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Organic Compounds to Combat Neglected Tropical Diseases, 2014, 231-26 6 231
CHAPTER 8
TUBERCULOSIS
Synthetic Organic Compounds as Potential Antitubercular Drugs:
A Review of the Progress Made in the Last Five Years
Jean Leandro Santos
1
, Guilherme F. dos Santos Fernandes
1
, Priscila Longhin
Bosquesi
1
, Leonardo B. Marino
2
, Clarice Q. F. Leite
2
, Chung M. Chin
1
and
Fernando Rogério
Pavan
2,*
1
Laboratory of Drug Research and Development, Faculty of Pharmaceutical
Sciences, Paulista State University- UNESP, Rodovia Araraquara Jaú Km, 01,
14801-902, Araraquara, SP, Brazil and
2
Laboratory of Mycobacteriology “Prof.
Dr. Hugo David”, Department of Biological Science, Faculty of Pharmaceutical
Sicences, Paulista State University - UNESP, Rodovia Araraquara Jaú Km, 01,
14801-902 Araraquara, SP, Brazil
Abstract: Tuberculosis (TB) is an airborne infectious disease caused by
Mycobacterium tuberculosis (MTB) bacteria that is both preventable and curable.
Although the mortality rate has decreased worldwide, the emergence of multidrug-
resistant MTB, extensively drug-resistant MTB, and MTB/human immunodeficiency
virus are stifling attempts to control TB and are associated with high rates of morbidity,
mortality, and impoverishment worldwide. Although the investment in research and
development has grown in recent years, the development of new candidate drugs has
not increased proportionally. Nevertheless, in the last few years we have seen some
evolution in the development of antitubercular drugs. After a gap of over 50 years
without any new drugs, several candidate drugs have been developed, offering new
hope for the treatment of drug-resistant strains of TB. Instead of focusing on recently
approved drugs or drugs close to approval, the objective of this review is to describe the
recent advances in the organic synthesis of drugs in early stages of development (hit-to-
lead) that have shown good results in vitro in terms of the minimum inhibitory
concentration, median inhibitory concentration, and selectivity index.
Keywords: Drug discovery, medicinal chemistry, tuberculosis.
*Address correspondence to Fenando Rogério Pavan: Laboratory of Mycobacteriology “Prof. Dr. Hugo
David”, Department of Biological Science, Faculty of Pharmaceutical Sicences, Paulista State University -
UNESP, Rodovia Araraquara Jaú Km, 01, 14801-902 Araraquara, SP, Brazil; Tel: (+55) 16 33014667;
E-mails: fernandopavan@fcfar.unesp.br and santosjl@fcfar.unesp.br
Send Orders for Reprints to reprints@benthamscience.net
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232 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
1. INTRODUCTION
Although the investment in research and development has grown, the development
of new candidate drugs for treating tuberculosis (TB) has not increased
proportionally. Nevertheless, over the last few years, we have seen some evolutions
in the development of candidate drugs against TB [1, 2]. After a gap of more than 50
years without any new drugs, several candidate drugs have been developed, offering
new hope for treatment of drug-resistant TB. TMC-207 (SIRTURO
®
; Janssen,
Beerse, Belgium) was the first of this ne w generation of small molecule drugs to be
approved by the United States Food and Drug Administration for the treatment of
multidrug-resistant TB. Others, including PA-824, OPC-67683, SQ-109, and LL-
3858, are currently undergoing clinical testing [1, 3]. Stakeholders worldwide are
now pinning their hopes on these new molecules, but what if they fail?
Unfortunately, strains resistant to these new mol ecules have already been reported
[4] because bacteria are constantly evolving. Spontaneous mutations are responsible
for the emergence of drug resistance, often occurring in genes encoding the enzyme s
responsible for activation of prodrugs or the drugs’ target proteins. In other words, a
single mutation is capable of inducing intrinsic drug resistance [5]. Extri nsic factors,
such as treatment failure, can also lead to increased bacterial resistance [6, 7],
beyond increased efflux pump activity [5]. Therefore, we must be prepared to
continue searching for new candidate drugs. For this reason, in this review, we
wished to focus on drugs in early stages (hit-to-lead) rather than drugs close to or
already approved. Our goal is to recognize the efforts of the numerous medicinal
chemistry research groups and reveal the promising results obtained to date to help
other groups to streamline their research. Accordingly, we focused our literature
review on new organic structures published in the last 5 years. There are three main
sources of potential new drugs: 1) natural products; 2) synthetic organic compounds;
and 3) synthetic inorganic compounds [8, 9]. There are many reviews focusing on
the biological activities of natural products [10-14], and we recently wrote a review
focusing on synthetic inorganic compounds [15]. Now, we will describe the
evolution of organic molecules over the last 5 years.
2. SEARCH STRATEGY
We searched Science Direct, Medline, Scopus and EMBASE for articles
published between 2008 and 2012 using the following keywords: antitubercular;
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 233
antitubercular activity; antimycobacterial; antimycobacterial activity;
antimycobacterial agents, and anti-Mycobacterium tuberculosis (MTB). Articles
describing natural products and inorganic compounds were excluded. We also
excluded articles focusing on mycobacteria other than MTB strain H37Rv.
Articles describing the development of compounds using target-based methods in
the absence of phenotypic information were also excluded. To identify potential
candidate drugs, we searched for compounds with a minimum inhibitory
concentration (MIC) < 10 µg/mL and a selectivity index (SI) > 10 [9]. SI was
defined as the median inhibitory concentration (IC50)/MIC.
2.1. ANTI-Mycobacterium Tuberculosis Drugs
The antitubercular drugs retrieved by this search are summarized in Table 1.
Several molecular modification strategies have been used to discover novel
antitubercular drugs.
Ahsan et al. described the synthesis and evaluation of new pyrazoline derivatives
using thiacetazone as a backbone [16]. Specifically, the authors proposed that the
rigidity of N-acyl hydrazone be increased by molecular annealing with other
compounds (Fig. 1). This strategy reduces the number of conformers and it has
been used to discover several new compounds.
NHCH
3
O N
NH NH
2
S
O
O
CH
3
CH
3
N
N
NH
2
S
CH
3
anelation
bioisosteric replacement
to oxygen
Figure 1: Production of the pyrazoline derivative by molecular modification of N-acyl hydrazone.
Ahsan et al. also proposed isosteric substitution of sulfur (thiocarbonyl) with
oxygen (carbonyl), which increased the antimycobacterial activity by about four
times and the SI values were > 161 [16, 17]. The same group also reported that
oxadiazole derivatives were active against MTB. In particular, they reported that
the compound 4-[(5-[(4-fluor-ophenylamino]-1,3,4-oxadiazol-2-yl)methylamino]-
1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one inhibited mycobacterial growth
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234 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
at a concentration of 0.78 µg/mL and isoni azid-resistant MTB at a concentration
of 3.12 µg/mL. This oxadiazole derivative did not violate Lipinski’s parameters.
Lipinski’s parameters, also known as the “rule of five”, is widely used as a filter
for drug-like properties based on the following essential drug-like properties: 1) >
5 H-bond donors; 2) molecular weight > 500 kDa; 3) LogP > 5; 4) and > 10
H-bond acceptors [18].
Ajay et al. reported the synthesis and evaluation of two 4-alkylaminoaryl phenyl
cyclopropyl methanones derivatives against MTB. The compounds synthesized
from 4-fluorochalcones were active against MTB strain H
37
Rv with MIC values
of 3.12–12.5 µg/mL. Interestingly, these comp ounds were also able to inhibit the
growth of Plasmodium falciparum in vitro with IC
50
values as low as 0.080 and
0.035 µg/mL and SI values of 4975 and 6948, respectively [19].
Some compounds with MICs < 0.10 µM against MTB have been reported. For
example, Ali et al. described a series of substituted phenyl-5,6-dimethoxy-1-oxo-
2,5-dihydro-1H-2-indenyl-methanone analogs with MICs ranging from 0.1–6.62 µM
and an IC
50
of 62.5 µg/mL in Vero cells [20] . Of these compounds, 5,6-dimethoxy-
1-oxo-2,5-dihydro-1H-2-indenyl-4-fluorophenylmethanone wa s the most promising
compound against MTB strain H
37
Rv and isoniazid-resistant MTB with an MIC of
0.10 µM in both strains (Fig. 2). Structure–activity relationship studies ha ve shown
that substitution of phenyl groups with an electron-accepting group, such as 4-fluoro,
increases antimycobacterial activity whereas substitution with an electron-donating
group decreases antimycobacterial activity.
Quinoxaline and quinoxaline, 1,4-di-N-oxide derivatives, display antiviral,
anticancer, antibacterial, and antiparasitic effects. Ancizu et al. synthesized and
evaluated 36 new 1,4-di-N-oxide-3-methylquinoxaline-2-carboxylic acid aryl
amide derivatives against MTB [23]. After confirming their antimycobacterial
properties, the cytotoxicity of each molecule was evaluated using Vero cells. If
the SI was ≥ 10, the compound was considered to be active against MTB. Based
on the structures of these molecules, the authors concluded that electron-accepting
groups (i.e. chloro) in the quinoxaline ring generally increase the
antimycobacterial activity of the derivatives, while electro-donating groups reduce
antimycobacterial activity (Fig. 3) [23].
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 235
O
O
CH
3
O
CH
3
O
F
electron withdrawing groups increase
antimycobacterial activity
Figure 2: 5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-4-fluorophenylmethanone is active at a
concentration of 0.10 µM in isoniazide-resistant and non-resistant MTB.
Furo[3,2-f]chromene derivatives were reported to inhibit the growth of
M. tuberculosis [21], and displayed cytotoxicity against Vero cells despite the
absence of mutagenic effects of the test compounds. Cytotoxicity is a common
undesirable effect observed in drug discovery that needs to be decreased to obtain
safe compounds for clinical use. Some molecular modification strategies, such as
the development of prodrugs, have been proposed to decrease the cytotoxicity of
these compounds [22].
N
+
N
+
NH
OO
-
O
-
CH
3
Cl
Cl
N
+
N
+
NH
OO
-
O
-
CH
3
Cl
Figure 3: Structures of quinoxaline 1,4-di-N-oxide derivatives with MICs of <0.2 µg/mL and an
SI > 500 against MTB.
De Logu et al. described the synthesis and antimycobacterial activities of N-aryl
phenazine-1-carboxamide derivatives against MTB strain H37Rv and drug-
resistant ATCC MTB strains [24]. Interestingly, the authors also evaluated the
intracellular activity of the test compounds against MTB phagocytosed by
macrophages. They reported that the compound [N-(4-bromophenyl)-5,10-
dihydrophenazine-1-carboxamide] was able to inhibit the growth of MTB strain
H37Rv at a concentration of 0.19 µg/mL (Fig. 4). The compound also
demonstrated activity against strains resistant to pyrazinamide, streptomycin, and
rifampicin. The compound was not cytotoxic. When administered at 5 mg/L, it
reduced the growth of mycobacterium phagocytosed in J774A.1 cells by 91.6%.
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236 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
The authors reported that the N-aryl phenazine-1-carboxamide subunit was the
effective pharmacophore, and its MICs ranged from 0.19 to 0.79 mg/L. The
authors also suggested that the antibacterial activity was mediated by the
inhibition of cellular superoxide dismutase.
N
N
NHOBr
pharmacophore subunit
N
-aryl or heteroaryl substituents
Variable Subunit
Figure 4: Structure of N-(3-bromophenyl)-5,10-dihydrophenazine-1-carboxamide, which had an
MIC of 0.19 µg/mL against MTB strain H
37
Rv and had low cytotoxicity.
Our review revealed that quinolone derivatives are the most active antitubercular
compounds with MICs < 0.3 µM. Dinakaran et al. synthesized and evaluated the
activities of 34 derivatives of 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-
oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid against MTB strain H
37
Rv
and multidrug-resistant MTB (MDR-MTB) [25]. The MICs of these compounds
ranged from 0.18 to 12.82 µM against MTB. The MICs of 2-(3-
(diethylcarbamoyl)piperidin-1-yl)-)-3-fluoro-5,12-dihydro-5-oxobenzothiazolo
[3,2-a]quinoline-6-carboxylic acid against MTB and MDR-MTB were 0.18 and
0.08 µM, respectively (Fig. 5). In vivo, oral administration of 50 mg/kg body
weight of this compound reduced the bacterial load in the lung and spleen to 2.78
and 3.12 log10 protection, respectively [25]. In a similar study, the same research
group synthesized 30 derivatives of 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-
methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (ofloxacin
derivatives). These compounds had MICs of 0.18–12.82 against MTB. Of note, the
compound 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-
dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij] quinolone -6-carboxylic
acid had MICs of 0.19 µM and 0.09 µM against MTB and MDR-MTB,
respectively. The SI for this compound was 695. In vivo experiments revealed that
this compound inhibited mycobacterial growth by decreasing the mycobacterial
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 237
load in the lung and spleen by 1.91 and 2.91 log10 protections. The authors
suggested that the antitubercular effects of this compound involved inhibition of
the supercoiling activity of DNA gyrase. Meanwhile, structure–activity
relationship studies revealed that the antimycobacterial activity of this compound
was increased by 1.1–8.8 times by introducing a nitro group at position C8 [26]
(Fig. 5).
N
OO
OH
S
F
N
N
O
CH
3
CH
3
N
OO
OH
F
N
NO
CH
3
N
O
OH
NO
2
electron withdrawing substituent
electron withdrawing substituent
anelation
anelation
(Dinakaran, Senthilkumar et al., 2008a)
(Dinakaran, Senthilkumar et al., 2008b)
MIC = 0,39 uM
MIC = 0,19 uM
N
OO
OH
F
N
N
O
CH
3
CH
3
CH
3
O
NO
2
electron withdrawing substituent
(Sriram, Yogeeswari et al., 2011)
MIC = 0,16 uM
Figure 5: Structures of fluoroquinolone derivatives with MICs of 0.16–0.39 µM against MTB.
Sriram et al. described the development of several fluoroquinolone derivatives [27].
One of these compounds, namely 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropa-
noyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
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238 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
acid (Fig. 5), was active in vitro with MICs of 0.16 and 0.04 µM against MTB in the
logarithmic growth phase and in starved culture conditions, respectively. Based on
the results of docking studies, the authors suggested that this compound inhibits
MTB isocitrate lyase, an enzyme involved in the glyoxylate pathway, which
incorporates carbon during the growth of microorganisms cultured with acetate or
fatty acids as the primary carbon sources [27].
The two most active compounds identified in this review were reported by
Senthilkumar et al. in two papers published in 2009 [26, 28]. In the first report,
the authors synthesized and evaluated 51 derivatives of 1-(cyclopropyl/2,4-
difluorophenyl/t-butyl)-1,4-dihydro-6-fluoro-7-(sub secondary amino)-4-
oxoquinoline-3-carboxylic acid, and evaluated their effects against MTB strain
H
37
Rv and MDR-MTB. The authors found that 7-(3-(diethylcarbamoyl)
piperidin-1-yl)-1-cyclopropyl-6- fluor o- 1 ,4-di hydr o- 4-oxoqui noli ne- 3- car boxyli c
acid (Fig. 6) was the most active compound in vitro with an MIC of 0.09 µM
against both MTB and MDR-MTB. In vivo, oral administration of 50 mg/kg
body weight of this compound decreased the mycobacterial load in the lung and
spleen tissue to 2.53 and 4.88 log10 protections, respectively. Structure–activity
relationship studies demonstrated that the antimycobacterial activity imparted by
the N
1
substituent was in the order of cycl opropyl > tert-butyl > 4-fluorophenyl.
Substitutions at position C7 yielded the following activity order: substituted
piperidines > substituted piperazines > fused piperazines and piperidines >
(thio)-morpholines. Furthermore, previous st udies conduc ted by Dinakaran et al.
[26] showed that substitution with a nitro group increased the antimycobacterial
activity. Considering these structure–activity relationships, the authors
synthesized and tested the antimycobacterial activity of the compound 7-(4-
((ben-zo[d][1,3]dioxol-5-yl)methyl)piperazin-1-yl)-1-cyclopropyl-1,4-dihydro-
6-nitro-4-oxoquinoline-3-carboxylic acid. Of the compounds originally
evaluated, this compound showed the greatest activity in vitro with MICs of
0.08 and 0.16 µM against MTB a nd MDR-MTB, respectively (Fig. 5). The SI of
this compound was > 1580. In vivo studies also showed that this compound
decrease the bacterial load in the lung and spleen to 2.78 and 4.15 log10
protections, respectively, after administration at a dose of 50 mg/kg body weight
[28].
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 239
N
OO
OH
O
2
N
N
N
N
H
O
Cl
MIC = 0,09 uM
(Senthilkumar, Dinakaran, Yogeeswari, China
et al
., 2009)
cyclopropyl > tert-butyl > 4-flurophenyl
piperidines > substituted piperazines > fused piperazines and piperidines > (thio) morpholines
Electron-withdrawing substituent
N
OO
OH
O
2
N
N
N
O
O
(Senthilkumar, Dinakaran, Yogeeswari, Sriram
et al
., 2009)
MIC = 0,08 uM
Figure 6: Structure–activity relationship of piperidine and piperazine quinolone derivatives active
against MTB with MICs < 1 µM.
Pyrazinamid is a prodrug that undergoes biotransformation in vivo by the enzyme
pyrazinamidase to generate an active metabolite, pyrazinoic acid. Pyrazinoic acid
accumulates inside the bacillus at acidic pH, disrupting the membrane potential
and interfering with energy production. Pyrazinoic acid also inhibits the enzyme
fatty acid synthase-I, which is required for the synthesis of fatty acids in bacteria.
Therefore, synthesis and evaluation of novel pyrazinamid analogs is an important
strategy to identify candidate drugs that show greater activity than the parent
compound. Dolezal et al. synthesized 20 amide derivatives and found that
lipophilic substitution of the phenyl group with 3,4-methyl or trifluoromethyl-
phenyl groups, for example, increases antimycobacterial activity (Fig. 7).
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240 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
However the authors did not test whether the compounds are converted to
pyrazinoic acid in vivo [29].
N
N
NH
2
O
pyrazinamide
N
N
NH
O
CF
3
lipophilic substituents
molecular
modification
MIC = 6.25 ug/mL
Figure 7: Synthesis of pyrazinamide derivatives that are more active against MTB than th e parent
drug.
Gosh et al. reported several glycosyl thioacetamide derivatives with MICs of 1.56
µg/mL and SI > 10. The authors found that changes in the stereochemistry of the
sugar moiety hardly affected the MIC and proposed that sulfonyl acetamide
derivatives could mimic the tetrahedral transition state of fatty acid biosynthesis.
However, it was also reported that lipophilicity is an important physicochemical
property for antitubercular drugs and the authors did not conduct studies to test
the important of this property [30]. The compound 2-[4-(1H-[1,2,4]-triazol-1-
yl)phenyl]-1-(3-fluorobenzyl)-4,6-difluoro-1H-benzo[d]imidazole synthesized by
Jadhav et al., and had an MIC of 0.36 µg/mL a nd SI of 156, which suggested it
was an interesting derivative for further studies [31]. Beyond its antimycobacterial
activity, the compound was also active in vitro against several bacterial species,
including Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and
Salmonella typhosa. Structure–activity relationship studies revealed that the
presence of a halogen at position 3 in the benzyl subunit increases antibacterial
activity (Fig. 8) [31].
The molecular hybridization approach was used by Kakwani et al. to synthesize
several cinnamide derivatives. The authors used 1,2-ethylenediamine as the parent
compound to design hybrid compounds containing α,β-unsaturated carbonyl moiety
(trans-cinnamic). α,β-unsaturated compounds such as trans-cinnamic acid possess
antimycobacterial activities and had synergistic effects when administered in
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