and some gram-negative
organisms. RMP is effective against MTB H37Rv
with the following MICs: RIFAP, 0.031 μg/mL; RIFAB, <0.015 μg/mL; RIF 0.25, μg/mL; and RIFAL,
<0.015 μg/mL (49). Many RIF-resistant MTB mutants are cross-resistant with RIFAP and RIFAB, but
others do show some differential sensitivity. Hepatitis and serious hypersensitivity reactions including thrombocytopenia, hemolytic anemia, and renal
failure have been reported (50). Hepatotoxicity is
generally rare and probably not associated with the
rifamycins alone but it manifests with these drugs in
combinations with other TB treatments.
Fluoroquinolones. Fluoroquinolones are part of
the family of synthetic derivatives of nalidixic acid
with broad-spectrum antimycobacterial activity.
Their bactericidal action occurs due to the inhibitory effects of ATP-dependent enzymes, topoisomerase II (DNA gyrase), and topoisomerase IV
that are involved in the several processes, such as
DNA transcription and multiplication in Mycobacteria. Several members of this class have been used as
the second-line drugs for the treatment of MDR TB.
Gatifloxacin and moxifloxacin have shown better in
vitro activity against MTB than the older fluoroquinolones, i.e., ofloxacin and ciprofloxacin. In vitro activity of MOXI against MTB H37Rv is MIC 0.5 μg/
mL (51). Comparative MICs for others quinolones
are as follows: CIP, 0.5 μg/mL; OFL, 0.71 μg/mL;
LEV, 0.35 μg/mL; and GATI, 0.125 μg/mL. MOXI
is more active against M. kansasii than M. avium
complex. Prolongation of the QT interval is a general
feature of the action of fluoroquinolones. Quinolones are associated with specific tendinitis-type events,
and LEV seems to be associated with the highest rates
among these drugs.
p-Aminosalicylic Acid. The treatment of tubercu-
43
losis started in the 1940s when para-aminosalicylic
acid and streptomycin were introduced in practice.
Interestingly, it has no effect against other bacteria, but it is highly effective against MTB. One of
the suggested action modes of PAS is the interference process with iron acquisition by the salicylatedependent biosynthesis involved in iron uptake in
Mycobacteria. PAS is bacteriostatic. The MIC of
aminosalicylic acid against MTB is <1.0 μg/mL for
9 strains including 3 MDR strains, but 4 and 8 μg/
mL for 2 other MDR strains. PAS is inactive in vitro
against M. avium (52) and is contraindicated in patients with serious renal disease due to accumulation
of toxic metabolites.
Compounds Under Preclinical or Clinical Trials.
No new drug classes have been introduced into the
treatment of tuberculosis over the past 50 years (53).
In recent years, a scientific approach, using genetic engineering of MTB, played an important role
for validation and screening new libraries of compounds to determine more effective anti-TB agents.
The fluoroquinolones mentioned in this review
are only a few representatives of the family of at least
25 related antibacterials currently used in preclinical
and clinical trials or in practice (Fig. 7). PD-161148
and CS-940 have been selected based on their potent broad-spectrum activity against gram-negative,
gram-positive, and anaerobic bacteria. CS-940 was
screened against 100 clinical isolates of MTB and was
found to have an average MIC of 0.25–0.5 μg/mL
and to be more potent than ofloxacin, ciprofloxacin, and balofloxacin. PD-161148 was also tested
against various clinical isolates of MTB, where it
was compared with the desmethoxy analogue and
ciprofloxacin and showed to be 3 to 4 times more
active. Quinolone sitafloxacin (DU-6859a) is under
Fig. 7. The most active derivatives of fluoroquinolones against
Mycobacterium tuberculosis
Medicina (Kaunas) 2011;47(Suppl 2)
44
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
trials in Japan and the United States. Sitafloxacin
was found to be equipotent with gatifloxacin and
sparfloxacin; it is more active than levofloxacin and
ofloxacin when tested against MTB – MICs at which
90% of strains of MTB inhibited were ~0.2 μg/mL.
T-3811ME is unique among the other broad-spectrum quinolones because it lacks the presence of a
fluorine atom at the 6-position of the ring. Against
10 strains of MTB, T-3811ME has an MIC90 value
of 0.0625 μg/mL.
The oxazolidinone class of antibiotics is a new
promising class of synthetic antimicrobial agents
with a unique mechanism of action in inhibiting protein synthesis (Fig. 8). The first antibiotic
of oxazolidinone class – linezolid (U-100766) – is
approved and also is being studied for the treatment of MDR TB. Oxazolidinones PNU-100480
containing a thiomorpholine moiety in place of the
morpholine unit present in linezolid have been reported to be particularly active against MTB with
MICs of 0.125 μg/mL. The Dong-A Pharmaceutical has reported several new oxazolidinones (DA7157, DA-7218, and DA-7867) having somewhat
improved in vitro potency, compared with linezolid
against M. tuberculosis, M. kansasii, and M. marinum (54–55). According to literature data, one of
the most advanced oxazolidinones is ranbezolid
(RBx 7644) (56), which was tested in clinical trials in 2004 (57). Moreover, the presence of a nitro
group on its structure raises the question whether
their activity is due to the inhibition of the ribosome or to another mechanism related to the many
nitro-bearing antibacterials. Other oxazolidinones,
such as the AstraZeneca compound AZD 256387,
are being progressed clinically for the treatment of
MDR bacterial infections (58).
It was reported in the late 1990s that a series of
antimycobacterial pyrroles demonstrated significant
in vitro and in vivo activity against sensitive and resistant strains of MTB. After identification of the
initial compound BM 212, further structure-activity
studies were undertaken in vitro, and compound (I)
was shown to have an effect on the mycobacterial
growth inside the macrophages (Fig. 9). Another research group also carried out structural optimization
studies, and the isoniazid-bearing derivative (II) was
shown to be active in vivo on a murine model infected with resistant MTB strains (59). However,
Fig. 8. The most active derivatives of oxazolidinones against Mycobacterium tuberculosis
Pyrroles and Pyrroles
With Isoniazid-Bearing
Derivatives
Fig. 9. The most active derivatives of pyrroles against Mycobacterium tuberculosis
Medicina (Kaunas) 2011;47(Suppl 2)
Structure-Activity Relationships of Antituberculins
45
Nitroimidazo-Oxazine
and Nitroimidazo-Oxazole
Derivatives
Fig. 10. The most active derivatives of nitroimidazo-oxazine and nitroimidazo-oxazole against Mycobacterium tuberculosis
the presence of an isoniazid-bearing derivative, as
a pharmacophoric unit, on its structure raises the
question which part is active. The latest compound
LL-3858 is in progress of preclinical studies. Literature data have reported (60–61) that in vitro activity
of LL-3858 against MTB is 0.12–0.025 μg/mL.
The first bicyclic nitro-bearing imidazoles were
reported in the late 1970s (62). The Ciba-Geigy 5-nitroimidazole derivative CGI-17341 showed a considerable potential for the treatment of TB (Fig. 10).
In vitro, at 0.04 to 0.3 μg/mL, the compound inhibited both drug-susceptible and MDR strains of MTB
and showed no cross-resistance with INH, RIF, STR,
or ETH (63). Further work with the nitroimidazooxazine family led to recognition of the effect it has
on MTB, which led to the discovery of PA-824.
PA-824 has in vitro potency of 0.15–0.3 μg/mL
against MTB H37Rv compared with 0.03 μg/mL of
INH. PA-824 has very specific activity, possibly due
to its unique reducing activity; it appears to be limited
to the MTB complex as there is very limited efficacy
against M. smegmatis and M. avium. OPC-67683 is
closely related to PA-824 and may share a similar mode of action. It has in vitro potency against
MTB H37Rv (0.012 μg/mL) (64). OPC-67683 is
described as mycobacteria-specific; moreover, it is
active against M. kansasii and M. tuberculosis, while
PA-824 showed activity only against M. tuberculosis
(65). Phase I OPC-67683 clinical trial has been performed in Japan since 2006.
The broad and potent activity of 4-thiazolidinones has established them as one of the biologically
important pharmacophoric units (Fig. 11). According to the literature data, one of the most advanced
thiazolidinones is D155931 and its ester D157070,
selective killing nonreplicating Mycobacteria (66).
Unfortunately, no literature data are available about
preclinical or clinical trials of this class of potential
active antimycobacterial compounds.
A combinatorial library of 67 238 analogues
was made based on the ethylene-diamine core of
ethambutol, and many chemical libraries having a
ethylene-diamine scaffold were generated using a
novel synthetic approach (67–69). SQ109 is a novel
ethambutol analogue (Fig. 12). Remarkably, SQ109
Fig. 11. The most active derivatives of thiazolidinones
against Mycobacterium tuberculosis
turned out to be a very efficient antimycobacterial,
also effective against MDR strains. SQ109 is particularly active against M. tuberculosis (0.25–5 μg/
mL), M. bovis (0.25 μg/mL), and M. marinum (8
μg/mL) (68), but less active against M. avium and
M. smegmatis (69). Clinical studies of SQ109 started
in 2007.
In 2004, Andries et al. first described the work
done by Johnson & Johnson in the research and
development of TMC207 (Fig. 13) (70). TMC207
is a first-in-class diarylquinone. The compound,
identified by screening against M. smegmatis, has a
unique mechanism of action targeting the c subunit
of ATP synthase (47). It has in vitro activity against
MTB H37Rv (0.06 μg/mL). TMC appears to be
specific for Mycobacterium, particularly against M.
tuberculosis, M. bovis, M. avium, M. kansasii, and
M. smegmatis (71). In fact, 20 molecules in series of
diarylquinone have a MIC below 0.5 μg/mL. The
most active compound TMC207 (Tibotec) is being
currently investigated in human clinical trials.
Concluding remarks
Over the last 40 years, no new classes of antitubercular drugs have been developed and introduced
in practice; moreover, multidrug-resistant and ex-
Medicina (Kaunas) 2011;47(Suppl 2)
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
46
TMC207
1,2-Ethylenediamine
Derivative
Fig. 12. The most active compound of ethylenediamine
derivatives against Mycobacterium tuberculosis
Fig. 13. The most active compound of diarylquinone
derivatives against Mycobacterium tuberculosis
tensively drug-resistant Mycobacteria complicate
the treatment and control of the disease across the
globe. The tubercle bacillus is an astonishing microorganism, but also the biggest enemy associated
with drug-resistance. The search for new antituber-
cular active molecules brings challenges and opportunities for the science to defeat an old disease.
Statement of Conflict of Interest
The authors state no conflict of interest.
Prieštuberkuliozinių junginių struktūros ir aktyvumo sąsaja
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
Lietuvos sveikatos mokslų universiteto Medicinos akademijos Vaistų chemijos katedra
Raktažodžiai: tuberkuliozė, Mycobacterium tuberculosis, prieštuberkulioziniai vaistai.
Santrauka. Tuberkuliozė, sukelta Mycobacterium tuberculosis, yra pirmaujanti mirties priežastis visame
pasaulyje XXI amžiuje. Daugiau kaip prieš 50 metų klinikinėje praktikoje pradėta taikyti keleto vaistų terapija pacientų, užsikrėtusių tuberkulioze, gydymui, sąlygojo naujų rezistentiškų formų atsiradimą. Dėl ŽIV
sinergizmo su šia liga vis blogėjanti situacija lemia didelį paplitimą ir mirtingumą. Dėl atsparių padermių
didėja neveiksmingų prieštuberkuliozinių vaistų kiekis ir, deja, dauguma vaistų, kurie dabar vartojami tuberkuliozei gydyti, buvo sukurti prieš 40 metų ar daugiau, todėl šia infekcine liga pastarąjį dešimtmetį
mokslininkai susidomėjo iš naujo. Šiame straipsnyje trumpai aptariami prieštuberkulioziniai vaistai, kurie
dabar vartojami klinikinėje praktikoje, bei naujausi vaistų junginiai, su kuriais atliekami ikiklinikiniai ir
klinikiniai tyrimai, įvertinant trumpą jų veikimo mechanizmą, susijusį su biocheminių taikinių sąveika.
References
1. 2011 Global Tuberculosis Control Report, World Health
Organization. Available from: URL: http://www.who.int/
tb/publications/global_report/2011/gtbr11_full.pdf
2. Zhang Y, Post-Martens K, Denkin S. New drug candidates
and therapeutic targets for tuberculosis therapy. Drug Discov Today 2006;11(1-2):21-7.
3. Duncan K, Barry CE. Prospects for new antitubercular
drugs. Curr Opin Microbiol 2004;7:460-5.
4. Imramovsky A, Polanc S, Vinsova J, Kocevar M, Jampilek
J, Kaustova J. A new modification of anti-tubercular active
molecules. Bioorg Med Chem 2007;15:2551-9.
5. Andries K, Verhasselt P, Guillemont J, Gohlmann HW,
Neefs JM, Winkler H, et al. A diarylquinoline drug active
on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223-7.
6. Guillemont JEG, Pasquier ETJ, Lancois DFA. Patent WO
2005 70,430. Chem Abstr 2005;143:193916f.
7. Guillemont JEG, Pasquier ETJ. Patent WO 2005 70,924.
Chem Abstr 2005;143:194012v.
8. Guillemont JEG, Pasquier ETJ, Lancois DFA. Patent WO
2005 75,428. Chem Abstr 2005;143:229731h.
9. Andries KJM, Goehlmann HWH, Neefs JMM, Verhasselt PKM, Winkler J, De Jonge M, et al. Patent WO 2006
35,051. Chem Abstr 2006;144:365369u.
10. Guardiola-Diaz HM, Foster LA, Mushrush D, Vaz AD.
Azole-antifungal binding to a novel cytochrome P450 from
Mycobacterium tuberculosis: implications for treatment of
tuberculosis. Biochem Pharmacol 2001;61:1463-70.
11. McLean KJ, Marshall KR, Richmond A, Hunter IS, Fowler K, Kieser T, et al. Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiol
2002;148:2937-49.
12. Ahmad Z, Sharma S, Khuller GK, Singh P, Faujdar J, Katoch VM. Antimycobacterial activity of econazole against
multidrug-resistant strains of Mycobacterium tuberculosis
Int J Antimicrob Agents 2006;28:543-4.
13. Leys D, Mowat CG, McLean KJ, Richmond A, Chapman
SK, Walkinshaw MD, et al. Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features
of cytochrome P450. J Biol Chem 2003;278:5141-7.
14. Munro AW, McLean EG, Marshall KR, Warman AJ, Lewis
Medicina (Kaunas) 2011;47(Suppl 2)
Structure-Activity Relationships of Antituberculins
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
G, Roitel O, et al. Cytochromes P450: novel drug targets in
the war against multidrug-resistant Mycobacterium tuberculosis. Biochem Soc Trans 2003;625-30.
Erickson HP. FtsZ, a prokaryotic homolog of tubulin? Cell
1995;80:367-70.
Bramhill D. Bacterial cell division. Annu Rev Cell Dev Biol
1997;13:395-424.
Wang J, Galgoci A, Kodali S, Herath KB, Jayasuriya H,
Dorso K, et al. Discovery of a small molecule that inhibits
cell division by blocking FtsZ, a novel therapeutic target of
antibiotics. J Biol Chem 2003:278:44424-8.
Sutherland AG, Alvarez J, Ding W, Foreman KW, Kenny
CH, Labthavikul P, et al. Structure-based design of carboxybiphenylindole inhibitors of the ZipA-FtsZ interaction. Org Biomol Chem 2003;1:4138-40.
Jennings LD, Foreman KW, Rush TS, Tsao DHH, Mosyak
L, Li Y, et al. Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction. Bioorg
Med Chem Lett 2004;14:1427-31.
Jennings LD, Foreman KW, Rush TS 3rd, Tsao DH, Mosyak L, Kincaid SL, et al. Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. Bioorg Med Chem 2004;
14:5115-31.
Margalit DN, Romberg L, Mets RB, Hebert AM, Mitchison
TJ, Kirschner MW, et al. Targeting cell division: small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring
assembly and induce bacterial lethality. Proc Natl Acad Sci
USA. 2004;101:11821-6.
Stokes NR, Sievers J, Barker S, Bennett JM, Brown DR,
Collins I, et al. Novel inhibitors of bacterial cytokinesis
identified by a cell-based antibiotic screening assay. J Biol
Chem 2005;280:39709-15.
Ito H, Ura A, Oyamada Y, Tanitame A, Yoshida H, Yamada
S, et al. A 4-aminofurazan derivative-A189-inhibits assembly of bacterial cell division protein FtsZ in vitro and in
vivo. Microbiol Immunol 2006;50:759-64.
Grandoni JA, Marta PT, Schloss JV. Inhibitors of branchedchain amino acid biosynthesis as potential antituberculosis
agents. J Antimicrob Chemother 1998;42:475-82.
Grandoni J. Patent U.S. 5998420. Chem Abstr 1999;127:
326510.
Choi KJ, Yu YG, Hahn HG, Choi JD, Yoon MY. Characterization of acetohydroxyacid synthase from Mycobacterium tuberculosis and the identification of its new inhibitor from the screening of a chemical library. FEBS Lett
2005;579:4903-10.
Munier-Lehmann H, Chaffotte A, Pochet S, Labesse G.
Thymidylate kinase of Mycobacterium tuberculosis: a chimera sharing properties common to eukaryotic and bacterial enzymes. Protein Sci 2001;10:1195-205.
Li de la Sierra I, Munier-Lehmann H, Gilles AM, Barzu O,
Delarue M. X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 A resolution. J Mol Biol 2001;311:87-100.
Fioravanti E, Adam V, Munier-Lehmann H, Bourgeois D.
The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3´-azidodeoxythymidine
monophosphate suggests a mechanism for competitive inhibition. Biochem 2005;44:130-7.
Douguet D, Munier-Lehmann H, Labesse G, Pochet S. A
computer-aided ligand design for structure-based drug design. J Med Chem 2005;48:2457-68.
Hilliard JJ, Goldschmidt RM, Licata L, Baum EZ, Bush K.
Multiple mechanisms of action for inhibitors of histidine
protein kinases from bacterial two-component systems. Antimicrob Agents Chemother 1999;43:1693-9.
Stephenson K, Yamaguchi Y, Hoch JA. The mechanism
of action of inhibitors of bacterial two-component signal
transduction systems. J Biol Chem 2000;275:38900-4.
Weidner-Wells MA, Ohemeng KA, Nguyen VN, FragaSpano S, Macielag MJ, Werblood HM, et al. Amidino ben-
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
47
zimidazole inhibitors of bacterial two-component systems.
Bioorg Med Chem Lett 2001;11:1545-8.
Matsushita M, Janda KD. Histidine kinases as targets for
new antimicrobial agents. Bioorg Med Chem 2002;10:85567.
Stephenson K, Hoch JA. Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms. Curr Med
Chem 2004;11:765-73.
Furuta E, Yamamoto K, Tatebe D, Watabe K, Kitayama
T, Utsumi R. Targeting protein homodimerization: a novel
drug discovery system. FEBS Lett 2005;579:2065-70.
Crowle AJ, Douvas GS, May MH. Chlorpromazine: a drug
potentially useful for treating Mycobacterial infections.
Chemother 1992;38:410-9.
Bettencourt MV, Bosne-David S, Amaral L. Comparative in vitro activity of phenothiazines against multidrugresistant Mycobacterium tuberculosis. Int J Antimicrob
Agents 2000;16:69-71.
Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A,
Helm D, et al. Inhibitors of type II NADH:menaquinone
oxidoreductase represent a class of antitubercular drugs.
Natl Acad Sci U S A 2005;102:4548-53.
Garbe TR. Co-induction of methyltransferase Rv0560c by
naphthoquinones and fibric acids suggests attenuation of
isoprenoid quinone action in Mycobacterium tuberculosis.
Can J Microbiol 2004;50:771-8.
Tsenova L, Mangaliso B, Muller G, Chen Y, Freedman VH,
Stirling D, et al. Use of IMiD3, a thalidomide analog, as an
adjunct to therapy for experimental tuberculous meningitis.
Antimicrob Agents Chemother 2002;46:1887-95.
Rastogi N, Labrousse V, Khye SG. In vitro activities of
fourteen antimicrobial agents against drug susceptible and
resistant clinical isolates of Mycobacterium tuberculosis
and comparative intracellular activities against the virulent
H37Rv strain in human macrophages. Curr Microbiol 1996;
33:167-75.
Zhang Y, Mitchison D. The curious characteristics of
pyrazinamide: a review. Int J Tuberc Lung Dis 2003;7:6-21.
Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs
WR Jr, et al. Mechanism of thioamide drug action against
tuberculosis and leprosy. J Exp Med 2007;204:73-8.
Tranquilino T, Fajardo RS, Guinto RV, Cellona RM, Abalos
EC, Dela C, et al. A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy. Am J Trop
Med Hyg 2006;74:457-61.
Maus CE, Plikaytis BB, Shinnick TM. Molecular analysis
of cross-resistance to capreomycin, kanamycin, amikacin,
and viomycin in Mycobacterium tuberculosis. Antimicrob
Agents Chemother 2005;49:3192-7.
Falzari K, Zhu Z, Pan D, Liu H, Hongmanee P, Franzblau
SG. In vitro and in vivo activities of macrolide derivatives
against Mycobacterium tuberculosis. Antimicrob Agents
Chemother 2005;49:1447-54.
Erturan Z, Uzun M. In vitro activity of linezolid against
multi-drug-resistant Mycobacterium tuberculosis isolates.
Int J Antimicrob Agents 2005;26:78-80.
Williams DL, Spring L, Collins LP, Miller LB, Heifets RJ,
Gangadharam TP. Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998;42:1853-7.
Vernon AA. Rifamycin antibiotics, with a focus on newer
agents. In: Rom WN, Garay SM, editors, Tuberculosis. 2nd
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
p. 759-71.
Aubry A, Veziris N, Cambau E, Truffot-Pernot C, Jarlier V,
Fisher LM. Novel gyrase mutations in quinolone-resistant
and -hypersusceptible clinical isolates of Mycobacterium
tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother 2006;50:104-12.
Nopponpunth V, Sirawaraporn W, Greene PJ, Santi DV.
Cloning and expression of Mycobacterium tuberculosis and
Medicina (Kaunas) 2011;47(Suppl 2)
48
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Liudas Šlepikas, Jonas Salys, Hiliaras Rodovičius, Eduardas Tarasevičius
Mycobacterium leprae dihydropteroate synthase in Escherichia coli. J Bacteriol 1999;181:6814-21.
Laughon BE. New tuberculosis drugs in development. Curr
Top Med Chem 2007;7:463.
Vera-Cabrera L, Gonzalez E, Rendon A, Ocampo-Candiani
J, Welsh O, Victor M, et al. In vitro activities of DA-7157
and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis. Antimicrob Agents Chemother 2006;
50:3170-2.
Vera-Cabrera L, Richard J, Wallace Jr, Ocampo-Candiani
J, Welsh O, Choi SH, et al. In vitro activities of the novel
oxazolidinones DA-7867 and DA-7157 against rapidly and
slowly growing mycobacteria. Antimicrob Agents Chemother 2006;50:4027-9.
Das B, Rudra S, Yadav A, Ray A, Rao AV, Srinivas AS, et
al. Synthesis and SAR of novel oxazolidinones: discovery of
ranbezolid. Bioorg Med Chem Lett 2005;15:4261-7.
Bush K, Macielag MJ, Weidner-Wells MA. Taking inventory: antibacterial agents currently at or beyond Phase 1.
Curr Opin Microbiol 2004;7:466-76.
IMS R & D Focus, update date 12-20-1999. Available from:
URL: http://library.dialog.com/bluesheets/html/bl0445.
html
Arora SK, Sinha N, Jain A, Upadhayaya RS, Jana GH, Ajay
S, et al. Patent WO 200426828. Chem Abstr 2004;140:
287261d.
Arora SK, Sinha N, Sinha RK, Uppadhayaya RS, Modak
VM, Tilekar A. Presented at 44th Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC).
2004; Presentation F115.
Sinha RK, Arora SK, Sinha N, Modak VM. In vivo activity
of LL4858 against Mycobacterium tuberculosis. Presented
at 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 (ICAAC). Abstract
F-1116 2004.
Agrawal KC, Bears KB, Sehgal RK, Brown JN, Rist PE,
Rupp WD. Potential radiosensitizing agents. Dinitroimida-
zoles. J Med Chem 1979;22:583-6.
63. IMS R & D Focus, update date 11-03-1997. Available from:
URL: http://library.dialog.com/bluesheets/html/bl0445.
html
64. Matsumoto M, Hashizume H, Tomishige T, Kawasaki M,
Tsubouchi H, Sasaki H, et al. OPC-67683 a nitro-dihydroimidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006;3(11):e466.
65. Doi N, Disratthakit A. Characteristic antimycobacterial
spectra of the novel anti-TB drug candidates OPC-67683
and PA-824. Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy 2006, (ICAAC), San
Francisco, CA. Poster F1-1377a.
66. Bryk R, Gold B, Venugopal A, Singh J, Samy R, Pupek K,
et al. Selective killing of nonreplicating Mycobacteria. Cell
Host Microbe 2008;3:137-45.
67. Protopopova M, Hanrahan C, Nikonenko B, Samala R,
Chen P, Gearhart J, et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library
of 1,2-ethylenediamines. J Antimicrob Chemother 2005;
56:968-74.
68. Bogatcheva E, Hanrahan C, Nikonenko B, Samala R, Chen
P, Gearhart J, et al. Identification of new diamine scaffolds
with activity against Mycobacterium tuberculosis. J Med
Chem 2006;49:3045-8.
69. Barbosa F, Nacy C, Einck L, Protopopova M. In vitro antifungal susceptibility testing of drug candidate SQ109
against Candida albicans. Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC),
San Francisco, CA. Agents Chemother 2006; F1 1371.
70. Chen P, Gearhart J, Protopopova M, Einck L, Nacy CA.
Synergistic interactions of SQ109, a new ethylene diamine,
with front-line antitubercular drugs in vitro. J Antimicrob
Chemother 2006;58:332-7.
71. Andries K, Verhasselt P, Guillemont J. A diarylquinoline
drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223-7.
Received 20 October 2010, accepted 27 July 2011
Straipsnis gautas 2010 10 20, priimtas 2011 07 27
Medicina (Kaunas) 2011;47(Suppl 2)