WORLD JOURNAL OF PHARMACEUTICAL RESEARCH

Transcrição

World Journal of Pharmaceutical Research
Das et al.
World Journal of Pharmaceutical
Research
SJIF Impact Factor 5.045
Volume 4, Issue 1, 1536-1570.
Research Article
ISSN 2277– 7105
NEW INSIGHTS INTO ANTI-TUBERCULAR POTENTIAL OF
TRIAZOLE SCAFFOLD
*Rina Das and Dinesh Mehta
Faculty of Pharmaceutical Sciences, Maharishi Markendeshwar University, Mullana,
Ambala, 133207. HR, India.
Article Received on
11 Nov 2014,
ABSTRACT
Revised on 06 Dec 2014,
Accepted on 31 Dec 2014
current problem of tuberculosis therapy is caused by the improper use
TB is a worldwide problem and it is a global health emergency. The
of antibiotics in chemotherapy of TB patients which gives rise to
*Correspondence for
multi-drug resistant (MDR) strains.
Author
compounds featuring five member ring of two carbon atoms and three
Rina Das
Triazoles are heterocyclic
nitrogen atoms as part of the aromatic five-member ring and possess
Faculty of Pharmaceutical
Sciences, Maharishi
almost all types of biological activities. This diversity in the
Markendeshwar
therapeutical response profile has attracted the attention of many
University, Mullana,
researchers to explore this skeleton to its multiple potential against
Ambala, 133207. HR,
several activities. Present article is sincere attempt to review chemistry,
India.
synthesis, spectral studies of triazoles and to study triazoles
synthesized in last few years which have shown potent antitubercular activity.
KEYWORDS: Antitubercular activity, Antitubercular drugs, Triazoles, Tuberculosis (TB).
INTRODUCTION
Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (MTB)
aerobic bacilli belonging to the family Mycobacteriaceae , first identified in 1882 by Robert
Koch. It is a chronic bacterial infection, spread through the air, and, which can mainly attack
the lungs, although can affect other organs as well.[1-7] The cell wall of the bacilli has a high
lipid content resulting in a high degree of hydrophobicity that resists decolorization by acid
alcohol after staining with basic fuchsin.[8-9] For this reason, the organism is often referred to
as an “acid-fast” bacillus (AFB). The bacillus thrives in oxygen rich environments, such as
the apices of the lung, the renal parenchyma, and the growing ends of bones.[9-10]
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Tuberculosis (TB) is caused by Mycobacterium of the „„tuberculosis complex‟‟, together with
mainly M. tuberculosis (MTB). Other Mycobacterium species such as M. bovis, M.
africanum, M.canetti and M. microti can also cause TB. TB is an airborne transmissible
infection caused by spreading of aerosolized droplets of MTB.[11] Mycobacteriums belong to
the order actinomycetales and family Mycobacteriaceae. Several species, including MTB, M.
bovis, M. microti, M. canetti, M. africanum, M. kansasii, M. avium, and M. leprae, are
intracellular pathogenic bacteria of higher vertebrates.[12] The MTB complex contains three
other TB producing mycobacteriums such as M. bovis, M. africanum and M. microti. The
first two mycobacteriums are very rarely cause disease in immune capable people. On the
other hand M. microti is not typically pathogenic; the prevalence of M. microti infections has
been under estimated.[13, 14] The non tuberculous mycobacterium (NTM) causes neither TB
nor leprosy, but cause pulmonary diseases resembling TB. The TB requires longer periods of
treatment to entirely eliminate mycobacterium from the body.[15, 16]
The current WHO-approved treatment for TB, known as directly observed therapy short
course (DOTS), involves an intensive phase with three or four different drugs viz. isoniazid
(INH, 1), rifampin (RIF, 2), pyrazinamide (PZA, 3), and ethambutol (EMB, 4) for a
minimum of 6 months.[17]
H
HO
O
O
N
OH
H
NH2
HO
O
OH
O
NH
O
N
N
O
N
O
OH
O
N
Fig 1: Isoniazid (INH, 1).
Fig2: Rifampin (RIF, 2).
OH
O
N
H
N
N
H
NH2
HO
N
Fig 3: Pyrazinamide (PZA, 3).
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Fig 4: Ethambutol (EMB, 4).
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CH3
O
H
HO
HO
O
HO
OH
O
O
O
O
N
NH-CH3
HO
N
NH2
NH2
OH
NH2
NH2
Fig 5: Streptomycin (SM, 5).
Most of the drugs in the current tuberculosis regime result from research performed over 50
years ago.[18] There is an urgent need to develop more potent and fast acting anti-TB drugs
with new modes of action to overcome the cross-resistance with current drugs and low
toxicity profiles that can be tolerated for long treatment periods required for TB
chemotherapy.[19] Development of resistance to existing drugs is a constantly growing
phenomenon that has concerned researchers throughout the world, and now has reached
alarming levels for TB. This combined with the recent decline in the development of new
drugs to combat them can be anticipated to lead to infectious diseases lacking ready treatment
regimens.[20]
The current TB drugs can be divided into two categories: First-line drugs and Second-line
drugs. The first-line drugs include INH (1), RIF (2), PZA, (3), EMB, (4) and Streptomycin
(SM, 5). The first-line drugs combine the greatest level of efficacy with an acceptable degree
of toxicity. Designed to reduce the bacterial population as rapidly as possible and to prevent
the emergence of drug-resistant bacteria. These drugs are best given as combination of
preparations unless one of the components cannot be given because of resistance or
intolerance.[21]
The second-line drugs include Kanamycin (6), Cycloserine (7), p-aminosalicylic acid (PAS,
8), Ethionamide (9), Prothionamide (10), Thiacetazone (11) and Fluoroquinolones (FQ, 12).
OH
OH
HO
O
O
NH3
HO
O
NH3
NH
O
O
NH3
HO
OH
O
NH3
Fig 6: Kanamycin (6)
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NH2
Fig 7: Cycloserine (7)
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Das et al.
S
NH2
O
OH
N
OH
H2N
CH3
Fig 8: p-Aminosalicylic acid (PAS, 8)
Fig 9: Ethionamide (9)
H3C
H
N
N
NH2
N
O
S
S
H3C
H2N
N
Fig 10: Prothionamide (10)
Fig 11: Thiacetazone(11)
R
R
N
R
HO
F
O
O
R
Fig 12: Fluoroquinolones (FQ, 12)
The second-line drugs are potentially nephrotoxic, therefore no two drugs from this group
should be employed simultaneously or in combination with streptomycin. [22] They are utilized
in cases of resistance, retreatment or intolerance to the first-line drugs.[23] They can also be
categorized as either Bacteriostatic which include EMB (4) and PAS (8) or Bactericidal
which include INH (1), RIF (2), SM (5) and FQ (12). The mechanisms of action and
resistance of TB drugs have been reviewed by Silva and Anisa.[24] These drugs can be
grouped as cell wall synthesis inhibitors, nucleic acid synthesis inhibitors, protein synthesis
inhibitors, and energy inhibitors.
Concurrent resistance to atleast two or more of the five first line anti-TB drugs (INH, RIF,
PZA, EBT, and SM) is Multi Drugs Resistance and Extensively Drugs Resistant (MDR-TB
and XDR-TB) MTB[25] MDR-TB treatment is long lasting, less effective, costly, and poorly
tolerated.[26] The XDR-TB is resistance to at least INH and RIF in addition to any quinolone
and atleast one injectable second-line drug (capreomycin, amikacin, and kanamycin). The
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principles of treatment for MDR-TB and XDR-TB are the same but the main difference is
that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of
reduced number of effective treatment options.[27-31] Hence there is an urgent need for novel
drugs that are active against MTB in order to shorten the duration of TB therapy.
This article aims to review the work reported on the synthesis of triazoles with antitubercular
activity during past few years. Triazoles are heterocyclic compounds featuring five member
ring of two carbon atoms and three nitrogen atoms as part of the aromatic five-member ring.
Triazole refers to either one of a pair of isomeric chemical compounds with molecular
formula C2H3N3, having a five membered ring of two carbon atoms and three nitrogen atoms.
The two isomers (Fig: 13) are.
H 1
N
H 1
N
N2
5
N 2
5
3
4N
1,2,4-triazole
4
N 3
1,2,3-triazole
Fig 13: Isomers of triazoles.
1,2,3-Triazole is one of a pair of isomeric chemical compounds with molecular formula
C2H3N3, called triazoles, which have a five-membered ring of two carbon atoms and three
nitrogen atoms. 1, 2, 3-Triazole is a basic aromatic heterocycle.
Synthetic routes of Triazoles
Many methods are available to synthesize 1, 2,4-triazole and its derivatives, out of which
some are as depicted below.
1. From diacylhydrazide[32]
HN
NH
H3CCO
N
+
N
H2NCH3
COCH3
Me
Me
N
Me
Scheme 1
2. 2. From acyl thiocyanates[33]
R
N
RCOCl
NH4SCN
RCON=C=S
S
N
N
H
R
Scheme 2
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3. From Esters[34]
H2N-NH2
RCOOR
N
R-CONHNH2
N
R-CONHNH-C-S-K+
SH
N
H
R
S
Scheme 3
4. Triazoles may be prepared by heating acid hydrazide with amides e.g. formyl hydrazide
andformamide give triazole.[35]
NH2
N
O=C
+
H-C=O
NH
NH
+ 2H2O
N
H2N
Scheme 4
5. From condensation of Hydrazide or a mono substituted hydrazine with di-acylamine[36]
Hydrazide or a mono substituted hydrazine is condensed with adi-acylamine in the presence
of a weak acid, for example phenyl hydrazine and N-formyl benzamide. Reaction gave 1,5diphenyl-1,2,4-triazole (Fig. 5) in good yields.
NH
Ph-NHNH3 + PhCONHCHO
H
Ph
C2H5OH
N
N
Ph
HN
N
Ph
N
Scheme 5
6. From aminoguanidine and formic acid.[37]
NH2
H2N-C-NH-NH2
HCOOH
N H3PO2
H2O
H2N-C-NHNH-C-H
NH
NH
N
O
N
H
N
N
N
H
Scheme 6
7. From 1,2,4-oxadiazole[38]
N
N
NH3
N
N
O
N
H
Scheme 7
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8. By decarboxylation of 1,2,4-triazole -5-carboxylic acid[39]
N
N
N
N
COOH
N
H
N
H
Scheme 8
9. From 4-amino-1,2,4-triazole[40]
N
N
H3PO4
H2O
N
N
N
N
H
NH2
Scheme 9
10. From 1,3,5- triazines[41]
N
N
N
H2N-NH2.HCl
N
N
H
N
Scheme 10
Biological Activities
The 1, 2, 4-triazole nucleus has been incorporated into a wide variety of therapeutically
important agents. Ribavirin (antiviral),[42] Rizatriptan (antimigraine),[43] Vorozole, Letrozole
and Anastrozole (antitumor)[44] are some examples of drugs containing 1, 2, 4-triazole
moiety.
Posaconazole, Fluconazole and Itraconazole,[45,46] that are efficient antifungal drugs used in
current treatment. A number of biological activity such as antibacterial antifungal [47,48] antiinflammatory, analgesic[49] anticonvulsant,[50] anticancer[51,52] antitumor,[53,54] antiviral,[55]
antileishmanial,[56] potassium channel activators,[57] antiplatelet[58] and anti-oxidant[59] have
been associated with N- substituted triazole attached with different hetrocyclic nuclei.
In the design of new bioactive agents, the development of hybrid molecules through the
combination of different pharmacophores in the same structure may lead to compounds
having more efficiency in biological activity. Systematic structural modifications of the
amide-1,2,3-triazole leads to develop of bioisosteric relationship in the molecule.[60] It has
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been noticed continuously over the years that interesting biological activities were associated
with triazole derivatives.
Some Biologically Active Triazole Derivatives
Amitrole [61] (Fig: 14) (3-amino-1H-1,2,4-triazole) is used as a herbicide and also to defoliate
cotton plants before mechanical harvesting
H2N
N
N
N
H
Fig: 14
The clinically useful derivatives of 1,2,3-triazole includes Tazobactam[62] (Fig:15) which is
used in combination with β-lactam antibiotics as antibacterial and Fig:14[63] (Fig:16)used as
an anticonvulsant.
O
O
S
F
CH2
N
CH3
N
CH2 HN
N
N
N
N
O
CONH2
F
Fig: 15
Fig:16
The derivatives of 1,2,4- triazole of therapeutic importance includes Rizatriptan[64]
Trazodone[65] (Fig:18) an antidepressant, Dapiprazole[66] (Fig:19) a miotic agent,Ribavirin[67]
(Fig:20) an antiviral agent, Israpafant[68] (Fig:21) an antiasthmatic, Lotrifen[69] (Fig:22)
anabortifacient and Rilmazafone[70] (Fig:23)a potent sedative and hypnotic agent.
(CH2)N(CH3)2
N
N
CH3
N
H
N
Fig: 17
O
Cl
N
N
(CH2)3
N
N
N
Fig: 18
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N
N
N
H3C
(CH2)2
N
N
Fig: 19
N
N
CONH2
N
S
N
N
O
HO CH2
N
H3C
N
Cl
OH
HO
Fig: 20
Fig:21
N
(CH3)2NCO
CH2NHCOCH2NH2
N
N
Cl
N
OC
N
N
Fig:22
Cl
Cl
Fig:23
Some derivatives of 1H-1,2,4- triazole are also found to be useful as potent antiestrogens,
major examples of which are Anastrozole[71] (Fig:24) , vorozole[72] (Fig:25) and letrozole[73]
(Fig:26).
CN
N
N
C(CH3)2
N
CH3
CN
Fig:24
C(CH3)2
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N
N
N
CH
N
N
CH3
N
Cl
Fig: 25
N
N
N
CH
CN
NC
Fig: 26
Antifungal activity exhibited by many potent antifungal agents is attributed to the presence of
triazole ring system. Major examples of triazole containing antifungal agents include
Fluconazole[74] (Fig:27), Voriconazole[75] (Fig:28) and Itraconazole[76] (Fig:29).
F
N
OH
N
C
F
F
CH2 CH
C
F
N
CH3
OH
CH2
N
CH2
N
N
F
N
N
N
N
N
Fig: 27
Fig:28
Cl
O
Cl
N R
N
CH2-O
H
N
N
O
N
N
R=
N
CH3
CH-C2H5
N
O
Fig: 29
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The triazole ring has been fused at 1,2-position of 1,4-benzodiazepines to give Estrazolam[77]
(Fig:30) and Triazolam[78] (Fig:31)the potent hypnotic agents and Alprazolam[79] (Fig:32) a
potent antipsychotic agent.
N
N
R
30] R=H,X=Cl,Y=H
31] R=CH3,X=Cl,Y=Cl
N
NH2
32] R=CH3,X=Cl,Y=H
Y
X
A brief review of triazoles associated with antimycobacterial activity is presented below.
Sanna et al.[80] synthesized a series of 3-aryl substituted-2-(1H(2H)-benzotriazol-1(2)yl)acrylonitriles for a preliminary invitro evaluation of antitubercular activity. They reported
that several compounds showed interesting activity in the preliminary screening with a
percent growth inhibition of Mycobacterium tuberculosis between 40 and 99% at the
concentration of 12.5 µg/mL. The most effective derivatives were also tested in vitro against
M. avium.
Klimesova et al.[81]evaluated a series of 3-benzylsulfanyl derivatives of 1,2,4-triazole and 4methyl-1,2,4-triazole for their invitro antimycobacterial activity against Mycobacterium
tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as
minimum inhibitory concentrations. The compounds exhibited only a moderate or slight anti
mycobacterial activity with MICs falling into a range of 32> 1000 µmol/L. The most active
substances bear two nitro groups or a thioamide group on the benzyl moiety. As regards to
cytotoxicity effect, the evaluated compounds could be considered as moderately toxic.
Zahajska et al.[82] prepared a set of four types of benzazoles, 1,2,4-triazole, and pyridine-2carbonitrile/-2-carbothioamide
substituted
with
1-naphthylmethylsulfanyl
or
pyridylmethylsulfanyl to modify the structure of benzylsulfanyl derivatives. The compounds
were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis,
M.avium, and two strains of M. kansasii. The MIC values were in the range of 2 to
>1000mol/L. Introduction of a pyridyl moiety into the molecule generally decreased the
activity. A naphthyl moiety did not affect the activity when substituted with a phenyl ring.
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The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide(MIC
= 2 - >62.5 mol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (MIC = 2 >32 mol/L).
Kaplancikli et al. [83] synthesized new 3-alkylsulfanyl-1,2,4-triazole derivatives(Fig. 33) and
evaluated them for antitubercular activity by broth microdilution assay, the Microplate
Alamar Blue Assay, in BACTEC 12B medium using BACTEC 460 Radiometric System
against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 µg/ml and the tested
compounds showed considerable inhibition ranging from 58-84%.
S
N
NH
N
O
HS
S
Cl
Fig: 33
Costa et al [84] described the synthesis, in vitro anti-Mycobacterium tuberculosis profile, and
the SAR study of new N-substitutedphenyl-1,2,3-triazole-4-carbaldehydes (Fig. 34).Two
compounds screened for the inhibitory activity against Mycobacterium tuberculosis H37Rv
were able to inhibit the growth of the mycobacterium. Interestingly, these compounds
exhibited the best inhibition with MIC values of 2.5 µg/mL, similar to pharmaceuticals
currently used in the treatment of tuberculosis. Their SAR study indicated the importance of
the hydrogen bond acceptor subunit, the position in the aromatic ring, the planarity of triazole
and phenyl rings in these compounds, and a correlation between the uniform highest occupied
molecular orbital (HOMO)coefficient distribution and the anti-tubercular activity. The
significant activity of two compounds pointed them as promising lead molecules for further
synthetic and biological exploration
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OHC
N
N
N
Compound
3a
3k
R
3,5-DiCl
4-CH3
R
Fig: 34
Banfi et al.[85] investigated different series of imidazole and triazole derivatives having an
azomethine linkage to pyridine-2-carboxamidohydrazone to develop new antimycobacterial
and antifungal drugs. MICs of the compounds were evaluated by reference assay and as well
as employing recently developed Microdilution Resazurin Assay (MRA). It was found that
halogenated derivatives showed good activity; most of the compounds had inhibitory action
against Mycobacterium tuberculosis reference and clinical strains, with MICs in the range 464 mg/L. Molecular modeling investigations showed that the active new compounds may
interact at the new potent site of mycobacterial cytochrome P450-dependentsterol-14αdemethylase and that the calculated binding free energy values are in agreement with the
corresponding MIC values.
In 2007 Shiradkar M et al.[86] synthesized a series of N-{4-[(4-amino-5-sulfanyl-4H-1,2,4triazol-3- yl)methyl]-1,3-thiazol-2-yl}-2-substituted-amides (Fig:35) in good yields. The
compounds were screened for antitubercular activity against Mycobacterium tuberculosis
H37Rv strain by broth micro dilution assay method. The in vitro antitubercular activity
reports of tested compounds against M. tuberculosis strain H37Rv showed moderate to better
activity.
R
S
N
N
N
N
SH
NH2
R= H, CH3, NH2, NHCH3
Fig: 35
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Mahendra Ramesh Shiradkar et al,[87] reported the synthesis of various derivatives of N-{4[(4-amino-5- sulphanyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-2-substituted amides
(Fig:36) and tested for antibacterial and antitubercular potency. Compound 5a with R=
NHCOCH2Cl and Ar = 4Cl-C6H4 showed good antitubercular activity.
N
N
Active
R
Ar
compound
5a
-NHCOCH2Cl 4Cl-C6H5
SCH2COOCH3
N
NH
N
O
S
R
Ar
Fig: 36
Mahendra Shiradkar et al,[88] synthesized analogues of thiazolyl triazoles (Fig:37) and tested
for their antimycobacterial and antimicrobial activities. Compound with R= NHCOCH 2Cl
showed good antitubercular activity.
NH
N
N
O
R
S
N
N
S
N
N
N
NH2
SH
Fig: 37
Carta et al.[89] studied activity of 3-methyl-9-substituted-6-oxo-6,9-dihydro-3H-[1,2,3]triazolo[4,5-h]quinolone carboxylic acids(Fig. 38) and their esters as a new class of
antiinfective agents against MDR Mycobacterium tuberculosis. In antitubercular screening
against H37Rv and clinically isolated strains of M.tuberculosis several derivatives showed
MIC90 in the range 0.5-3.2µg/mL. Preliminary SAR studies suggested that in general the
presence of an alkyl substituent on triazole nucleus was more favorable than propenyl or
benzyl groups for better antitubercular activity. One compound showed no cytotoxicity and
proved to bethe most potent derivative exhibiting MIC90=0.5 µg/mL against all strains of M.
tuberculosis and infected human macrophages (J774-A1)tested .
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COOH
H3C N
N N
N
H
Fig: 38
A series of 4-arylidenamino-4H-1,2,4-triazole-3-thiol derivatives were synthesized and
evaluated by Ozdemir et al.[90] for antituberculosis activity against Mycobacterium
tuberculosis H37Rv (ATCC 27294), using the BACTEC 460 radiometric system and
BACTEC 12B medium. One compound showed significant activity at 6.25 µg/mL with a
87% inhibition.
Biswajit Kumar Singh and coworkers[91] prepared5-Azido-5-deoxy-xylo-, ribo-, and
arabinofuranoses by the reaction of the respective 5-O-(methanesulfonyl) or ptoluenesulfonyl derivatives with NaN3 in DMF. The intermediate 5-azido-5-deoxy
glycofuranoses on 1,3-cycloaddition with different alkynes in the presence of CuSO4 and
sodium ascorbate gave the corresponding sugar triazoles(Fig :39) in very good yields. The
synthesized sugar triazoles were evaluated for their antitubercular activity against
Mycobacterium tuberculosis H37Rv, where one of the compounds displayed mild
antitubercular activity in vitro with MIC 12.5 µg/mL.
N
N
N
O
OMe
R
OH
OH
Fig: 39
A series of novel N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5yl)phenyl]thioureas and three S-alkylated representatives of the former, N-alkyl/aryl-N'-[4(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas
was
studied
by
Kucukguzel et al for antimycobacterial activity against Mycobacterium tuberculosis H37Rv
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as well as Mycobacterium fortuitum ATCC 6841 which is a rapid growing opportunistic
pathogen.[92] Some compounds were found to possess the same MIC value as that of
tobramycin against M. fortuitum ATCC 6841whereas other compounds had positive response
against M.tuberculosis H37Rv at varying degrees. One compound was identified as the most
potent derivative of the series with an MIC value of 6.25 µg/mL and selectivity index of
1.6.[92] Further, they designed a series of novel 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4dihydro-3H-1,2,4-triazole-3-thiones and several related thioureas, N-alkyl/aryl-N'-{4-[(4alkyl/aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thioureas(Fig.40) for
evaluation of their antimycobacterial potency. All compounds were evaluated in vitro for
antimycobacterial against Mycobacterium tuberculosis H37Rv. One compound was the most
active compound with 79% inhibition against M. tuberculosis H37Rv.
H
N
NH
N NH
S
O
N
S
CH2
Fig: 40
A novel series of 4-pyrrol-1-yl benzoic acid hydrazide analogs, derived 5-substituted-2-thiol1,3,4-oxadiazoles,
5-substituted-4-amino-1,2,4-triazolin-3-thione
(Fig.
41)
and
2,5-
dimethylpyrroles were designed and synthesized in good yields by Joshi et al.[93] Compounds
were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive
and Gram negative bacteria and for antitubercular activity against Mycobacterium
tuberculosis H37Rv strain by broth dilution assay method. Some compounds exhibited very
good antibacterial and antitubercular activities.
O
NH
N
N
N N
N
Fig 41
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Singh et al.[94] reported preparation of 5-azido-5-deoxy-xylo-, ribo-, and arabinofuranoses
and their intermediate 5-azido-5-deoxyglycofuranoses which on 1,3-cycloaddition with
different alkyne safforded the corresponding sugar triazoles in very good yields. The
synthesized sugar triazoles were evaluated for their antitubercular activity against
Mycobacterium tuberculosis H37Rv, where one ofthe compounds displayed mild
antitubercular activity in vitro with MIC 12.5 µg/mL.
Gill et al.[95] Synthesized a series of novel clubbed [1,2,3] triazoles(Fig. 42) with fluorine
benzimidazole series of H37Rv strain inhibitors. As a part of SAR studies, they had
incorporated fluoro substituent at positions 2, 3 & 4 in different variations on the phenyl ring
attached to triazole nucleus. Replacement of fluoro with trifluoromethyl group resulted in a
substantial loss of biological activity. This loss may indicate retardation in the intracellular
transport due to highly electronegativity in one region. In case of electron donating groups,
like methyl substitutions resulted in loss of activity. The biological data generated revealed
that compounds having an electron withdrawing group like fluoro attached to triazole nucleus
may prove a template for anti tuberculosis activity for further development. Some of the
derivatives are under further evaluation showing better and considerable activity compared to
rifampin.
N
F
N
N
N
N
F
F
F
Fig: 42
A series of 1-nitrobenzyloxybenzotriazoles was synthesized and tested against four
Mycobacterium strains by Augustynowicz-Kopec et al.[96] High antimycobacterial activity,
comparable with that of isoniazide, was found for 5,6-dichloro-1-(3,5-dinitrobenzyloxy)-1Hbenzotriazole (Fig. 43).
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Das et al.
-
O
O
N+
N
O
-O
N
N
N+
Cl
O
Cl
Fig: 43
Gupte et al.[97] Demonstrated synthesis, biochemical, and biological evaluation of a
systematic series of 2-triazole derivatives (Fig.44) of 5'-O-[N-(salicyl)sulfamoyl]adenosine
(Sal-AMS) and described them as inhibitors of aryl acid adenylating enzymes
(AAAE)involved in siderophore biosynthesis by Mycobacterium tuberculosis. SAR revealed
a remarkable ability to tolerate a wide range of substituents at the 4-position of the triazole
moiety, and a majority of the compounds possessed subnano molar apparent inhibition
constants. However, the in vitro potency did not always translate into whole cell biological
activity against M. tuberculosis, suggesting that intrinsic resistance plays an important role in
the observed activities.
OH
N N
N
N
NH2
N
NH
O
O
S
N
N
O
HO
OH
OH
Fig: 44
Castagnolo et al.[98] Reported a series of novel enantiomerically pure azole derivatives(Fig.
45). The new compounds, bearing an imidazole and a triazole moiety, were evaluated as
antimycobacterial agents. One of them proved to have activity against Mycobaterium
tuberculosis comparable to those of the classical antibacterial/antifungal drugs such as
econazole and clotrimazole.
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Das et al.
Br
N
N
N
N
N
Fig: 45
A series of fluorinated 1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid derivatives was
designed and synthesized by Abdel-Rahman et al.[99] These compounds were screened
against Mycobacterium tuberculosis H37Rv strain at 6.25 µg/mL concentration. One
compound,
the
7-oxo-2-(trifluoromethyl)-4,7-dihydro-1,2,4-triazolo[5,1-a]pyrimidine-6-
carboxylic acid (Fig.46) was found to be a very potent inhibitor, being able to inhibit 92%
growth of M. tuberculosis H37Rv at 6.25 µg/mL concentration. At the same time, it proved to
be nontoxic to mammalian cells (IC50> 62.5 µg/mL in verocells).
O
O
N N
OH
N
N
H
F
F
F
Fig: 46
Newly 1,2,4 triazoles analogs (Fig:47) were synthesized by NB Patel et al.[100]and carried in
vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Compound 3(3-pyridyl)-5-(4-methylphenyl)-4-(N-4-chloro-1,3-benzo thiazol-2-amino)-4H-1,2,4 triazole
showed better antitubercular activity compared to rifampicin.
N
N
N
CH3
NH
N
N
S
R= 4-Cl
R
Fig: 47
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Das et al.
A series of 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole and 1,3,4- oxadiazole
derivatives (Fig:48) were synthesized and were evaluated for their preliminary cytotoxicity,
antimicrobial and antitubercular activity against Mycobacterium tuberculosis H37Rv strain
by broth dilution assay method.[101] Antimycobacterial activity tested against M. tuberculosis
indicated that compounds 4b and 6g exhibited twofold enhanced potency than parent
compound and the results indicate that some of them exhibited promising activities and they
deserve more consideration as potential antitubercular agents. The tested compounds
possessed moderate to good inhibition, compounds 6g and 6i showed comparatively good
activity against all tested microbial strains and excellent inhibition towards M. tuberculosis
H37Rv at MIC 4 mg/mL.
N
Compound
6g
N
N
R
Cl
SH
N
S
6i
NH
HC
HC
R
Fig: 48
Different 1,4-Disubstituted -1,2,3-triazoles(Fig:49) were developed by Tripathi and
coworkers[102] and were screened for antitubercular activity against Mycobacterium
tuberculosis H37Rv and compounds 9,12 and 14 exhibited antitubercular activities with MIC
ranging from 12.5 to 3.12 ug/ml.
N
N
O
N
Compound
R
9
-4CHO
12
-4CHO
14
-2,5-DiMe
R1
R
R1
-(CH2)4CH3
-(CH2)5CH3
-CH2OH
Fig: 49
Kumar et al.[103] Studied a series of 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole
(Fig. 50) and 1,3,4-oxadiazole derivatives for their antitubercular activity against
Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. One compound
exhibited promising antitubercular activity with MIC value of 4 µg/mL when compared with
standard drug INH having MIC value of 0.25 µg/mL. This result indicates that it deserve
more consideration as potential antitubercular agent.
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Das et al.
H3C
N N
N
S
CH3
N
N
SH
Cl
Fig: 50
Patel
et
al.[104]
Synthesized
3-(3-pyridyl)-5-(4-methylphenyl)-4-(Nsubstituted-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole analogs (Fig. 51) and evaluated for antitubercular
activity against Mycobacterium tuberculosis H37Rv strain using Lowenstein-Jensen medium
and antimicrobial activity against various bacteria and fungi using broth microdilution
method. Some compounds emerged as promising antimicrobials. It was also observed that the
promising antimicrobials have proved to be better antituberculars. One compound showed
better antitubercular activity with MIC value of 25 µg/mL when compared with standard drug
rifampicin having MIC value of 40 µg/mL.
N
N
N
CH3
N
HN
S
N
Cl
Fig: 51
Various 4-substituted N-phenyl-1,2,3-triazole derivatives were synthesized by N Nubia
Boechat(Fig:52) using click chemistry.[105] The derivatives were screened in vitro for
antimicrobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294)
using the Alamar Blue susceptibility test. Derivatives of isoniazid (INH), (E)-N0-[(1-aryl)1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, exhibited significant activity
with MIC values ranging from 2.5 to 0.62 μg/mL. In addition, they displayed low
cytotoxicity against liver cells (hepatoma HepG2) and kidney cells (BGM), thereby providing
a high therapeutic index. The results demonstrated the potential and importance of
developing new INH derivatives to treat mycobacterial infections.
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Das et al.
N
N
N
R
Fig: 52
N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives were
synthesized by Mandal S and coworkers[106] (Fig:53). These derivatives were synthesized in
good yields and some of them showed a promising antitubercular profile. The Nacylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis
H37Rv strain (MIC = 2.5 lg/mL) similar to or better than the current drugs on the market.
The theoretical structure– activity relationship study suggested that the presence of the furyl
ring and the electronegative group (NO2) as well as low lipophilicity and small volume group
at R position are important structural features for the antitubercular profile of these
molecules.
Ar
O
N
H
N
H
N
Compound
8n
R
H
Ar
N
N
CH3
O
NO2
N
H
R
Fig: 53
Rapid synthesis of 1,2,3-triazole derivatives(Fig : 54) has been achieved via Huisgen's 1,3dipolar cycloaddition between alkyl/arylazides and diethyl/dimethyl acetylenedicarboxylate
in excellent yields under solvent-free conditions by Shanmugavelan P and coworkers.[107] In
vitro antitubercular activity of these triazoles were screened against Mycobacterium
tuberculosis H(37)Rv strain. Four of the compounds(2b,2d,2e,3d) showed MIC in the range
of 1.56-3.13 μg/mL proving their potential activity.
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Das et al.
N
N
O
N
R
N
O
N
R
O
O
CH3
O
O
O
O
CH3
CH3
CH3
compound of the series 2
compound of the series 3
Fig: 54
Analogues of Gallic acid [3, 4, 5-trihydroxybenzoic acid, C6H2(OH)3 COOH] containing
triazole nucleus (Fig:55) were synthesized.[108] Then all synthesized compounds were
subjected to investigation for their antitubercular activity against M.Tuberculosis H37Rv
strain using MABA method and Rifampicin as the standard. The results of which showed that
among the synthesized compounds few compounds showed equivalent activity as that of
standard while remaining compounds found to be less active when compared to standard.
Compounds S2 and S5 with Ar =-3NO2 and -4OH showed good antitubercular activity.
HO
N
HO
N
HO
Compound
S1
S2
S3
S4
S5
N
NHC2H5
N=CH-Ar
Ar
-3,4,5-OCH3
-3NO2
-4NO2
-3OH
-4OH
Fig: 55
Shashikant Patten et al.[109] Synthesised 5-mercapto 1,2,4-triazole derivatives (Fig:56) and
evaluated for antimicrobial, anti-inflammatory, antitubercular activities. Compounds 5g and
5h with Ar = p-NH2-C6H4 showed very good antitubercular activity.
N
Ar
N
N
SH
N
NH
Ar
N
SH
N
5g,h = Ar = p-NH2-C6H4
O
SO2NH2
Fig: 56
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Suhyun Kim and coworkers[110] designed and synthesized 1H-1,2,3-triazoles derived from
econazole (Fig : 57).The majority of triazole derivatives have been prepared by microwaveassisted click chemistry. The prepared triazoles had no antifungal activities. However, most
of the hydroxy-triazoles (10) turned out to have antitubercular activities. Overall, hydroxytriazoles 10 were more active than their corresponding ether-triazoles . While the MIC value
of hydroxy-triazole 10d was as good as econazole (16 lg/mL), the MIC value of 10a was twofold more active than econazole, suggesting that this 1H- 1,2,3-triazole scaffold could be
further optimized to develop Mtb specific agents.
R
N
N
Cl
Compound
10a
10d
R
n-Bu
cyclohexyl
N
OH
Cl
Fig: 57
A novel series of some 2-(4,5-disubstituted-4,5-dihydro-3H-1,2,4-triazol-3-yl) pyrazine (B1B9) derivatives (Fig:58) were prepared from N'-substituted pyrazine-2-carbohydrazide by
Dighe NS and coworkers.[111] The compounds were evaluated for antibacterial activity,
antifungal activity, antitubercular and anti-inflammatory activities. Among the synthesized
compounds some compounds found to possess all these activities. Compounds B2, B4, and
B7 has showed promising antitubercular activity.
N N
N
N
N
R
H
Ar
OH
Ar
B4
OMe
CH=CH-
R
Fig: 58
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Compound
B2
B7
O
CH=CH-
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Das et al.
CONCLUSION
This review is an attempt to explore the anti-tubercular potential of triazole scaffold in
medicinal chemistry and drug development. The plethora of research effort scarried out focus
that myriad spectrums of promising anti-tubercular activity exhibited by triazole derivatives.
Information provided in this manuscript can be found useful for further investigations on this
scaffold. Moreover, rational design and development of the novel antitubercular agents
incorporating this nucleus can help in dealing with escalating problems of the microbial
resistance and also to meet the need for an effective antitubercular therapy for the treatment
of MDR tuberculosis.
Various studies suggested that electron donating groups, like methyl substitutions resulted in
loss of activity. The biological data generated revealed that compounds having an electron
withdrawing group like fluoro attached to triazole nucleus may prove a template for anti
tuberculosis activity for further development. It was also suggested that in general the
presence of an alkyl substituent on triazole nucleus was more favorable than propenyl or
benzyl groups for better antitubercular activity. Studies also indicated that the presence of the
furyl ring and the electronegative group (NO2) group present in the molecule are important
structural features for the antitubercular profile of the molecules.
SAR studies also revealed a remarkable ability to tolerate a wide range of substituents at the
4-position of the triazole moiety, and a majority of the compounds possessed subnanomolar
apparent inhibition constants. However, the in vitro potency did not always translate into
whole cell biological activity against M. tuberculosis, suggesting that intrinsic resistance
plays an important role in the observed activities. Studies indicated the importance of the
hydrogen bond acceptor subunit, the position in the aromatic ring, the planarity of triazole
and phenyl rings in these compounds, and a correlation between the uniform HOMO
coefficient distribution and the anti-tubercular activity.
The examples used in this manuscript demonstrate the usefulness of triazole derivatives as,
thereby confirming that these compounds can still have a place in the tool-kit of the modern
medicinal chemist to synthesize novel anti-tubercular drugs.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of interest.
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Das et al.
ACKNOWLEDGEMENT
The authors wish to thank Maharishi Markandeshwar University, Mullana, India
for all necessary facilities.
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