A REVIEW: TRIAZOLE GOOD ANTI-MYCOBACTERIAL AGENT

www.wjpps.com Vol 9, Issue 6, 2020.

1755

Gajanan et al. World Journal of Pharmacy and Pharmaceutical Sciences

A REVIEW: TRIAZOLE GOOD ANTI-MYCOBACTERIAL AGENT

Birendra Shrivastava, Gajanan Bhagwat*, Rajesh Patil and Sampat Navale

1Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Jaipur

National University, Jaipur-302017, Rajasthan, India.

2Healing Hands & Herbs (R&D Center) 101, Mangalmurti Complex, Shukrawar Peth, Tilak

Road, Pune 411002. Maharashtra, India.

3Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk.), Pune 411 048.

Maharashtra,

India.

4Delight Institute of Pharmacy, Koregaon Bhima, Pune 412216. Maharashtra, India.

ABSTRACT

Tuberculosis (TB) is an ancient chronic infectious disease caused

mainly by pathogen Mycobacterium tuberculosis (Mtb). According to

the latest world health organization (WHO) report there were 8.7

million TB cases, including 1.1 million cases among people with HIV.

In 2011 alone 1.4 million people died because of TB, including half a

million are women and 430,000 people co-infected with HIV.

Additionally, the evolution of its new virulent forms like multi drug

resistant tuberculosis (MDR-TB) and extremely drug resistant

tuberculosis (XDR-TB) has become a major threat to human kind. Out

of new TB cases nearly 1.4 million people were reported HIV infected.

The worst scenario is mortality with estimate of nearly 1.4 million

deaths due to TB in 2015. Therefore, the discovery and development of

effective anti-tuberculosis drugs with novel mechanism of action have become an insistent

task for infectious diseases research programs. The literature reveals that, heterocyclic

moieties have drawn attention of the chemists, pharmacologists, microbiologists and other

researchers owing to its indomitable biological potential as anti-infective agents. Among

heterocyclic compounds, triazole (1,2,3-triazole/1,2,4- triazole) nucleus is one of the most

important and well-known heterocycles, which is a common and integral feature of a variety

of natural products and medicinal agents. Triazole core is considered as a privileged structure

in medicinal chemistry, are widely used as “parental” compounds to synthesize molecules

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 6, 1755-1782 Review Article ISSN 2278 – 4357

Article Received on

20 April 2020,

Revised on 10 May 2020,

Accepted on 30 May 2020

DOI: 10.20959/wjpps20206-16405

*Corresponding Author

Gajanan Bhagwat

Healing Hands & Herbs

(R&D Center) 101,

Mangalmurti Complex,

Shukrawar Peth, Tilak Road,

Pune 411002. Maharashtra,

India.


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with medical benefits, especially with infection related activities. In the present review, we

have collated published reports on this versatile core to provide an insight so that its complete

therapeutic potential can be utilized for the treatment of tuberculosis. This review also

explores triazole as a potential targeted core moiety against tuberculosis and various research

ongoing worldwide. It is hoped that, this review will be helpful for new thoughts in the quest

for rational designs of more active and less toxic triazole-based anti-tuberculosis drugs.

KEYWORDS: Triazole; 1,2,3-triazole,1,2,4- triazole.

INTRODUCTION

Tuberculosis (TB) is an ancient chronic infectious disease caused mainly by pathogen

Mycobacterium tuberculosis (Mtb). According to the latest world health organization (WHO)

report there were 8.7 million TB cases, including 1.1 million cases among people with HIV.

In 2011 alone 1.4 million people died because of TB, including half a million are women and

430,000 people co-infected with HIV. Additionally, the evolution of its new virulent forms

like multi drug resistant tuberculosis (MDR-TB) and extremely drug resistant tuberculosis

(XDR-TB) has become a major threat to human kind.[1]

MTB is an obligate, intracellular,

non-motile bacillus that primarily infects humans. The bacterium is also known for its lipid-

rich cell wall, which is impermeable to most dyes. MTB also divides at an incredibly slow

pace, taking 15 to 20 hours.[2]

Mycobacteria can be classified into non-pathogenic organisms,

such as Mycobacterium smegmatis, which is fast growing and most often used as a laboratory

model for MTB research, and pathogenic organisms, which cause diseases in humans and

animals, such as MTB and Mycobacterium bovis.[3]

MTB is generally transmitted via the

inhalation of respiratory droplets, and grows best in the oxygen-rich tissues of the lung.[4]

Within the lung, this is typically phagocytosed by alveolar macrophages, predominantly via

the human macrophage mannose receptor in addition to complement receptors.[5]

Following

phagocytosis, MTB generally remains within the phagosome, preventing its maturation and

acidification in order to avoid being destroyed,[6]

but it has also been observed residing in the

cytoplasm,[7]

TB has been one of the deadliest diseases over the past few decades affecting

nearly one third of the world‟s population[8]

with new infection occurring at 1% of population

each year.[9]

According to world health organization (WHO) studies, in 2012, there were 8.8

million new cases of TB (13% co-infected with HIV) and 1.4 million people died from TB

including one million HIV negative people.[10]

The estimated 8.8 million new cases every

year correspond to 52,000 deaths per week or more than 7,000 each day.[11,12]

These number


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shows ever, are only a partial depiction of the global TB threat. More than 80% of TB

patients are in the economically productive age of 15-49 years, which results in tremendous

economic and social problems. It was estimated that nearly 1 billion more people will be

infected with TB in the next 20 years. About 15% of that group (150 million) will exhibit

symptoms of the disease, and about 3.6% (36 million) will die from TB if new disease

prevention and treatment measures are not developed.[13]

There were around 1.3 million TB-

related deaths worldwide. Over 95% of TB deaths occur in low- and middle-income

countries, and it is among the top three causes of death for women aged 15 to 44. In 2012, an

estimated 530000 children became ill with TB and 74000 HIV-negative children died of

TB.[14]

These data facilitated chemists and biologist to discovery of novel drug targets,

assisted the understanding of the biological phenomenon of MTB. Currently, the six to nine-

month multidrug protocol used in the treatment of TB is highly effective with drug-

susceptible TB, but poor patient compliance promotes development of drug resistance.[15]

Although, the existing method of curing is very effective against TB, the length of treatment,

the toxicity and the potential for drug-drug interactions are factors that highlight the need for

new anti-TB drugs.[16,17]

In addition, MTB is resistant to some of the first and second line

drugs.[18]

Therefore, effective new drugs.[19]

and strategies.[20]

are essential to treat the TB

bacilli.

It has been established that heterocyclic compounds play an important role in designing new

class of structural entities for medicinal applications. Among pharmacologically important

heterocyclic compounds, triazole and its derivatives are attracted considerable attention in

fields, such as medicinal and agrochemical research as well as in the material sciences due to

their unique structure and properties.[21]

Triazole, also known as pyrrodiazole is one of the

classes of organic heterocyclic compounds containing a five membered diunsaturated ring

structure composed of three nitrogen atoms and two carbon atoms at non-adjacent positions.

This may be of two types, the 1, 2, 3-triazoles (1) and the 1,2,4-triazoles (2).[22]

1,2,3-Triazole (Fig. 01) is an unsaturated, aromatic, five-membered, π-excessive nitrogen

heterocycle with a 6π electron ring system, comprised of three regular nitrogen and two

carbon atoms with two double bonds. Out of three nitrogen atoms, one is a pyrrole type and

the other two are pyridine types. All the atoms in 1,2,3-triazoles are sp2 hybridized and

available 6π electrons are delocalized around the ring, responsible for its aromatic character.

The ionization energy of 1,2,3-triazole is 10.06 eV, which is greater than imidazole (8.78 eV)


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and pyrrazole (9.15 eV). 1,2,3-Triazoles are mainly classified into three groups: (1)

monocyclic 1,2,3-triazoles, (2) benzotriazoles, and (3) 1,2,3-triazolium salts. The monocyclic

1,2,3-triazoles are further classified into three subclasses depending on the position of the NH

proton. The 1H- and 2H-1,2,3-triazoles are in equilibrium in solution as well as in the gas

phase and are aromatic in nature, while the 4H-1,2,3-triazole is nonaromatic. The 1,2,3-

triazolium salts also exist in two isomeric forms. (Fig.02)

Fig. 01: Structure of 1, 2, 3-triazole.

Fig. 02: Structure of Monocyclic 1, 2, 3-triazoles classification & 1,2,3-Triazolium salts.

1,2,4-Triazole (Fig. 03) is a five-membered, π-excessive, aromatic nitrogen heterocycle,

comprised of two carbon and three nitrogen atoms present at the 1-, 2-, and 4-positions of the

ring. All the atoms in 1,2,4-triazoles are sp2 hybridized and have 6π electrons delocalized

over the ring, responsible for its aromatic character. It is also known as s-

triazole(symmetrical). 1,2,4-Triazole exists in two tautomeric forms known as 1H-1,2,4-

triazole and 4H-1,2,4-triazole and it is very difficult to separate them due to their rapid

interconversion.


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Fig. 03: Structure & numbering of 1, 2, 4-Triazole.

Fig 04: Tautomeric Structure of 1,2,4-Triazole

The diverse pharmacological activities of 1,2,4-triazoles as antifungal, antiviral, herbicidal,

and catalase inhibitors induced deep interest to discover new entities for their broader

applications. There are numerous 1,2,4-triazole-based drugs in clinical use for the treatment

of various diseases. Some of the important drugs available in the market such as fluconazole,

itraconazole, Posaconazole, ravuconazole, voriconazole (anti-fungal), Rizatriptan

(Antimigraine) and Rivavirin (Antiviral) [23](Fig. 05)


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Fig. 05: Structure of fluconazole, itraconazole, Posaconazole, ravuconazole,

voriconazole, Rizatriptan and Rivavirin

In the recent past, triazole nucleus has gathered an immense attention among chemists as well

as biologists as it is one of the key building elements due to their chemotherapeutical values

.[24, 25]

Triazole and its derivatives are important class of bioactive molecules in the field of

drugs and pharmaceuticals. They exhibit significant wide range of pharmacological activities

such as anti-microbial,[26,27]

anti-inflammatory, anaesthetic,[28]

analgesic,[29]

anti-

neoplastic,[30]

anti-convulsant,[31]

anti-proliferative,[32]

anti-cancer,[33]

anti-malarial,[34]

and

anti-viral activities.[35]

Also, they show phosphodiesterases enzyme inhibitor,[36]

hepatitis

C,[37]

β lactamase inhibitors,[38]

fungicidal,[39]

insecticidal,[40]

and plant growth inhibitor,[41]

activity and many more. To list a few triazole derivatives, terconazole,[5]

itraconazole,[6]

fluconazole,[7]

bittertanol,[8]

cyproconazole,[9]

(fungicides), trazodone[10]

(anti-depressant) and

triazolam[11

(sedative and hypnotic), which are actively used in pharmacological field.

This broad spectrum of biological and biochemical activities has been further facilitated by

the synthetic versatility of trizole, which allows creating a large number of structurally

diverse derivatives and this has been reviewed by several authors.[42-45]

Among other


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heterocyclic derivatives, triazole compounds were reported as most promising candidates

towards anti-TB activity.[46-50]

It is still a challenge for the pharmaceutical chemist to develop

more effective and less toxic agents to treat signs and symptoms of TB disorders. A large

amount of effort has been invested in the past decade to develop triazole based compounds as

modulator of anti-TB agent, which is active on different clinically approved therapeutic

targets showing excellent therapeutic potency. By looking into the importance of this

therapeutic area we decided to collect the literature on anti-TB triazole derivatives, the

indispensable anchor in medicinal chemistry. In this review, it is attempted to shed light and

compile published reports on triazole derivatives along with some opinion on different

approaches to help the medicinal chemists in designing future generation potent yet safer

anti-TB agents.

1,2,3-Triazole derivatives for treatment of tuberculosis.

Reddyrajula and co-worker describe the modification of pyrazinamide structure using

bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets

of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for

their in vitro inhibitory potency against mycobacterium tuberculosis H37Rv. The pyrazine-

1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity

as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds,

seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56

μg/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the

synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several

bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well.

Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the

molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME

prediction revealed good oral bioavailability for the potent molecules. (Fig. 06).[51]


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Fig. 06: Structure of Pyrazinamide & Its derivative.

Reddyrajula and co-worker synthesize a library consisting of four sets of phenothiazine

incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36

new hybrid molecules were synthesized and screened for in vitro growth inhibition activity

against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested

compounds, nineteen compounds exhibited significant activity with MIC value 1.6 μg/mL,

which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In

addition, all these compounds are proved to be non-toxic (with selective index > 40) against

VERO cell lines. However, these compounds did not inhibit significantly the growth of

Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity

profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide),

indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain.

Also, we report the molecular docking studies against two target enzymes (Inh A and

CYP121) to further validate the antitubercular potency of these molecules. Furthermore,

prediction of in silico-ADME and pharmacokinetic parameters indicated that these

compounds have good oral bioavailability. The results were suggest that this phenothiazine

incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the

development of new antitubercular leads. (Fig. 07).[52]


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Fig. 07: Structure of Phenothiazine incorporated 1, 2, 3-triazole.

Ramprasad J. & Co-worker were designed new quinoline–triazole hybrid analogs in a six-

step reaction sequence involving versatile reactions like Vilsmeier–Haack and click reaction

protocol. The design were based on the structural modification of bedaquiline moiety and

involves molecular hybridization approach. The structure of the synthesized product was

elucidated by single crystal X-ray diffraction study. The synthesized target compounds were

screened for their antitubercular activity against Mycobacterium bovis. Interestingly, two

compounds of the series (8d and 8m) showed significant inhibition with MIC of 31.5 and

34.8 μM. Compounds bearing 3-fluoro phenyl and n-octyl groups on the 1,2,3-triazole ring

emerged as the most potent leads among the compounds tested. Further these hit compounds

were also screened for their cytotoxic effect on human embryonic kindey 293 (HEK293) cells

and other cancer cell lines such as HeLa (Cervical), PC3 (Prostate), Panc-1 (Pancreatic) and

SKOV3 (Ovarian) indicating to be safer with the minimal cytotoxicity. (Fig. 08),[53]


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Fig. 08: Structure of Bedaquiline.

Menendez and co-workers described synthesis of 1,2,3-triazoles bearing alkyl and aryl/alkyl

chain by using click chemistry and examined their anti-TB activity against MTB H37Rv

strain. Compounds (13) and (14), evinced promising inhibition effect with MIC values of

0.50 and 0.25 μg/mL, respectively. Of particular interest, compound (14) possessing the best

MIC value of 0.6 μM. The length of the alkyl chain is important, which in turn affects the

anti-TB activity, the 12-carbon chain derivatives found 8-10 fold more active than 9 and 10-

carbon chain. (Fig. 09),[54]

Fig. 09: Structure of the compound.[13,14]

Raju K.S., & Co-Worker were synthesize A series of novel 1H-pyrrolo [2,3-d] pyrimidine-

1,2,3-triazole derivatives. Through the copper-catalyzed azide-alkyne cycloaddition via

reaction of 7-(prop-2-ynyl)-7H-pyrrolo [2,3-d] pyrimidine and aryl, heteroaryl and alkyl

azides in the presence of CuSO4·5H2O and sodium ascorbate. These compounds were

evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis

H37Rv strain. Most of these pyrrolopyrimidine-triazole hybrids exhibited good anti


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tubercular activity. The antimycobacterial assay results showed that the minimum inhibitory

concentration of compounds 4q and 4r were 0.78 µg/mL. The molecular docking results also

had shown highest Moldock score for same compounds. These novel compounds exhibited

good inhibition activities and further structure-activity studies of the derivatives had shown

promising features to use in antitubercular therapy. (Fig. 10),[55]

Fig. 10: Structure of 1H-pyrrolo [2,3-d] pyrimidine-1,2,3-triazole derivatives.

A series of novel 1,2,3-triazole fused spirochromone conjugates have been synthesized

bearing both spirochromone moiety as well as a 1,2,3-triazole moiety. Some of the

compounds have exhibited potential activity against Mycobacterium tuberculosis (virulent

strain H37Rv). In particular 5e proved to be the most potent derivative exhibiting MIC = 0.78

μg/mL.[56]

(Fig. 11)

Fig. 11: Structure of the compound 5e.


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Geo F. & Co-Worker were synthesized and biological evaluation of fourteen moxifloxacin-

acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against

both drug-susceptible (MTB H37Rv), rifampicin-resistant and multidrug-resistant

Mycobacterium tuberculosis strains were reported, and cytotoxicity towards VERO cells as

well as inhibitory activity against MTB DNA gyrase were also discussed. The structure-

activity relationship and structure-cytotoxicity relationship demonstrated that substituents on

the C-3 and C-5/C-7 positions of isatin framework were closely related with the anti-

mycobacterial activity and cytotoxicity. The most active hybrids 8h and 8l (MIC: 0.12–

0.5 μg/mL) showed excellent activity which was no inferior to the parent moxifloxacin

against the tested drug-susceptible, rifampicin-resistant and multidrug-resistant

Mycobacterium tuberculosis strains, demonstrating their potential application as novel anti-

tubercular candidates.[57]

(Fig. 12)

Fig. 12: Structure of Moxifloxacin derivative.

Kim and co-workers were designed and synthesized 1H-1,2,3-triazoles (3) derived from

econazole (1) as antitubercular agents. The majority of triazole derivatives have been

prepared by microwave-assisted click chemistry. It turned out that all of the prepared

triazoles had no antifungal activities. However, most of the hydroxy-triazoles (6a and 10)

apparently turned out to have antitubercular activities. Overall, hydroxy-triazoles 10 were

more active than their corresponding ether-triazoles 11. While the MIC value of hydroxy-

triazole 10d was as good as econazole (16 μg/mL), the MIC value of 10a was two-fold more


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active than econazole, suggesting that this 1H-1,2,3-triazole scaffold (3) could be further

optimized to develop Mtb specific agents.[58]

(Fig. 13)

Fig. 13: Structure of the compound 1 and 3.

Dongamanti A. & Co-worker were synthesized a new series of coumarin-1,2,3-triazole

hybrids under microwave irradiation method. Several dimers of coumarin based 1,2,3-triazole

derivatives were synthesized and their antimycobacterial and antimicrobial activities were

investigated. The antimycobacterial activity screening results revealed that compounds 6i and

6j were the most active against Mycobacterium tuberculosis H37Rv strain. The active

compounds were further evaluated for cytotoxicity with HEK cell lines and exhibited less %

of inhibition. The same synthetic hybrids were evaluated for their antimicrobial activity

against various bacterial strains and fungal strains and compounds 6e, 6h, 6i and 6j were

found to be the most promising antimicrobial potent molecules. Furthermore, the active

compounds against Mycobacterium tuberculosis were evaluated for their molecular docking

studies against pantothenate synthetase (PS) enzyme of MTB and the docking results are in

well agreement with the antitubercular evaluation results.[59]

(Fig. 14)


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Fig. 14: Structure of coumarin-1,2,3-triazole hybrids

A series of β-d-ribofuranosyl coumarinyl-1,2,3-triazoles were synthesized by Cu-catalyzed

cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62–70%

overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-

conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in

nature and some of them were found to be more active than one of the first line

antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420

times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin,

ethambutol and streptomycin) against multidrug resistant clinical isolate 591. Study of in

silico pharmacokinetic profile indicated the drug like characters for the test molecules.


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Further, transmission electron microscopic experiments revealed that these compounds

interfere with the constitution of bacterial cell wall possibly by targeting mycobacterial InhA

and DNA gyrase enzymes. Study conducted on the activities of the test compounds on

bacterial InhA and DNA gyrase revealed that the most bactericidal test compound, N1-(β-d-

ribofuranosyl)-C4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding

directly linked conjugate N1-(β-d-ribofuranosyl)-C4-(4-methylcoumarin-7-yl)-1,2,3-triazole

(11b) significantly inhibited the activity of both the enzymes. The results were further

supported by molecular docking studies of the compound 6b and 11b with bacterial InhA and

DNA gyrase B enzymes. Further, the cytotoxicity study of some of the better active

compounds on THP-1 macrophage cell line using MTT assay showed that the synthesized

compounds were non-cytotoxic.[60]

(Fig. 15)

Fig. 15: Structure of β-d-ribofuranosyl coumarinyl-1,2,3-triazoles derivatives.

A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5–7) were accomplished

starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-

azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (3) through click

chemistry approach. Thus obtained compounds in 5–7 series were evaluated for in vitro

antimycobacterial activity against Mycobacterium smegmatis (MC2 155) and also verified

the cytotoxicity. These studies engendered promising lead compounds 5q, 7b and 7c with

MIC (μg/mL) values 15.34, 16.18 and 16.60, respectively. Amongst these three compounds,

2-(4-(4-methoxybenzoyl)-1H-1,2,3-triazol-1-yl)-N-(5-phenyl-3-(trifluoromethyl)-1H-

pyrazol-4-yl) acetamide (5q) emerged as the most promising antitubercular agent with lowest


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cytotoxicity against the A549 cancer cell line. This is the first report to demonstrate the

pyrazolo triazole hybrids as potential antimycobacterial agents.[61]

(Fig. 16)

Fig. 16: Structure of 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids.

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in

excellent yields by the popular „click chemistry‟ approach and evaluated in vitro for their

anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain).

Among the series, six compounds exhibited significant activity with minimum inhibitory

concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant

cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular

docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-

ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding

interactions.[62]

(Fig. 17)

Fig. 17: 1,2,3-triazole derivatives.

A series of novel piperidine, piperazine, morpholine and thiomorpholine appended

dibenzo[b,d]thiophene-1,2,3-triazoles were designed and synthesized utilizing azide–alkyne

click chemistry in the penultimate step. The required azide building block 6a–e was


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synthesized from commercial dibenzo[b,d]thiophene in good yields following five step

reaction sequence. All the new analogues 8a–f, 9a–f, 10a–f, 11a–f & 12a–f were

characterized by their NMR and mass spectral analysis. Screening all thirty new compounds

for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, resulted

8a, 8f and 11e as potent analogues with MIC 0.78 μg/mL, 0.78 μg/mL & 1.56 μg/mL,

respectively, and has shown lower cytotoxicity. Interestingly, all six piperazine appended

dibenzo[b,d]thiophene-1,2,3-triazoles 11a–f exhibited Mtb inhibition activity with MIC 1.56–

12.5 μg/mL. To some extent, the data observed here indicated Mycobacterium tuberculosis

inhibition among the appendages is in the order, piperazine > thiomorpholine > morpholine.

[63] (Fig. 18)

Fig. 18.

Rangappa S. Keri & Co-worker, is review that the 1,2,3-triazole at all position with varied

substituents has produced potent anti-TB activity. However, 2nd and 3rd position of the

nuclei are unsubstituted. The 1-position of 1,2,3-triazole may be unsubstituted or substituents

may vary from alkyl and aryl, heterocylcyclic groups. Among them, 1,2,3-triazoles with

substituted alkyl chain (with 12- carbon chain), phenyl with halogen, chloro substituents on

coumarin, chloro substituted benzothiazole, dibenzo-[b,d]thiophene showed promising

activities. The 4- and 5- position of1,2,3-triazole nuclei are more because of the conjugation

and substituents may range from functional groups like halogens, alkene linker,

glycoconjugates, heteroaryl groups enhance the anti-TB activity.[64]

(Fig. 19).


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Fig. 19: 1,2,3-Triazole Structural requirements.

1,2,4-Triazole derivatives for treatment of tuberculosis

Shridhar M.R. & Co-worker were synthesized a series of N-{4-[(4-amino-5-sulfanyl-4H-

1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-2-substituted-amide (1a–d) derivatives and

characterized by IR, 1H NMR, mass spectral and elemental analyses. The compounds were

evaluated for their preliminary in vitro antibacterial activity against Staphylococcus aureus,

Escherichia coli, Pseudomonas aeruginosa and Salmonella typhosa and then were screened

for antitubercular activity against Mycobacterium tuberculosis H37 Rv strain by broth

microdilution assay method. The antibacterial data of the tested compounds indicated that

most of the synthesized compounds showed better activity against bacteria compared to

reference drugs. The in vitro antitubercular activity reports of tested compounds against M.

tuberculosis strain H37 Rv showed moderate to better activity.[65]

(Fig. 20)

Fig. 20.


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Daniele Zampieri & Co-worker were synthesized 2-Aryl-3-(1H-imidazol-1-yl and 1H-1,2,4-

triazol-1-yl)-1H-indole derivatives and tested for their in-vitro antifungal and

antimycobacterial activities. These indole derivatives were devoid of antifungal activity

against the tested strains of Candida spp. Yet, they exhibited an interesting antitubercular

activity against Mycobacterium tuberculosis reference strain H37Rv.[66]

Patel N. & Co-worker were report the antimycobacterial and antimicrobial evaluation of

newly synthesized 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3-benzothiazol-2-

amino)-4H-1,2,4-triazole 6a–j in good yields. All the synthesized compounds have been

established by elemental analysis, IR, 1H NMR, 13CNMR and Mass spectral data. In vitro

antimycobacterial activity was carried out against (Mycobacterium tuberculosis) H37Rv

strain using Lowenstein-Jensen medium and antimicrobial activity against two Gram positive

bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram negative bacteria

(Escherichia coli, Pseudomonas aeruginosa) and three fungal species (Candida albicans,

Aspergillus niger, Aspergillus clavatus) using the broth microdilution method. Compounds

2e, 6a, 6g, 6h, and 6j exhibited promising antimicrobial activity whereas compound 6j

showed very good antimycobacterial activity.[67]

Seelam and co-workers reported the synthesis of 1,2,4-triazole-fused pyrazolo derivatives as

anti-mycobacterial agents. The compounds with the electron withdrawing groups (-Cl, -NO2,

- Br) have shown high activity against MTB H37Rv. Among the synthesized compounds

(36a-c), and (37a-b) demonstrated good anti-TB activity with MIC value of 3.125 μg/mL.[68]

(Fig. 21)


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Fig. 21.

A new series of new diphenylamine containing 1,2,4-triazoles were synthesized from 4-

arylideneamino-5-[2-(2,6-dichlorophenylamino) benzyl]-2H-1,2,4-triazole-3(4H)-thiones 3a–

f. The synthesized compounds were screened for in-vitro antimycobacterial and antibacterial

activities. The synthesized compounds 4a, 4e and 4d have shown potential activity against

Mycobacterium tuberculosis H37Rv strain with MIC of 0.2, 1.6 and 3.125 μM respectively.

To investigate the SAR of diphenylamine containing 1,2,4-triazole derivatives in more

details, CoMFA (q2-0.432, r2-0.902) and CoMSIA (q2-0.511, r2-0.953) models on M.

tuberculosis H37Rv were established. The generated 3D-QSAR models are externally

validated and have shown significant statistical results, and these models can be used for

further rational design of novel diphenylamine containing 1,2,4-triazoles as potent

antitubercular agents.[69]

(Fig. 22)


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Fig. 22.

A series of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives were designed on

basis of structural similarity to the known FAS II inhibitors. Topliss operational method was

used to optimize the potency of molecules. The minimum inhibitory concentration (MIC) of

all synthesized compounds was determined against Mycobacterium tuberculosis H37Rv

using resazurin microtitre assay (REMA) plate method. The synthesized compounds exhibit

antimycobacterial activity in the range of 5–95 μM with a good safety profile.[70]

(Fig. 23)

Fig. 23.

Mundhe and coworkers reported the synthesis of substituted clubbed triazolyl-thiazole

derivatives and tested their potential for anti-TB activity. Compound (45) (MIC = 0.04 μM)

demonstrated potent activity, which is almost equipotent to INH (MIC = 0.03 μM) and

without any notable cytotoxicity. By considering the activity of reported molecule that,

Lepinski‟s rule of five can be bend and molecules which do not obey it, can be treated as

drug candidates.[71]


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Sarkar D & Co-Worker propargylated 1,2,4-triazolethiols and their sulphones, corresponding

1,2,3-triazole derivatives as anti-TB agents against M. bovis BCG and MTB H37Rv.

Compounds (51-58) found effective against both the stages (active as well as dormant) of the

bacilli of M. bovis BCG and M. tuberculosis. These compounds of the invention are also

useful in active as well as dormant phases of mycobacterium.[72]

Rangappa S. Keri & Co-worker, is review that, 1,2,4-triazole also substituted at all position

expect 3rd position, with varied substituents has produced potent anti-TB activity. The 2nd

position of 1,2,4-triazole having substituted with morpholino methyl, sulfhydryl group

displayed a good anti-TB activity. The 4- and 5-position of 1,2,4-triazole, substituents with

benzylidene amino group, 4-pyridyl, dihydroxyl, phenoxymethyl, 3,4-dimethoxy, nitro

substituent, furan ring, thiazole enhance the anti-TB activity.[64]

(Fig. 24)

Fig. 21.

CONCLUSIONS

Tubercular infections pose a continuous and serious threat to human health and life in recent

years. There has been an increased use of anti-TB agents and has resulted in the development

of resistance. This has given rise to search for molecules acting on a novel target or a multi

targeted combination therapy. With the increase in the number of new compounds screened

against mycobacteria, the opportunity exists to develop a novel drug to cure and complete

eradication of TB. Numerous outstanding achievements revealed that triazole-based

compounds possess extensively potential anti-TB activity. Information provided in this

review article is a result of compilation of the outcomes of research articles reporting anti-TB

applications of triazole derivatives. Triazole derivatives, which also regarded as a new class


1777


of effective anti-TB candidates owing to their potential anti-TB activity profiles, inhibit the

growth of mycobacteria by blocking lipid biosynthesis and/or additional mechanisms which

is one of the most attractive strategies for effective anti-TB drug. Triazole containing

derivatives, which may show promising in vitro and in vivo anti-TB potency and might be

able to prevent the drug.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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A REVIEW: TRIAZOLE GOOD ANTI-MYCOBACTERIAL AGENT

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