Research and Review

TRIAZOLES: A VERSATILE Keywords: Heterocyclic ring, , 1, THERAPEUTIC AGENT 2, 4-Triazole, Pharmacological activity,

*Khange S.G., , Deshmukh V.K., Mohite . P.B., Pandhare R.B., MES College of INTRODUCTION Pharmacy ,Sonai, Ahmednagar, M.S., S Appala Raju, H.K.E.‘S College of Azoles are five membered Heterocyclic Pharmacy,Gulbarga,Karnataka compounds with two or more * Corresponding Author: heteroatoms E-mail:[email protected] in which at least one is nitrogen. Azoles

are found widely in natural sources ABSTRACT and there are several drugs available which contain ring discussed in The five membered heterocyclic rings Table 1. containing at least one nitrogen atom are Azoles, important like 4 3 Isoxazole, Thiazole, Pyrazole, Triazole, N and Tetrazole. 1,2,4-Trizoles, which 5 N N 2 contains three nitrogen in five membered H heterocyclic 1 ring are of importance possessing high 1H-1,2,4-triazole medicinal value and reported various pharmacological activities such as Here we will focus on 1,2,4- anticancer, hypoglycaemic activity, Triazoles, which are by far the best- antifungal, antimicrobial, known class antiinflammatory, anticonvulsant, of triazoles five membered heteroatoms antitubercular and antidepressant with three nitrogen atoms in the ring activity. The present attempt is to review and consist wide variety of medicinal the importance of medicinal aspects activity. The action of azole on mycotic of 1, 2, 4-Triazole ring. biochemistry and physiology has been studied extensively. At high

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concentrations hydrogen atom (or substituent) on either (micromolar) the azoles are fugicidal and hydrazide nitrogen or on amide nitrogen. at low concentrations (nanomolar), Parent 1, 2, 4-triazole (1-H form) is in they are fungistatic 1-3,6. tautomeric equilibrium with 1, 3, 4- triazole (4H form).The interconversion of Synonyms –Triazole, Pyrrodiazoles, 1-H two tautomeric forms occurs rapidly and Triazole. their separation is difficult1.

1, 2, 4-triazole tautomer is Constitution and chemistry of preferred over 1, 3, 4- triazole tautomer Triazoles: (less symmetrical 1H form is favoured Triazoles ring is basically of two types over symmetrical 4H- form) i.e. 1, 2, 3 and 1, 2, 4-Triazole.The 4 H 3 1 2 N N derivatization of Triazole ring is based on 5 N 5 N 2 3 the phenomenon of bioisosterism N N H1 4 in which replacement of oxygen of 1, 2, 4-Triazole 1, 3, 4-Triazole oxadiazole nucleus with nitrogen atom yields triazole analogue. Out of the two triazoles 1, 2, 4-Triazole is considered to 1,2,4- triazole have wide variety be derived form benzene by replacement of activity4.1,2,4-Triazole is one of a pair of -CH=CH-by –NH- and the of isomeric chemical compounds with replacement of two –CH=by two –N= molecular formula C2H3N3 called atoms. The replacement of -CH=CH- in triazoles, which have a five membered benzene by –NH enhance the electron ring of two carbon atoms and three density and hence makes 1, 2, 4-triazole nitrogen atoms. 1,2,4-Triazole is a basic susceptible towards electrophilic attack aromatic heterocycle. 1,2,4-Triazoles can as compared to benzene. But the be prepared using the Einhorn-Brunner replacement of two –CH=by two –N= reaction or the Pellizzari reaction5.1, 2, 4- atoms causes the resulting 1,2,4-triazole Triazoles are cyclic hydrazidines with to be nearly unreactive towards

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electrophiles.Therefore 1,2,4-triazoles its possible pharmacological activities fails to undergo nitration, sulfonation, like antifungal, antibacterial, anti-HIV, and N-oxidation. However, 1, 2, 4- anticancer, antituberculine, antiviral etc. triazole anion undergoes alkylation and Importance of Triazoles in acylation very readily 7.1, 2, 4-Triazoles Phytochemicals: undergo nucleophilic substitution, if substituted with electron withdrawing According to survey 1,2,4-Triazoles also substituents, the reactivity of 1,2,4- show some activity like 1,2,4-Triazole triazole ring towards nucleophile is shows fungicides activity against some enhanced in 1,2,4-triazolium cations and fungus that are responsible for follicular mesoionic 1,2,4-triazoles. disc are in ―Vinca minor Z‖. Thus it shows activity in plants Need for the study also. Various Triazole heterocyclic ring containing derivatives are known but its Importance of Triazoles as Analytical practical applications have been hitherto Reagents: very little. The most of triazoles are easily prepared with good stability. But Substituted 1,2,4, triazoles find many the starting materials are quite expensive useful applications. Some of them are or sensitive intermediates appear which used depressed industrial synthesis and its as analytical reagents for determination wide applications. The Literature reviews of boron8, antimony9 suggests the synthesis of triazole and cobalt10, other triazoles find many derivatives and their remarkable synthetic uses as halogenating antifungal, antibacterial, anticancer, anti- agents11 or as activating polymeric tubercular and antidepressant, reagents12. Now 1,2,4- hypoglycemic activities13-28. triazoles derivatives are widely used as Medicinal utilities of Triazole biocides and as antifungal derivatives promote to synthesize new agents13. Several 1,2,4-triazoles potential triazole derivatives and evaluate

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derivatives find applications as B) Anti-inflammatory activity photographic reagents. Anti-inflammatory activity has been Importance of Triazoles containing shown by [(4-Amino 5-Disubstituted-4- compounds: H-1, 2,4-triazole-3yl) thio] alkanoic acids16. Literature survey of 1,2,4-Triazoles reveals different biological activity. Important activity of them is discussed here.

A) Antimicrobial agents 4-Amino-3-Aryloxy alkyl, 5-Mercapto-1, Schiff bases of Triazole(s) show 2,4-Triazoles also show this activity17. antibacterial as well as antifungal activity13 like-5-phenyl, 4-(substituted)amino, 3- mercapto 1,2,4-triazoles show anti- microbial activity14.4-Amino-5—Aryl-1, 2,4- triazole-3- thione and their derivatives Here show antimicrobial activity15. R1 = H, R2 = H, CH3, Cl

R3 = H, CH3 R4 = H, Cl

Some new 3-substituted-4-Amino-5- 18 mercapto- (4H)-1,2,4-Triazoles .

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aryl), 4-(alkyl, 3-mercapto) 1,2,4- Triazole show hypoglycemic agents22.

1-acyl triazoles also act as anti- inflammatory agents19.

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

R‘= CH3,C2H5, C3H7,C4H3

R=p–H2NSO2C6H4

or R = p – ClC6H4

Like this 5-(substituted aryl), 4-ethyl, 3- Some 5- Aryl,-2-H-tetrazole, 2-aryl-2H- Mercapto-1, 2,4-Triazole show tetrazole-2 acetic acids and [(4-phenyl-5- Hypoglycaemic activity22. aryl-4H-1,2,4triazole-3yl) thio] as possible super oxide scavengers D) Antidepressant agents and anti-inflammatory agents20,21. Some substituted triazoles also acts as C) Hypoglycaemic agents: antidepressant like 2,4-Dihydro-3H-1, 2,4-triazole-3-thiones potential Substituted-1, 2,4-Triazoles also show antidepressant agents23. hypoglycemic activity like 5-(substituted

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

N Ar=C6H5 R1 = R2 = CH3 R NH O2N

E) Antifungal activity O

Substituted 1,2,4-Triazoles also show Cl good antifungal activity like.Some 5-substituted, 4-(substituted N N aryl), 3-mercapto 1,2,4-triazole show N R antifungal activity24. Similarly 5(p-Sec- NH O2N O .amyl benzene) methoxy-, 3-mercapto S O 1,2,4-Triazole show good antifungal 25 activity . H3C

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

activity27.

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

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and anticonvulsants27. Also some 2,4-

R CH3 N Dihydro-3H- 1,2,4-triazoles-3-ones as N 29 N anticonvulsant agents . N N R1 N S N S

N

R

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 H) Anti tumor agents activities28. Some 1,2,4-triazole derivatives as potential anti-tumor agents29.

G) Anti Convulsant agents

Some substituted triazoles also found as possible anticonvulsants like, new- substituted Mercapto-triazoles and Some new unsymmetrical 3, 5-Diaryl- thiazolidiones and their MAO Inhibitory 4H-1, 2, 4-triazole derivatives and were

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tested for anticancer activity, compound cell lines, exhibited remarkable chosen for its higher anticancer activity anticancer potential33. 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. , U.S.P.

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

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iii. , 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.

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CONCLUSION REFERENCES So, from above study it is 1. Joule, J. A. and Mills, K., In predictable that 1,2,4-triazoles is an Heterocyclic important pharmacophore and have a Chemistry,;1995(4):1-14. wide range of therapeutic properties. It 2. Thomas L.L., David A.W., plays vital role as medicinal agents due to Victoria F.R., William Z., Foye‘s different biological activities. At present Principles of Medicinal several-marketed preparation of triazoles Chemistry;2008 (6):510,586,624, are available like Flutrox, Zocon, 1116-17, 1311. Fluzone, Trazadone, Trazonil, Trazalon 3. Delgando, Zaime, N. and Remers etc.Thus we can conclude that 1,2,4- A. Williams and Wilson & triazole is an important emerging moiety Gisvold‘s, Text in pharmaceutical study and a lot of work Book of Organic, Medicinal and can be carried out by integrating 1, 2, 4- Pharmaceutical Chemistry; triazole moiety with other heterocyclic 1998(10):189. ring systems like oxdiazole, , 4. Kartritzky, A.R., Hand Book of azatidinone, thiazolidone etc. to obtain Heterocyclic better pharmacological activity. Chemistry;1985(1):87.

ACKNOWLEDGEMENT 5. Thomas L.G., Heterocyclic Chemistry; 2007( 3):305-307. The authors are thankful to Principal, 6. Donald J. A., Burger‘s Medicinal Prof. V.K.Deshmukh, M.E.S. College of Chemistry and drug discovery; Pharmacy and Mula Education Society, 2007;3(6):632. 7. Gupta R.R., Mahendra K., Gupta Sonai, for encouragement and availing of V., Heterocyclic Chemistry-II; the necessary facilities during the course 20005:503-512. of investigation. 8. C. Jr. Temle, Chem. Hetyrocycl. Compd;1981(37):1.

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9. J.B.Polya and M. Woodruff, Aust. P.B.,Indian Drugs;1988; 25(7): J. Chem; 301-304. 1973(26):1585. 19. Talawar, M. B., Bennur, S. C., 10. C. Calzolari and L. Favretto, Kankanwadi, S. K. and Patil, P. Analyst; 1968(93):494. A., Indian J. Pharm. Sci., 1995, 11. J. B. Polya, A.R.Kartitkzy, C.W. 57(5), 194-197. Rees, Comprehensive 20. Wade, P. C., Vogt, B., Richard, Heterocyclic Chemistry; Kissick, T. P., Simpkins, J. M., 1984(5):733. Palmer, D. M and Millonig, R. 12. Mokotoff, M.Jhao, S.M. Roth, J. C.,J. Med. Chem.;1982(25): A.. Shelley, J.N. Slavoskiand N. 331-333. M. Kouttab, J. Med. 21. Maxwell, J. R., Wasdeahl, D. A., Chem;1990(33):354. Weltson, D. C. and Stenberg, V. 13. Rao, G.K., Rajasekran, S. and I., J. Med.Chem;1984(27):1565- Attimarad, M., Indian J. Pharm. 1570. Sci.;2000:475- 477. 22. Mhasalkar, M.Y., Shah, M.H. and 14. Patel, K.D., Mistry, B.D. and Nikam, S.T.,J. Med. Chem; Desai, K.R., J. Indian Chem. 1971;14(3):260-262. Soc.;2002(79): 964-965. 23. Kane, M.J., Dudley, M.W., 15. Eweiss N. F., Bahajaj A. A. and Sorensen, M.S. and Miller, F.P.,J. Elsherbimi E. A.,J. Heterocyclic Med. Chem; Chem; 1986(23):1451-57. 1988(31):1253-1258. 16. Udupi R. H., Kushnoor A. and 24. Mishra, R.K., Tiwari, R.K. and Bhatt A. R., J. Indian Chem. Soc.; Bahel, S.C.,J. Ind. Chem. 1999(76):461-62. Soc;1991(68):110-112. 17. Sung K. and Lee A.R., Heterocyclic 25. Gupta, A.K.S. and Misra, H.K., Chem;1992(29):1101. Ind. J. Chem.; 1979(17):185-187. 18. Prasad, A.R., Rao, A.N., Ramalingan, T. and Sattur, 54 International Journal of Current Research and Review www.ijcrr.com Vol. 02 issue 3 Mar-Apr 2010

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Table 1: Name of drugs having azole ring Azole Drugs Category Isoxazole Cycloserine Antibacterial Sulfisoaxazole Antimicrobial

Thiazole Thiabendazole Anthelmintic Thiamizs Vitamin B1 Imidazole Antifungal Ketoconazole Antifugal Pilocarpine Cholinarsia Pyrzole Betazole Histamine releasing drug Thiadiazole Acetazolamide Carbonic-n-hydrose inhibitor Triazole Fluconazole Antifungal Itraconazole Antifungal Trazodone Antidepressant

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