International Journal of Current Research and Review (IJCRR)

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IJCRR - Vol 02 Issue 03, March

Pages: 44-56

Date of Publication: 30-Nov--0001


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TRIAZOLES: A VERSATILE THERAPEUTIC AGENT

Author: Khange S.G., Deshmukh V.K., Mohite P.B., Pandhare R.B.

Category: Healthcare

Abstract:The five membered heterocyclic rings containing at least one nitrogen atom are Azoles, important like Isoxazole, Thiazole, Pyrazole, Triazole, and Tetrazole. 1,2,4-Trizoles, which contains three nitrogen in five membered heterocyclic ring are of importance possessing high medicinal value and reported various pharmacological activities such as anticancer, hypoglycaemic activity, antifungal, antimicrobial, antiinflammatory, anticonvulsant, antitubercular and antidepressant activity. The present attempt is to review the importance of medicinal aspects of 1, 2, 4-Triazole ring.

Keywords: Heterocyclic ring, Azoles, 1, 2, 4-Triazole, Pharmacological activity, antifungal.

Full Text:

INTRODUCTION

Azoles are five membered Heterocyclic compounds with two or more heteroatoms in which at least one is nitrogen. Azoles are found widely in natural sources and there are several drugs available which contain azole ring discussed in Table 1.

Here we will focus on 1,2,4- Triazoles, which are by far the bestknown class of triazoles five membered heteroatoms with three nitrogen atoms in the ring and consist wide variety of medicinal activity. The action of azole on mycotic biochemistry and physiology has been studied extensively. At high concentrations (micromolar) the azoles are fugicidal and at low concentrations (nanomolar), they are fungistatic 1-3,6 . Synonyms - Triazole, Pyrrodiazoles, 1-H Triazole.

Constitution and chemistry of Triazoles:

Triazoles ring is basically of two types i.e. 1, 2, 3 and 1, 2, 4-Triazole.The derivatization of Triazole ring is based on the phenomenon of bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen atom yields triazole analogue. Out of the two triazoles 1,2,4- triazole have wide variety of activity4 .1,2,4-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. 1,2,4-Triazole is a basic aromatic heterocycle. 1,2,4-Triazoles can be prepared using the Einhorn-Brunner reaction or the Pellizzari reaction5 .1, 2, 4- Triazoles are cyclic hydrazidines with hydrogen atom (or substituent) on either hydrazide nitrogen or on amide nitrogen. Parent 1, 2, 4-triazole (1-H form) is in tautomeric equilibrium with 1, 3, 4- triazole (4H form).The interconversion of two tautomeric forms occurs rapidly and their separation is difficult1 . 1, 2, 4-triazole tautomer is preferred over 1, 3, 4- triazole tautomer (less symmetrical 1H form is favoured over symmetrical 4H- form)

1, 2, 4-Triazole is considered to be derived form benzene by replacement of -CH=CH-by - NH- and the replacement of two -CH=by two - N= atoms. The replacement of -CH=CH- in benzene by - NH enhance the electron density and hence makes 1, 2, 4-triazole susceptible towards electrophilic attack as compared to benzene. But the replacement of two -CH=by two - N= atoms causes the resulting 1,2,4-triazole to be nearly unreactive towards electrophiles.Therefore 1,2,4-triazoles fails to undergo nitration, sulfonation, and N-oxidation. However, 1, 2, 4- triazole anion undergoes alkylation and acylation very readily 7 .1, 2, 4-Triazoles undergo nucleophilic substitution, if substituted with electron withdrawing substituents, the reactivity of 1,2,4- triazole ring towards nucleophile is enhanced in 1,2,4-triazolium cations and mesoionic 1,2,4-triazoles.

Need for the study

Various Triazole heterocyclic ring containing derivatives are known but its practical applications have been hitherto very little. The most of triazoles are easily prepared with good stability. But the starting materials are quite expensive or sensitive intermediates appear which depressed industrial synthesis and its wide applications. The Literature reviews suggests the synthesis of triazole derivatives and their remarkable antifungal, antibacterial, anticancer, antitubercular and antidepressant, hypoglycemic activities13-28 .

Medicinal utilities of Triazole derivatives promote to synthesize new potential triazole derivatives and evaluate its possible pharmacological activities like antifungal, antibacterial, anti-HIV, anticancer, antituberculine, antiviral etc.

Importance of Triazoles in Phytochemicals:

According to survey 1,2,4-Triazoles also show some activity like 1,2,4-Triazole shows fungicides activity against some fungus that are responsible for follicular disc are in ?Vinca minor Z?. Thus it shows activity in plants also.

Importance of Triazoles as Analytical Reagents:

Substituted 1,2,4, triazoles find many useful applications. Some of them are used as analytical reagents for determination of boron8 , antimony9 and cobalt10, other triazoles find many synthetic uses as halogenating agents11 or as activating polymeric reagents12. Now 1,2,4- triazoles derivatives are widely used as biocides and as antifungal agents13. Several 1,2,4-triazoles derivatives find applications as photographic reagents.

Importance of Triazoles containing compounds:

Literature survey of 1,2,4-Triazoles reveals different biological activity. Important activity of them is discussed here.

A) Antimicrobial agents

Schiff bases of Triazole(s) show antibacterial as well as antifungal activity13 like-5-phenyl, 4-(substituted)amino, 3- mercapto 1,2,4-triazoles show antimicrobial activity14.4-Amino-5-Aryl-1, 2,4- triazole-3- thione and their derivatives show antimicrobial activity15 .

B) Anti-inflammatory activity

Anti-inflammatory activity has been shown by [(4-Amino 5-Disubstituted-4- H-1, 2,4-triazole-3yl) thio] alkanoic acids16 .

4-Amino-3-Aryloxy alkyl, 5-Mercapto-1, 2,4-Triazoles also show this activity17

Here

R1 = H, R2 = H, CH3, Cl

R3 = H, CH3 R4 = H, Cl

Some new 3-substituted-4-Amino-5- mercapto- (4H)-1,2,4-Triazoles18 .

1-acyl triazoles also act as antiinflammatory agents19 .

Some 5- Aryl,-2-H-tetrazole, 2-aryl-2Htetrazole-2 acetic acids and [(4-phenyl-5- aryl-4H-1,2,4triazole-3yl) thio] acetic acid as possible super oxide scavengers and anti-inflammatory agents20,21 .

C) Hypoglycaemic agents:

Substituted-1, 2,4-Triazoles also show hypoglycemic activity like 5-(substituted aryl), 4-(alkyl, 3-mercapto) 1,2,4- Triazole show hypoglycemic agents22 .

R= CH3,C2H5,Cl,F, NO2, NH2

R'= CH3,C2H5, C3H7,C4H3

R=pp-H2NSO2C6H4

or R = p - ClC6H4

Like this 5-(substituted aryl), 4-ethyl, 3- Mercapto-1, 2,4-Triazole show Hypoglycaemic activity22 .

D) Antidepressant agents

Some substituted triazoles also acts as antidepressant like 2,4-Dihydro-3H-1, 2,4-triazole-3-thiones potential antidepressant agents23 .

E) Antifungal activity

Substituted 1,2,4-Triazoles also show good antifungal activity like.Some 5-substituted, 4-(substituted aryl), 3-mercapto 1,2,4-triazole show antifungal activity24. Similarly 5(p-Sec- .amyl benzene) methoxy-, 3-mercapto 1,2,4-Triazole show good antifungal activity25 .

Several 3-(4'-nitrophenyl)-4-(4''-chloro benzamido)-5-substituted phenyl)-4H- 1,2,4-triazole and 3-(4'-nitrophenyl)-4- (4''-methyl benzenesulphonamido)-5- substituted phenyl)-4H-1,2,4-triazole.

have been synthesized and shown significant antifungal activity against C.albicans and C.krusei26 .

Various novel Mannich bases derived from 3-(4,6-disubstituted -2- thiomethyl)3-amino-5-mercapto-1,2,4- triazoles showed good antifungal activity27 .

F) Anti Tubercular agents

Substituted 1,2,4-triazoles also show anti tubercular activities like-α-[5-(2-furyl)-1,2,4-triazoles-3yl thio] acehydrazide and related compounds show anti-tubercular activities28 .

G) Anti Convulsant agents

Some substituted triazoles also found as possible anticonvulsants like, newsubstituted Mercapto-triazoles and thiazolidiones and their MAO Inhibitory. and anticonvulsants27. Also some 2,4- Dihydro-3H- 1,2,4-triazoles-3-ones as anticonvulsant agents29 .

H) Anti tumor agents

Some 1,2,4-triazole derivatives as potential anti-tumor agents29 .

Some new unsymmetrical 3, 5-Diaryl- 4H-1, 2, 4-triazole derivatives and were tested for anticancer activity, compound chosen for its higher anticancer activity in the preliminary tests with the cancer.

Marketed Formulations Which Contain1,2,4-Triazole Ring

i.Terconozole, U.S.P.

It is a triazole derivative that is used exclusively for the control of valvo-vaginal moniliasis caused by candida albicans and other candida species.

ii. Itraconazole, U.S.P.

Itraconazole is an orally active, broad-spectrum antifungal agent that has become an important alternative to ketoconazole. The primary indications for itraconazole are for the treatment of systemic fungal infection including blastomycosis, histoplasmosis (including patients infected with HIV virus) and sporotrichosis2 .

iii. Fluconazole, USP

It is a water-soluble bis-triazole with broad-spectrum antifungal properties that is suitable for both oral and intravenous administration as the free base30, 2 .

iv. Trazodone

It is a triazolopyridine antidepressant, which selectively inhibits central serotonin uptake2 .

v. Triazolam

It is used as sedative and hypnotic31,2 .

vi. Bittertanol

It is used as broad-spectrum fungicide32, 2 .

CONCLUSION

So, from above study it is predictable that 1,2,4-triazoles is an important pharmacophore and have a wide range of therapeutic properties. It plays vital role as medicinal agents due to different biological activities. At present several-marketed preparation of triazoles are available like Flutrox, Zocon, Fluzone, Trazadone, Trazonil, Trazalon etc.Thus we can conclude that 1,2,4- triazole is an important emerging moiety in pharmaceutical study and a lot of work can be carried out by integrating 1, 2, 4- triazole moiety with other heterocyclic ring systems like oxdiazole, imidazole, azatidinone, thiazolidone etc. to obtain better pharmacological activity.

ACKNOWLEDGEMENT

The authors are thankful to Principal, Prof. V.K.Deshmukh, M.E.S. College of Pharmacy and Mula Education Society, Sonai, for encouragement and availing of the necessary facilities during the course of investigation.

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