BENZOTRIAZOLE: A HETEROCYCLIC MOLECULE WITH DIVERSIFIED PHARMACOLOGICAL ACTIVITIES
HTML Full TextBENZOTRIAZOLE: A HETEROCYCLIC MOLECULE WITH DIVERSIFIED PHARMACOLOGICAL ACTIVITIES
V. K. Singh 1, Poonam Rishishwar * 2, Peeyush Bhardwaj 1 and Shashi Alok 1
Institute of Pharmacy 1, Bundelkhand University, Jhansi - 284128, Uttar Pradesh, India.
Sri Satya Sai College of Pharmacy 2, Sehore, Madhya Pradesh, India.
ABSTRACT: 1,2,3-Benzotriazole (BTA) is a heterocyclic compound with three nitrogen atoms. The enormous investigations on derivatives of benzotriazole reveals wide applicability of this molecules for tagging and delivering huge number of heterocyclic nuclei. This molecule has been used for the analytical determination of silver as well as a restrainer in photographic emulsions. The effectiveness of 1,2,3-Benzotriazole (BTA) as drug precursors have been drawing attention for a long period. The derivatives of benzotriazole act as agonists for many biologically active proteins. For instance, corozole and alizapride have the inhibitory properties against different proteins and Benzotriazole esters have been reported to work as mechanism-based inactivators for severe acute respiratory syndrome (SARS) 3CL protease. The various derivatives synthesized by different research workers showed antimicrobial activities such as antibacterial, antifungal, antiviral, anthelmintics, antiprotozoal and antimycobacterial activity. The present article throws light on the different derivatives of benzotriazole and their related biological activity, and is reported chronologically. The chronologic development in the synthesis of its derivatives and related changes in therapeutic activity opens new channels for the researchers to work on benzotriazole molecules to develop some highly effective lead molecules.
Keywords: |
Benzotriazole, Antibacterial, Antifungal, Antiviral, Anthelmintics, Antiprotozoal And Antimycobacterial Activity
INTRODUCTION: As the micro-organisms are rapidly undergoing genetic changes and developing resistance against many antibiotics and therapeutic agents for various diseases more quickly than new drugs are being made available so the war against the infectious diseases has become a never ending process. Over the past few decades, there are great interest of triazole class arising due to their wide use in industry and agriculture. Benzotriazole and its derivatives have great significance in medicinal chemistry.
Benzotriazole derivatives are nitrogen containing bicyclic ring system and have been demonstrated for many biological activities, such as antibacterial, antifungal, anticancer, anti-inflammatory, analgesic, antimalarial and antitubercular activity 1. Benzotriazole derivatives also possess antihelminthics and antiprotozoal action. For example, 5, 6-dimethyl-1H-benzotriazole and 5,6-dibromo-1H-benzotriazole are antiprotozoal and active against Acanthamoeba castellani, N-heteroaryl benzotriazole derivatives are anti helminthics, 5-arylidene – 2 – aryl - 3- benzotri azoloacetamidyl) - 1,3-thiazolidin-4-ones are antibacterial, 1-[3-(4-benzotriazol-1/2-yl- 3-fluoro -phenyl) - 2 - oxooxazolidin -5- yl methyl] - 3 –substituted thiourea derivatives are reported antitubercular activity 2. Benzotriazole derivatives act as agonists for many proteins.
Benzotriazoles are often used as corrosion inhibitors, radioprotectors, and photo stabilizer in the production of plastic, rubber and chemical fiber 3. Along with these activities, benzotriazole is also important as a precursor in the synthesis of peptides, acid azides, preparation of 3-hydroxymethyl-2,3-dihydrobenzofurans and 3-hydroxymethylbenzofurans 2.
Benzotriazole have three tautomers, namely two 1H-forms and one 2H-form. In solution, the equilibrium lie almost entirely on the side of the 1H-forms 4. Benzotriazole is an extremely weak base, but with a pKa = 8.2, it is a stronger NH-acid than indazole, benzimidazole or 1,2,3-triazole 5.
The literature survey reveals that heterocyclic compounds bearing benzotriazoles as part of main molecule showed versatile biological activities particularly antibacterial, antifungal, antiviral, anti-inflammatory, anticonvulsant and anticancer activity. Benztriazole derivatives have effectively been proven as antimicrobials.
Synthesis: Benzotriazoles are synthesized by cyclocondensation of o-phenylenediamines with sodium nitrite in acetic acid (Fig. 1). The reaction involved the simple heating the reagents together. Conversion of the diamine into the mono-diazonium derivative is followed by spontaneous cyclization 6.
FIG. 1: SCHEME FOR SYNTHESIS OF BENZOTRIAZOLE
Biological Activity:
Antibacterial activity: A series of 1, 2, 3, benzotriazole derivatives containing pyrazolidine 3, 5 dione moiety were synthesized by diazotization of benzene-1,2-diamine with glacial acetic acid and were evaluated for antibacterial activities, against gram-positive organisms like S. aureus and B. subtilis as well as gram-negative organisms like E. Coli and P. vulgaris by diffusion agar media technique. Compound 1b (Fig. 2) was found to be good activity against E. coli. Compound 1h (Fig. 2) was found to be more effective against S. aureus. Compound 1f was found to have good activity against B. subtilis. Compound 1g (Fig. 2) was found to have good activity against P. vulgaris. Ciprofloxacin and Amoxicillin (100 μg/ml) were used as standard for screening 1.
Compound 1h Compound 1b Compound 1g
FIG. 2: COMPOUND 1h, 1b AND 1g
N-Substituted 2- (1H-benzotriazol – 1 - yl) - aceto hydrazide series (2a-2f) were synthesized from o-phenylenediamine and evaluated for antibacterial activity by agar plate disc diffusion method. Compound 2b, 2c and 2e (Fig. 3) showed good antibacterial activity against S. aureus, B. subtilis and E. coli but less potent than sulphacetamide 7.
Compound 2b
Compound 2c
Compound 2e
FIG. 3: COMPOUND 2b, 2c and 2e
A series of oxazolidinone containing benzotriazole derivatives were synthesized and exhibited antibacterial activity against many antibiotic- resistant microbial strains. Compound 3 (Fig. 4) showed excellent antibacterial activity against antibiotic resistant microbial strains 8.
FIG. 4: COMPOUND 3
A series of N-alkylated benzotriazole derivatives were synthesized and evaluated for antimicrobial activity. Compound 4 (Fig. 5) showed significant antimicrobial activity against many gram positive and gram negative bacteria 9.
FIG. 5: COMPOUND 4
A novel series of N-Substituted benzotriazole derivatives containing mannich bases (5a-5x) were synthesized by amine exchange reactions, from the N,N-dimethylaminopropiophenone hydrochlorides and benzotriazole. Antibacterial activities of the synthesized compounds were tested against B. subtilis, S. aureus, S. faecalis, E. coli, P. aeruginosa and E. cloacae using MHA media. Compounds 5d (Fig. 6), 5g, 5p 5r and 5x exhibited significant activity with MIC values of 1⋅56 μg/mL against B. subtilis. Compound 5s (Fig. 6) showed the most favourable antibacterial activity against B. subtilis, S. aureus, S. faecalis, P. aeruginosa, E. coli and E. Cloacae with MIC of 1⋅562 μg/mL, 1⋅562 μg/mL, 1⋅562μg/mL, 3⋅125 μg/ mL, 6⋅25 μg/mL and 6⋅25μg/mL respectively 10.
Compound 5d Compound 5s
FIG. 6: COMPOUND 5d AND 5s
A series of imidazole / benzotriazole substituted piperidine-4-one derivatives (6a–6j) were synthesized. The synthesized compounds were investigated for antimicrobial activity against selected bacterial strains. Among the compounds, fluoro and methoxy group substituted compound 6d (Fig. 7) showed good antimicrobial activity at minimum concentration 11.
Compound 6d
FIG. 7: COMPOUND 6d
Antifungal activity: Substituted 1,2,3-benzotriazole derivatives (7a-7e) are synthesized from benzimidazoles with 1-chloromethyl benzotriazoles and evaluated for their antifungal activity against P. oryzae, B. cinerea, A. niger, C. albicans and T. rubrum at 1000 ppm, 500 ppm and 100 ppm concentrations by solidified agar method. Compound 7b and 7e (Fig. 8) showed excellent antifungal activity. The inhibitory activity was compared with griseofulvin (standard drug) 12.
Compound 7b Compound 7e
FIG. 8: COMPOUND 7b AND 7e
Substituted benzotriazole derivatives containing pyrazolidinedione moiety (8a‐8i) were synthesized and their antifungal activity was tested against A. niger and C. albicans by cup plate diffusion method by measuring the zone of inhibition in mm. Compounds 8e, 8h and 8i (Fig. 9) were found to have good activity against A. niger while compound 8c was found to have good activity against C. albicans. Ketoconazole and Clotrimazole were used as a standard for screening 1.
Compound 8e Compound 8h
Compound 8i
FIG. 9: COMPOUND 8e, 8h AND 8i
Novel benzotriazolesulfonic acid derivatives were synthesized and have reported plant protecting properties and have antifungal activity against Oomycetes. Compound 9 (Fig. 10) showed excellent antifungal activity 13.
Compound 9
FIG 10: COMPOUND 9
N-Substituted 2 - (1H-benzotriazol-1-yl) - aceto hydrazide series (10a-10f) were synthesized and have reported antifungal activity against Candida albicans. Antifungal activity was evaluated by filter disc method. Compound 10a (Fig. 11) showed good anti-fungal activity against Candida albicans at 1000ug/ml concentration 7.
Compound 10a
FIG. 11: COMPOUND 10a
A series of 1H-1,2,3-benzotriazole derivatives were synthesized and evaluated for antifungal activity against clinical species of Candida. Compound 11a and 11c (Fig. 12) showed desirable antifungal activity 14.
Compound 11a
Compound 11c
FIG. 12: COMPOUND 11a and 11c
A series of 5(6)-(1N)-substituted benzotriazole derivatives (12a-12f) were synthesized using a crystalline oxirane intermediate. All the compounds were evaluated for inhibitory activity against various species of Candida and Aspergillus. Compounds 12b (Fig. 13), 12c, 12d and 12e exhibited potent antifungal activity, with the MICs for Candida spp. and Aspergillus niger, ranging from1.6 μg/mL to 25 μg/mL and 12.5 μg/mL to 25 μg/mL, respectively 15.
Compound 12b
FIG. 13: COMPOUND 12b
Anti-inflammatory activity: Some new chlorosubstituted phenoxyacetyl and propionylbenotriazoles were synthesised and evaluated for their anti-inflammatory activity. Trichlorophenoxy acetyl benzotriazole (compound 13) (Fig. 14) exhibited better anti-inflammatory activity than its propionyl derivatives 16.
Compound 13
FIG. 14C: OMPOUND 13
A series of benzotriazole containing 1,3,4-thiadiazole derivatives (14a-14f) were synthesized by 2-bromoacetyl benzofuran with-(H)-benzotriazole. The anti-inflammatory activity of the synthesized compounds was evaluated by carrageenan-induced edema method. Compound 14a (Fig. 15) was the most potent anti-inflammatory compound and decrease in the edema size 45% after 2h. Ibuprofen was used as a reference for evaluation of anti-inflammatory activity 17.
Compound 14a
FIG. 15: COMPOUND 14a
Analgesic activity: A series of chlorosubstituted phenoxyacetyl and propionylbenzotriazoles were synthesised and evaluated for analgesic activity. The 2,5-dichlorophenoxy acetyl benzotriazole (compound 15) (Fig. 16) exhibited moderately better analgesic activity among the series 16.
Compound 15
FIG. 16: COMPOUND 15
5-Arylidene-2- aryl - 3- (benzotriazoloacetamidyl)-1,3-thiazolidin-4-ones derivatives (16a-16j) were synthesized from ethyl acetoacetate and evaluated the analgesic activity by eddy and leimbach method. Compound 16h, 16i (Fig. 17) and 16j were found to be better analgesic activity. Acetylsalicylic acid was employed as a reference drug 18.
Compound 16h
Compound 16i
FIG. 17: COMPOUND 16h AND 16i
Antiviral activity: A novel series of dialkylamino side chain derivatives of benzotriazole were synthesized and reported as potential inhibitors of respiratory syncytial virus. Compound 17 (Fig. 18) was found to be most potent in series 19.
Compound 17
FIG. 18: COMPOUND 17
Halogenated benzotriazole nucleosides were synthesized and antiviral activity was tested against hepatitis C virus and other viral NTPase/helicases. Compound 18a (Fig. 19) was found to be good inhibitor of the West Nile virus enzyme with an RNA substrate (IC50-0.3um). Compound 18b (Fig. 19) also reported selective antiviral activity 20.
Compound 18a Compound 18b
FIG. 19: COMPOUND 18a AND 18b
Anticonvulsant activity: A series of benzotriazole containing 1,3,4-thiadiazole derivatives (19a-19f) were synthesized and evaluated for anticonvulsant activity in maximal electroshock seizure(MES) and subcutaneous metrazole (ScMet) test. Compounds 19a and 19d were found to be active in ScMet only, whereas the test compounds 19c (Fig. 20) was active in MES. Activity of compound 19c was similar to the second reference drug phenytoin. Valproic acid was used as a first reference drug 17.
Compound 19a Compound 19c
Compound 19d
FIG. 20: COMPOUND 19a, 19c AND 19d
Anticancer activity: There are various benzotriazole derivatives are synthesized and evaluated for anticancer activity. 4, 5, 6, 7-tetrabromobenzotriazole (compound 20a) (Fig. 21) was found to be most effective with high selective inhibition against proteinkinase CK2. Compound 20b (Fig. 21) also reported excellent anticancer activity 21.
Compound 20a Compound 20b
FIG. 21: COMPOUND 20a AND 20b
Benzotriazole-substituted benzoate derivative (compound 21a) (Fig. 22) was synthesized and evaluated for its anti-proliferative activity against several cancer cell lines. It could effectively inhibit the proliferation of human hepatocarcinoma BEL-7402 cell with low IC50 value of 0.082 mg/mL 22.
Compound 21a
FIG. 22: COMPOUND 21a
Anti-mycobacterial activity: Development of anti-tubercular agents is very tedious process therefore only one or two new drugs will arrive in the market from these efforts. The treatment of tuberculosis with combination of drugs has even not satisfactory in combating the disease due to bacterial resistance. There is need for effective anti-tubercular agents to win the battle against this millenary scourge 23, new class of benzotriazole derivatives triazoloquinolones were active against multidrug resistant M. tuberculosis (MDR-Mtb) was reported by Carta Antonio et al., 2011.
Anti-protozoal activity: The 5, 6-dimethyl and 5,6-dibromo derivatives of Benzotriazole were reported active against Acanthamoebacastellani by Katarzyna K et al., in 2004.
Anthelmentic activity: Benzotriazole derivatives of N-heteroaryl/diphenyl amino acetyl/propionyl were tested for anthelmentic activity. Apart from antimicrobial activity the Benzotriazole is important as a synthetic auxiliary 24-26, in synthesis of peptides 27, acid azides 28, preparation of 3-hydroxymethyl-2,3-dihydrobenzofurans and 3-hydroxymethylbenzofurans has been developed using benzotriazole mediated benzofuran ring closure was reported 29. Some derivatives of Benzotriazole are reported to have antiproliferative activity 30-33, pharmacological activities like analgesic, anticonvulsant, anti-inflammatory 34-35, inhibitors of human (CK2) protein kinase 36, agonist for 5-Ht receptor 37, metal corrosion inhibitors 38, cytochalasin B-mimetic activity 39, synthesis and biological activities of Benzotriazole derivatives was reviewed by BV Suma et al., 40.
The antimicrobial activity of Benzotriazole derivatives with reference and main investigator is arranged in chronological order in Table 1.
TABLE 1: ANTIMICROBIAL ACTIVITY OF BENZOTRIAZOLE DERIVATIVES
Year | Benzotriazole derivatives synthesized | Author / Investigators | Reported activity | Ref. No |
1992 | Chlorosubstitutedphenoxy acetyl and propionylbenotriazoles | M. Purohit and S.K. Srivastava | Antibacterial,
Antifungal |
41 |
1994 | Benzotriazolesulfinicacid
derivatives |
P. Ackerman and M. Schellenbaum | Antifungal | 43 |
1995 | Derivatives of 1-(N-heteroyl/ diphenyl aminoacetyl/propionyl) benzotriazole | R. K. Upadhaya
and S. D. Srivastava |
Antibacterial,
Antifungal, Anthelmentic |
42 |
2000 | Derivatives of 3-aryl substituted -2-(1H(2H)-benzotriazol-1(2)-yl) acrylonitrile | S. Paolo et al. | Antitubercular | 44 |
2002 | Benzotriazole derivatives of 2-aminothiophene-3carbonitrile, 2-thioxopyridine-3carbonitrile, 1,8 -naphthyridine-2-one, thieno [2,3-b] pyridine-5-carbonitrile andthieno[2,3-d]pyrimidine | A. O. Fatima et al. | Antibacterial,
antifungal |
45 |
2003 | Dialkylamino side chain substituted on the Benzotriazole | Kuo-Long Yu
et al. |
Respiratory syncytial
virus Inhibitor |
46 |
2004 | 5,6-dimethyl-1Hbenzotriazole and5,6-dibromo-1H-benzotriazole | K. Katarzyna et al. | inhibitor of
Acanthamoebacastellanii |
47 |
2005 | Oxazolidinone derivatives with positional and geometrical substitutions on benzotriazole | J. Das et al. | Antibacterial activity | 48 |
2005 | Benzotriazolyloxazolidinone
derivatives |
P.D. Prasad
and co-workers |
Antibacterial activity | 49 |
2005 | N-alkyl derivatives of 1H - benzotriazole | M. Bretner et al. | Antihelicase
Activity Against Flaviviridae |
50 |
2006 | 5-arylidene-2-aryl-3-
(benzotriazoloacetamidyl)-1,3- thiazolidin-4-ones |
K. C. Asati et al. | Antibacterial
activity |
18 |
2006 | Derivatives of N-alkylated
benzotriazole |
S. N. Swamy et al. | Antibacterial activity, Antifungal | 51 |
2006 | Benzotriazole esters | Chung-Yi Wu et al. | Anticoronovirus | 52 |
2006 | Derivatives of 1-[3-(4-benzotriazol-1/2-yl-3-fluoro-phenyl)-2-oxooxazolidin-
5-ylmethyl]-3-substituted-thiourea |
P. D. Prasad and
co-workers |
Antitubercular
activity |
53 |
2008 | Derivatives of 5-[2-(1,2,3-benztriazole)-1-yl-methyl]-1′-arylidene hydrazine-1,3,4-thiadiazoles and 5-[2-(1,2,3-benztriazole)-1-yl-methyl]-1′-(4′-substituted aryl-3′-chloro-2′-oxoazetidine)]-amino-1,3,4-thiadiazoles | D. K. Shukla and S.D. Srivastava | Antibacterial
and Antifungal activity |
54 |
2008 | Derivatives of Benzotriazoleesters1-(4-Dimethylamino-benzoyloxy)-Benzotriazole | H. V. Koen et al. | Anticorono-
virus(SARS) activity |
55 |
2009 | 2-(substituted)-5[(N-Benztriazolomethyl)-1,3,4-Thiadiazolyl]-4 thiazolidinones | K. P. Namdeo et al. | Antifungal | 56 |
2009 | Derivatives of 1-Trityl-1H-1,2,3-benzotriazole | Z. Rezaei et al. | Antifungal | 57 |
2010 | 1H-Benzotriazolylpropanone and2H-benzotriazolylpropanones | J. Wan and
co-workers |
Antibacterial
activity |
58 |
2010 | Acridine substituted Benzotriazolederivative | N. P. Singh et al. | Antibacterial
activity |
59 |
2010 | Derivatives of 2-(2,4-difluorophenyl)-1-(2,3-dihydro-1Hbenzotriazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol | D.P. Pallav et al. | Antifungal | 60 |
2011 | Imidazole/benzotriazole substitutedpiperidin-4-one derivatives | R. Ramachandran
et al. |
Antibacterial
activity, Antifungal |
61 |
2011 | Azetidinone derivatives ofbenzotriazole. | A. Dubey and
co-workers |
Antitubercular
activity |
62 |
2011 | Triazoloquinolones | C. Antonio
et al. |
Antitubercular
activity |
63 |
2012 | Benzotriazole derivatives substitutedwiththiazole moiety. | N. D. Gaikwad
and co-workers |
Antibacterial
activity, Antifungal. |
64 |
2012 | N-Substituted 2-(1Hbenzotriazol-1-yl)-acetohydrazide derivatives | J. S. Patel et al. | Antibacterial
activity, Antifungal |
65 |
2012 | Benzotriazole substituted withpyrozolidine 3, 5- dione. | B.V. Suma et al. | Antibacterial
activity |
66 |
2013 | 1,2,3-benzotriazolederivatives synthesized by ultrasonic andsolvent-free conditions | M. S. Sudhir et al. | Antifungal
activities |
67 |
2014 | Benzotriazolo-thiadiazolyl-imidazole derivative | V. K. Singh et al. | Anticonvulsant, Antimicrobial
activity |
68 |
2015 | 1H-benzotriazol-1-yl(2-hydroxy -5- [(e) phenyldiazenyl] phenyl) methanone derivatives | C. M. Jamkhandi et al. | Anti-inflammatory activity | 69 |
CONCLUSION: The present review of benzotriazole derivatives is focussed on screening of biological activities such as antibacterial, antifungal, antiviral, antiprotozoal, anthelmentic, anti-inflammatory, anticonvulsant etc. in which benzotriazole is act as a tagging molecule to deliver other pharmacologically active heterocyclic nuclei. Now it can be reasonable to expect that benzotriazole as tagging molecule will definitely play a remarkable role in medicinal chemistry. The investigated reports in this review definitely suggests the possibility to develop a lead compound in which benzotriazole is used as a tagging molecule to emerge new chemical entities (NCE’s) of benzotriazole having potential pharmacological activity.
FUNDING SOURCE: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ACKNOWLEDGEMENTS: Authors are thankful to Director, NISCARE, New Delhi, NML, AIIMS, New Delhi and CDRI, Lucknow (U.P.) for providing library facilities, Head and teaching staff of Institute of Pharmacy, Bundelkhand University, Jhansi, for their encouraging support.
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How to cite this article:
Singh VK, Rishishwar P, Bhardwaj P and Alok S: Benzotriazole: A heterocyclic molecule with diversified pharmacological activities. Int J Pharm Sci Res 2017; 8(2): 446-55.doi: 10.13040/IJPSR.0975-8232.8(2).446-56.
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Article Information
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446-456
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English
Ijpsr
V. K. Singh, P. Rishishwar *, P. Bhardwaj and S. Alok
Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh, India
vijayquantum@gmail.com
11 August, 2016
22 October, 2016
13 January, 2017
10.13040/IJPSR.0975-8232.8(2).446-56
01 February, 2017