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.

Here we will focus on 1,2,4-Triazoles, which are by far the best-known 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

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 difficult⁶.

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 from 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.

Method of synthesis:

1. Khosrow zamani et al in the year 2003 had been reported the synthesis of several 5-(isomeric pyridyl)-4-aryl-1, 2, 4-triazole-3-thiol/yl-thiomethyl/yl-thioethyl/yl-thiobenzyl and yl-thioglycolic acids as possible biologically active agents.⁸

2. Shuki Araki et al in the year 2009 had been reported with Synthesis of 3-(phenylazo)-1,2,4-triazoles by a nucleophilic reaction of primary amines with 5-chloro-2,3-diphenyltetrazolium salt via mesoionic 2,3-diphenyltetrazolium-5-aminides.⁹

3. Prasenjit ghosh et al in the year 2011 had been reported with Silver complexes of 1,2,4-triazole derived N-heterocyclic carbenes: Synthesis, structure and reactivity studies.¹⁰

4. Mobinikhaledi et al in the year 2010 had been reported with synthesis of newer Schiff’s bases. ¹¹

5. Olcay Bekircan et al in the year 2006 reported with Synthesis of New Bis-1,2,4-Triazole Derivatives.¹²

6. Alan R. Katritzky in the year 1999 had been reported with Novel One-Step Synthesis of Thiazolo[3,2-b]1,2,4-triazoles.¹³

7. Sultan T. Abu-Orabi et al in the year 2008 had been reported with Synthesis of some 1,2,4-Triazolyl-1,2,3-Triazole Derivatives: (1,3-Dipolar Cycloaddition Reaction).¹⁴

Pharmacological activities:

1. R.R. Somani et al in the year 2009 had been reported with the synthesis of 5-(N-substituted carboxamidomethylthio)–3-(3'-pyridyl) - 1, 2, 4-triazoles for their antitubercular activity and antifungal activity.¹⁵

2. Ganesh R. Kokil et al in the year 2010 had been reported with the synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various concentrations to obtain minimum inhibitory concentration (MIC).¹⁶

3. Laila A. Abou-zeid et al in the year 2010 had been reported with Synthesis, molecular modeling of novel 1,2,4-triazole derivatives with potential antimicrobial and antiviral activities.¹⁷

4. Baoan Song et al in the year 2011 had been reported with Synthesis and antifungal activity of new 1-(2,4-dichloro phenyl)-3-aryl-2-(1H-1,2,4-triazol-1-yl) prop-2-en-1-one derivatives.¹⁸

5. Zhe-Shan Quan et al in the year 2007 had been reported with Synthesis of some quinoline-2(1H)-one and 1, 2, 4 - triazolo [ 4 , 3 -a ] quinoline derivatives as potent anticonvulsants.¹⁹

6. Korany a. Ali et al in the year 2011 had been reported with synthesis of new functionalized 3-subsitituted [1,2,4]triazolo [4,3-a]pyrimidine dreivatives: potential Antihypertensive agents. ²⁰

7. Ningur Noyanalpan et al in the year 2007 had been reported with Synthesis of Some New 1-Acylthiosemicarbazides and 1,2,4-Triazol-5-Thiones, and Their Analgesic and Anti-Inflammatory Activities.²¹

8. Prasanta Kumar Sahoo et al in the year 2011 had been reported with Synthesis and Biological Evaluation of some new [1, 2, 4] triazole derivatives as Anticonvulsant Agent.²²

9. Kratika Shrivastav et al in the year 2010 had been reported with synthesis of Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-(2-(4-isobutyl phenyl) propyl)-4H-1,2,4-triazole-3-thiol (4) with acetic acid, substituted aromatic acids, phenyl isothiocynate, pyridine and urea through a one-pot reaction. These compounds were investigated for their antibacterial, antifungal, analgesic and antihelmentic. Some compound showed analgesic activity as compared to ibuprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains. These compound show better antihelmentic activity as compared to albendazole.²³

10. Alireza Foroumadi et al in the year 2010 had been reported with Synthesis of Two Novel 3-Amino-5-[4-chloro-2-phenoxyphenyl]-4H-1,2,4-triazoles with Anticonvulsant Activity.²⁴

11. Nawal A. El-Koussi et al in the year 2006 reported with Synthesis of 5-Phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3- arboxylic Acid Derivatives of Potential Anti-inflammatory Activity.²⁵

12. Vibhor K. Jain et al in the year 2010 had been reported with synthesis and antitubercular activity of some triazole derivatives of propylgallate.²⁶

13. Sevgi Karakuş in the year 2010 had been reported with Synthesis and cytotoxic activity of some 1,2,4-triazoline-3-thione and 2,5-disubstituted- 1,3,4-thiadiazole derivatives.²⁷

14. V. Padmavathi in the year 2009 had been reported with Synthesis, antimicrobial and cytotoxic activities of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles.²⁸

CONCLUSION:

The concept of research subscribed in this review indicates a wide spectrum of pharmacological activities exhibited by 1, 2, 4 Triazole derivatives. The biological profiles of these new generations of 1, 2, 4 Triazoles would represent a fruitful matrix for further development of better medicinal agents. An attempt is made to focus on some synthetic methods of triazoles including Base catalyzed synthesis and Traceless synthesis. It can act as an important tool for medicinal chemists to develop newer compounds possessing Triazole moiety that could be better agents in terms of efficacy and safety.

REFERENCES:

1. John HK, John MB. Wilson and Gisvold’s Text book of Organic medicinal and Pharmaceutical Chemistry. 11^th Edition, Philadelphia: Lippincott Williams and Wilkins; 2004: 1-4.

2. Wang JY, Hsueh PR, Jan IS, et al. . "Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas". Thorax 61 (10): October 2006; 903–8.

3. David HL , "Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis". Applied Microbiology 20 (5): 1970; 810–4.

4. "A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society". British Journal of Diseases of the Chest, 78 (4): 330–6.

5. Iseman M. D, "MDR-TB and the developing world--a problem no longer to be ignored: the WHO announces 'DOTS Plus' strategy". The International Journal of Tuberculosis and Lung Disease 2 (11): 1980; 867.

6. Sterling TR, Lehmann HP, Frieden TR, "Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis". BMJ 326 (7389): 2003; 574.

7. Ijaz K, Jereb JA, Lambert LA, "Severe of fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis". Clin Infect Dis . 42 (3):2006; 346–55.

8. Khosrow zamani, Khalil faghihi, M. Reza sangi and Javad zolgharnein, Synthesis of Some New Substituted 1,2,4-Triazole and 1,3,4-Thiadiazole and Their Derivatives, Turk J Chem,27 (2003) , 119-125.

9. Shuki Araki, Satoshi Hirose, Yoshikazu Konishi, Masatoshi Nogura and Tsunehisa Hirashita, Synthesis of 3-(phenylazo)-1,2,4-triazoles by a nucleophilic reaction of primary amines with 5-chloro-2,3-diphenyltetrazolium salt via mesoionic 2,3-diphenyltetrazolium-5-aminides, Beilstein Journal of Organic Chemistry 2009, 5, No. 8.

10. Chandrakanta dash, mobin M shaikh and prasenjit ghosh, Silver complexes of 1,2,4-triazole derived N-heterocyclic carbenes: Synthesis, structure and reactivity studies, J. Chem. Sci. Vol. 123, No. 2, March 2011, pp. 97–106.

11. Akbar Mobinikhaledi, Naser Foroughifara, Mansooreh Khanpoura and Sattar Ebrahimi, Synthesis of some novel Schiff bases containing 1,2,4‐triazole ring, European Journal of Chemistry 1 (1) (2010) 33‐36.

12. Olcay Bekircan and Hakan Bektas, Synthesis of New Bis-1,2,4-Triazole Derivatives, Molecules 2006, 11, 469-477.

13. Alan R. Katritzky, Alfredo Pastor, and Michael Voronkov, Novel One-Step Synthesis of Thiazolo[3,2-b]1,2,4-triazoles, http://pubs.acs.org.

14. Sultan T. Abu-Orabi, Nuha A. Abu-Naajb, Sami Klaiba, Lo´ay Al-Momania, Ibrahim Jibril, Synthesis of some 1,2,4-Triazolyl-1,2,3-Triazole Derivatives: (1,3-Dipolar Cycloaddition Reaction), Jordan Journal of Chemistry Vol. 3 No.4, 2008, pp. 337-347.

15. R.K. Mali, R.R. Somani, M.P. Toraskar, K.K. Mali ,P.P. Naik,P. Y. Shirodkar, Synthesis of some Antifungal and Anti-tubercular 1, 2, 4-Triazole Analogues, International Journal of ChemTech Research, Vol.1, No.2, pp 168-173, April-June 2009.

16. Ganesh R. Kokil, Prarthana V. Rewatkar, Sandeep Gosain, Saurabh Aggarwal, Arunima Verma, Atin Kalra and Suresh Thareja, Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives as Antifungal Agents, Letters in Drug Design and Discovery, 2010, 7, 46-49.

17. Sherin M. El-Feky, Laila A. Abou-zeid, Mohamed A. Massoud, Shady G. Shokralla and Hassan M. Eisa, Synthesis, molecular modeling of novel 1,2,4-triazole derivatives with potential antimicrobial and antiviral activities, Acta Pharmaceutica Sciencia 52: 353-364 (2010).

18. Yinwei Ruan, Linhong Jin, Jiang He, Song Yang, Pinaki S. Bhadury, Ming He, Zhenchao Wang and Baoan Song, Synthesis and antifungal activity of new 1-(2,4-dichloro phenyl)-3-aryl-2-(1H-1,2,4-triazol-1-yl) prop-2-en-1-one derivatives, African Journal of Pharmacy and Pharmacology Vol. 5(5), pp. 602-607, May 2011.

19. Li-Ping Guan,a, b Qing-Hao Jin,b Guan-Rong Tian,, Kyu-Yun Chai,c and Zhe-Shan Quan, Synthesis of some quinoline-2(1H)- one and 1, 2, 4 - triazolo [ 4 , 3 -a ] quinoline derivatives as potent anticonvulsants, J Pharm Pharmaceut Sci (www. cspsCanada.org) 10 (3): 254-262, 2007.

20. Korany a. Ali, eman a. Ragab, thoray a. Farghalyand mohamed m. Abdalla, synthesis of new functionalized 3-subsitituted [1,2,4]triazolo [4,3-a]pyrimidine dreivatives: potential antihypertensive agents, Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 2 pp. 237-247, 2011.

21. Yasemin D¨undar, Bilge C，akir, Esra K¨upeli,M. Fethi S，ahin, Ningur noyanalpan, Synthesis of Some New 1-Acylthiosemicarbazides and 1,2,4-Triazol-5-Thiones, and Their Analgesic and Anti-Inflammatory Activities, Turk J Chem 31 (2007) , 301 – 313.

22. Prasanta Kumar Sahoo, Sukumar Purohit and Priyadarshee Sahoo, Synthesis and Biological Evaluation of some new [1, 2, 4] triazole derivatives as Anticonvulsant Agent, Journal of Pharmacy Research 2011,4(1),145-147.

23. Kratika Shrivastava, Vivek Daniel, Pramod S. Kunwar, Swapnil Goyal, and V.D. Gupta , synthesis and biological activities of some novel 1,2,4-triazole [3,4-b][1,3,4] thiadiazole derivatives, Journal of Global Pharma Technology. 2010; 2(1): 72-80.

24. Mohammad Mahdavia, Tahmineh Akbarzadeha, Vahid Sheibanib, Maryam Abbasia, Loghman Firoozpoura, Sayyed Abbas Tabatabaic, Abbas Shafieed, Alireza Foroumadi, Synthesis of Two Novel 3-Amino-5-[4-chloro-2-phenoxyphenyl]-4H-1,2,4-triazoles with Anticonvulsant Activity, Iranian Journal of Pharmaceutical Research (2010), 9 (3): 265-269.

25. Safwat M. Rabea, Nawal A. El-Koussi, Hoda Y. Hassan, Tarek Aboul-Fadl, Synthesis of 5-Phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3- carboxylic Acid Derivatives of Potential Anti-inflammatory Activity, Arch. Pharm. Chem. Life Sci. 2006, 339, 32–40.

26. Sudeep K. Mandal, Dibyajyoti Saha, Vibhor K. Jain, Bindu Jain, sythesis and antitubercular activity of some triazole derivatives of propyl gallate, International Journal of Pharma Sciences and Research (IJPSR) Vol.1(11), 2010, 465-472.

27. Sevgi Karakuş, Ufuk Çoruh, Bilgehan Barlas-Durgun, Ezequiel M. Vázquez-López, Suna Özbaş-Turan, Jülide Akbuğa, Sevim Rolls, Synthesis and cytotoxic activity of some 1,2,4-triazoline-3-thione and 2,5-disubstituted- 1,3,4-thiadiazole derivatives, Marmara Pharmaceutical Journal 14: 84-90, 2010.

28. V. Padmavathi , G. Sudhakar Reddy , A. Padmaja , P. Kondaiah , Ali-Shazia, Synthesis, antimicrobial and cytotoxic activities of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles, European Journal of Medicinal Chemistry 44 (2009) 2106–2112.

Received on 11.11.2011 Modified on 08.12.2011

Asian J. Research Chem. 4(12): Dec., 2011; Page 1807-1811