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Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 241
combination with rifampicin. The authors also tested isosteric replacement of the
1,2-ethylenediamine subunit to obtain piperazine, homopiperazine and 2-(piperazin-
1-yl)ethanamide derivatives. Using this approach, the authors synthesi zed a hybrid
compound with an MIC of 5.1 µM and an SI of 121 (Fig. 9) [32].
Electron withdrawn substituents at phenyl subunit
MIC = 0,36 ug/mL
F
F
N
N
N
N
N
F
Figure 8: Structure of an imidazole derivative with antitubercular and antibacterial activities.
Figure 9: Use of molecular hybridization to synthesize cinnamide derivatives.
Molecular modification of isoniazid yielded several active compounds with MICs
of < 0.77 µM active against MDR-MTB strains (Fig. 10). Interestingly, some
modifications in the isoniazid structure yielded compounds that were active
against resistant strains but their antimycobacterial activities were weaker than the
parent compound [33]. Manjashetty et al. used microwave-assisted one-pot
reactions to synthesize several derivatives of isoniazide, including benzaldehydes
MIC = 5,1 uM
SI = 121
NH
CH
3
OH
NH
OH
CH
3
ethambutol
NH
NH
O
O
N
H
N
H
NH
NH
NH
N
NH
2
Isosteric replacement
R
R
NH
NH
O
O
Hybrid compound
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242 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
and a series of dimedone compounds. One of these compounds,N-[9-[2-
(benzyloxy)phenyl]-3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-10 (1H)
-acridinyl]isonicotinamide, was a promising candidate with MICs < 0.17 µM against
MTB and 0.69 µM against MDR-MTB [34].
The isonicotinoyl hydrazinocarbothioamide derivative 2-isonicotinoyl-N-[2-
(trifluoromethyl)phenyl]hydrazinecarbothioamide, which had an MIC of 0.58 μM
against MTB strain H
37
Rv and isonicotinoyl hydrazide (INH)-resistant MTB, was
synthesized by reacting INHwith substituted phenyl thiocarbamate. This
derivative (Fig. 10) was 1.24 and 157 times more active against MTB strain
H
37
Rv and INH-resistant MTB, respectively, than isoniazid. The SI for this
compound was > 359 [35].
Figure 10: Structures of isoniazide derivatives that were obtained by molecular modification
(adapted from: Manjashetty, Yogeeswari et al., 2011).
N
NH
O
NH
2
N
NH
O
N
MIC: 0,0004 uM
N
NH
O
N
CH
3
N
N
CF
3
MIC: 0,25 ug/mL
N
N
O
N
OH
CF
3
MIC: 0,77 uM
N
NH
O
N
CH
3
NH
NH
S
F
MIC: 0,45 uM
N
NH
O
N
CH
3
OH
N
N
H
MIC: 0,56 uM
N
NH
O
N
OO
CH
3
CH
3
CH
3
CH
3
O
MIC < 0,17 uM
isoniazid analogs obtained by
molecular modification
isoniazide
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 243
The combinatorial chemical approach using libraries containing large numbers of
individual compounds and mixtures is an important drug discovery strategy that
allows researchers to screen a large number of diverse compounds and has led to
the identification of several potential candidate compounds. Using this approach,
Nefzi et al. evaluated a series of chiral pentaamines and bis-heterocyclic
compounds that achieved inhibitory rates of 90%–100% against MTB strain
H
37
Rv, with MICs ranging from 2 to 7 µg/mL [36].
Singh et al. synthesized α,α’-(EE)-bis(benzylidene)-cycloalkanones with MICs
ranging from 6.25 to 1.56 µg/mL and evaluated their antitubercular activities [37].
The authors synthesized the compounds by reacting cycloalkanones with different
aromatic aldehydes using ethanolic KOH, with good yields. The EE configuration
of diastereoisomers was characterized by nuclear Overhauser effect nuclear
magnetic resonance experiments. The authors also have found that more active
compounds could be synthesized by substituting the phenyl ring with electron-
accepting groups, such as bromo and nitro groups (Fig. 11) [37].
O
R
R
R = Br (MIC = 1.56 ug/mL); NO
2
(MIC = 3.12 ug/mL)
(Sign, Pandey et al., 2011)
NN
CH
3
O
S
O
O
NH
NH
O
N
N
O
O
CH
3
CH
3
MIC = 1.56 ug/mL (MDR- MTB)
sulfonylurea derivative
(Sohn, Lee et al., 2008)
NH
CF
3
NH
S
NH
O
N
MIC = 0.58 uM
(Sriram, Yogeeswari et al., 2009)
O
N
+
O
-
O
O
N
MIC = 0.19 uM
(Tawari, Bhuva et al., 2010)
Figure 11: Structures of compound with different MICs values.
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244 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
Searches for new targets are essential to design new candidate drugs for the
treatment of TB. Acetohydroxy acid synthase is an enzyme that catalyzes the
conversion of two molecules of pyruvate to 2-acetolactate and CO
2
, a reaction that
is involved in the biosynthesis of the branched-chain amino acids leucine,
isoleucine, and valine, which are essential for mycobacterial survival. Sohn et al.
evaluated a series of sulfonylurea derivatives capable of inhibiting this enzyme
[38]. One sulfonylurea derivative displayed antimycobacterial activity comparable
with that of streptomycin, and was also active against intracellular MTB,
including drug-resistant MTB strains, with an MIC of 3.1 µg/mL.
Several 4-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives that were synthesized by
condensation of 5-nitro-2-furaldehyde with various ketones under acidic
conditions were found to be potent antitubercular compounds. In particular, (E)-3-
(5-nitrofuran -2-yl)-1-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one (Fig. 11) had an
MIC of 0.19 µM, which was much lower than that of isoniazide (1.8 µM) used as
a control. The SI was > 1800. Structure–activity data revealed that the nitrofuran
subunit was essential for the antimycobacterial activity of this compound [39].
Our literature search also identified several compounds with MICs of < 1 μM or <
1 μg/mL. Trivedi et al. [40] described the synthesis and pharmacological
properties of dihydropyrimidines as potential inhibitors of dihydrofolate reductase
(DHFR), a promising drug target for the treatment of mycobacterial infections.
DHFR plays an important role in the folate cycle and inhibition of DHFR
interrupts the supply of thymidine, which is essential for DNA biosynthesis. Of 30
dihydropyrimidines evaluated in their study, [ethyl 4-[3-(4-fluorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate]
and [ethyl 4-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate] (Fig. 12) were the most active
compounds with MICs of 0.02 μg/mL [40]. In 2011, the same group published a
similar study in which they substituted the N-pyrimidine ring at position N-1
position. In this study, the authors synthesized the compound diethyl 1-(2-chloro-
phenyl)-1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine-3,5-
dicarboxylate (Fig. 12), which had an MIC of 0.02 μg/mL [41].
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 245
Quinoxalines and their mono- and di-N-oxide derivatives display a broad range of
biological activities, including antiprotozoal and anticancer properties. This is
partly due to its chemical structure, which undergoes bioreduction under hypoxic
conductions, causing DNA damage. Based on this mechanism of action, Vicente
et al. synthesized a series of 3-phenylquinoxaline 1,4-di-N-oxide derivatives and
tested their activities against MTB. Interestingly, 34 of 70 compounds tested in
that study had an MIC of < 0.2 μg/mL. The most active compounds contained a
fluorine substitution at position 7 of quinoxaline or in the para position of the
phenyl group (Fig. 12) [42].
The compounds 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline
showed excellent antitubercular activities with MICs of < 0.2 μM. These
compounds were prepared in a single reaction step from anthranilic acid and 2-
coumaranone in phosphorus oxychloride. The compounds obtained in this step
were then reacted with alcohols and amines to yield 11-alkoxylated and 11-
aminated benzofuro[2,3-b]quinoline derivatives. The compound 11-
dimethylaminobenzofuro[2,3-b]quinoline (Fig. 11) had an MIC of 0.2 μg/mL and
showed low cytotoxicity against Vero cells with an IC
50
of > 30 μg/mL [43]. Paul
et al. also reported the synthesis and evaluation of bisquinoline derivatives, such
as 2-(3-bromophenyl)-6-chloro-3-[4-(6-chloro-4-phenyl-2-quinolyl)phenoxy]-4-
phenylquinoline, which was very potent with an MIC of 1.1 μM and displayed
low cytotoxicity [44].
Vavrikova et al. described the preparation of isoniazid hydrazones, although the
compounds were less active than the parent drug [45]. Therefore, the authors used
molecular modification methods to increase the antimycobacterial activities of
these compounds. They designed several hybrid drugs containing fluoroquinolone
or pyrazinamide subunits. These compounds had MICs of < 0.5 μg/mL and high
SI values [45].
Dobrikov et al. used molecular modification methods to synthesize 47 ethambutol
derivatives with MICs ranging from 0.65 μM to 14.03 µM. Some of these
derivatives were more potent than the parent drug. The “duplicated” compound
(Fig. 11) had an MIC of 0.65 μM and an SI > 375 [46].
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246 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
R = F or NO
2
(MIC = 0.02 uM)
(Trivedi, Dodiya et al., 2011)
MIC = 0.02 uM
(Trivedi, Bhuva et al., 2010)
N
N
N
H
NH
O
O
CH
3
CH
3
O
R
N
N
N
EtOOC
CH
3
CH
3
R
COOEt
Cl
N
+
N
+
F
O
-
O
-
CN
F
(Vicente, Perez-Silanes et al., 2009)
MIC = 0.02 ug/mL (SI > 124)
N
O
N
CH
3
CH
3
(Yang, Tseng et al., 2010)
MIC < 0.2 ug/mL (SI > 150)
N
OO
OH
F
N
NN
NHO
F
quinolone subunit
isoniazid derivative subunit
(Vavrikova, Polanc et al., 2011)
MIC = 0.5 ug/mL MDR-TB (SI > 1200)
NH
O
O
NH
CH
3
OH
CH
3
OH
(Dobrikov, Valcheva et al., 2012)
ethambutol derivative subunit
MIC = 0.65 uM (SI > 375)
Figure 12: Structures of potent antimycobacterial compounds with MICs ≤ 0.0.2 μM.
The tables presented in this review provide an extensive summary of the most
promising antitubercular compounds that were obtained in the last 5 years using
organic synthesis methods. It is possible to compare the antitubercular activities of
each compound, including the MIC against MTB strain H
37
Rv, IC
50
against Vero
cells (Table 1) or other cell types (Table 2), and SI.
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 247
Table 1: Class compounds of different synthetic organic compounds and the activity against MTB H37Rv, VERO cell and the calculation
of selectivity index of their best compound
Refs.
Class Compounds
MW Best Compound
MIC IC
50
SI
μg/m
L
μM μg/mL μM
IC
50
/
MIC
[17]
371,4
2
3-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-
3H-indeno[1,2-c]pyrazole-2-carbothioamide
1.16 3.12
d
62.50
e
168.30 54
[16]
355.3
6
3-(4-fluorophenyl)-
N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-
dihydro-3H-indeno [1,2-c] pyrazole-2-
carboxamide
0.29 0.83
d
>47.62
>134.00
e
>161
[18]
394.4
0
4-[(5-[(4-fluorophenylamino]-
1,3,4-oxadiazol-2-yl)methylamino]-1,2-dihydro-
1,5-dimethyl-2-phenylpyrazol-3-one
0.78
d
1.98 62.50
e
158.47 80
N
N
NH
2
S
F
O
O
CH
3
CH
3
N
N
NH
2
O
F
O
O
CH
3
CH
3
N
N
O
NH
N
O
N
CH
3
CH
3
NH
F
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248 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
Refs.
Class Compounds
MW Best Compound
MIC IC
50
SI
μg/m
L
μM μg/mL μM
IC
/
MIC
[19]
337.8
0
(2-(4-Chlorophenyl)cyclopropyl)(4-(furan-2-
ylmethylamino)
phenyl)methanone
3.12
d
9.23 256.00
e
757.84 82
[20]
314.3
0
5,6-dimethoxy-1-oxo-2,5-dihydro-
1H-2-indenyl-4-fluorophenylmethanone
0.03 0.10
d
62.5
e
198.85 1988
[47]
583.5
8
Dispiropyrrolothiazole derivative 0.21
d
0.36 >62.50
e
>107.10 >297
O
NH
2
O
Cl
O
F
O
O
CH
3
O
CH
3
N
S
N
NH
O
O
O
CH
3
O
CH
3
O
F
3
C
Tuberculosis
Organic Compounds to Combat Neglected Tropical Diseases 249
Refs.
Class Compounds
MW Best Compound
MIC IC
50
SI
μg/m
L
μM μg/mL μM
IC
50
/
MIC
[21]
364.4
3
(E)-3-(2-(4,5,7,7-Tetramethyl-8,9-dihydro-7H-
furo-
[3,2-f]chromen-2-yl)vinyl)pyridine
5.00
a
13.72
>100.00
e
>274.40 >20
[23]
359.8
0
7-Chloro-1,4-di-N-oxide-3-methylquinoxaline-2-
carboxylic
acid 2-phenylethylamide
<0.20
b
<0.56
>100.00
e
>277.93 >496
[24]
319.3
3
N-(4-fluorophenyl)-5,10-dihydrophenazine-1-
carboxamide
0.19
d
0.59
>200.00
e
>626.31
>105
2
[25]
495.5
6
2-(3-(diethylcarbamoyl)piperidin-1-yl)-)-3-
fluoro-5,12-dihydro-5-oxobenzothiazolo[3,2-
a]quinoline-6-carboxylic acid
0.19 0.39
d
64.42 130.00
e
333
O
O
N
NH
OCH
3
CH
3
CH
3
CH
3
CH
3
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250 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
Refs.
Class Compounds
MW Best Compound
MIC IC
50
SI
μg/m
L
μM μg/mL μM
IC
50
/
MIC
[26]
475.3
8
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]quinoline-6-carboxylic acid
0.09 0.19
d
62.75 132.00
e
695
[29]
295.2
5
N-(3-trifluoromethylphenyl)pyrazine-2-
carboxamide
6.25
b
21.17 >62.50
e
>211.68 >10
[30]
479.4
5
glycosyl thioacetamide derivative 1.56
d
3.25 >15.60
g
>32.54 >10
[31]
405.3
7
2-[4-(1H-[1,2,4]-triazol-1-yl)phenyl]-1-(3-
fluorobenzyl)-4,6-difluoro-1-H-benzo-[d]-
imidazole
0.36
b
0.89 50.00
f
123.34 139
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