Heterocycles make up an exceedingly important class of compounds. In fact, more than half of all known organic compounds are heterocycles. Many natural drugs are heterocyclic in nature. Many synthetic drugs are also heterocycles. Heterocyclic compounds occupy a central position among those molecules that make life possible. Heterocycles have been explored for developing pharmaceutically important molecules. In recent decades there has been constant interest in the chemistry of azoles because more than hundred azole derivatives are used today as drugs. Azoles are heterocyclic compounds characterized by a five-membered ring which contains an atom of nitrogen and at least one other noncarbon atom, nitrogen, sulfur or oxygen. These compounds are aromatic and have two double bonds.

Triazoles and related compounds

Five inembered aromatic rings with three nitrogen atoms are called triazoles. The two possible combinations of the five atoms account for vicinal(v) and syrnmetrical(s) triazoles In chemical absracts, v-triazoles is also listed as 1H-l,2,3-t-riazoie or pyrrodiazole and 2H-l,2,3-triazole or pyrrodiazole. The pyrrodiazole was occasionally used to designate triazole. The term osotriazole refers to derivatives of 2H-1,2,3-triazole particularly those prepared from osazones (Schemes 1 and 2).

Scheme 1: V-Triazole or 1,23 Triazole.

Scheme 2: S -Triazole or 152,4-Triazole.

Heterocyclic compounds bearing a symmetrical triazoles moiety have been reported to have a broad spectrum of pharmacological activities (Schemes 3-9).

Scheme 3: Fluconazole (Anti-fungal agent).

Scheme 4: Ribavirin (Antiviral agent).

Scheme 5:Rizatriptan (Anti-inflammatory Agent).

Scheme 6: Furamizole (Anti-bacterial agent).

Scheme 7:Nesapidil (Anti-arrhythmic agent).

Scheme 8: Zibotentan (Anticancer agent).

Scheme 9: Raltegravir (Antiretroviral drug - Treatment of HIV infection).

Triazoles have been reported to possess wide variety of biological activity. Some of these activities are mentioned here.

Anti-inflammatory activity: Anti-intlammatory activity of some new 2,5-di-substituted 1,3,4-oxadiazoIe derivative (1) [1]. The presence of n-butyl amino group at 2^nd position of 1,3,4-oxadiazole nucleus la showed maximum activity, where as the presence of cyclohexyi amino group lb showed minimum activity (Scheme 10).

Scheme 10:Anti-intlammatory activity of some new 2,5-di-substituted 1,3,4-oxadiazole
derivative.

1a R=CH₃CH₂CH₂CH₂

1b R= C₆H₁₁

1c R=p-Cl-C₆H₄

1d R=p-F-C₆H₄,

1e R=p-CH₃-C₆H₄

In vitro inhibition of cyclooxygenase and 5-lipooxygenase activities of 1,3,4-oxadiazole derivatives (2) [2] (Scheme 11).

Scheme 11:In vitro inhibition of cyclooxygenase and 5-lipooxygenase activities
of 1,3,4-oxadiazole derivatives (2).

2b R=2,6-di-Ci, 3-CH₃

2b R=3-CF₃

2b R=2,3-(CH₃)₂

These compounds are dual inhibitors of cyclooxygenase and 5-Lox. Among these 2c is more active (80%) than 2a and 2b.

The inflammatory, analgesic and antihypertensive properties of 3,6-diaryl-l,2,4 triazoies[3,4-a] phthalazines (3a and 3b) [3] (Scheme 12).

Scheme 12: 3,6-diaryl-l,2,4 triazoies[3,4-a] phthalazines.

3a=R = C₆H₅- R₁=H, p-OCH₃, 3,4-dimethoxy, p-CH₃, o –NO₂,

3b=R =p- CH₃C₆H₄, R₁= H, p-OCH₃, 3,4 - dimethoxy, p-CH₃, o-NO₂

Compounds of 3a series exhibited promising antiflammatory activity (40, 51 and 52%) compared to phenylbutazone at a dose of 100 mg/kg body wt. These compounds also showed mild to moderate analgene activity (4-40%) in comparison to aspirin (60%) at 100 mg/ kg body wt. Some of these compounds at a dose of mg/kg, -i.v also produced rapid fall in blood pressure followed by quick recovery whereas hydrakizine at 2 mg/kg i.v. produced gradual and transient fail in the blood pressure (42 mm Hg) with long duration and slow recovery.

Anti-inflamatory activity of 3-(substituted phenyl)4’(substitued phenyl) 5-(aIkyl/alkenyl-rnercapto)-l H-1,2,4 triazoies (4a-h) [4] (Scheme 13).

Scheme 13:Anti-inflamatory activity of 3-(substituted phenyl)4’(substitued
phenyl(aIkyl/alkenyl-rnercapto)-l H-1,2,4 triazoies.

4a R=Cl R₁ =H R₂=CH₃

4b R=Cl R₁ =H R₂=C₂H₃

4c R=Cl R₁ =H R₂=CH₂CH=CH₂

4d R=OH R₁ =H CH=CH₂CH₃

4e R=OH R₁ =p-Br R₂=C₂H₅

4f R=OH R₁ =p-Br R₂=CH₂CH=CH₂

4g R=OH R₁ =o-CHi R₂=CH₃

4h R=OH R₁ =o-CH, R₂=CH₂CH₂CH₃

Significant anti-inflammatory activity was observed in compounds, which contain halogen group in any of the phenyl ring at position 4 and allyl or propyl group at position 5 (compound 4c and 4f). Compound 4f showed maximum inhibition of 47% in comparison to other compounds.

Anti-inflammatory acitivity of 3-[2{(phenyl/methyl)benzylidene) aminojoxy] methyl/ethyl-4-amino-5-mercapto-l,2,4-triazole (5a-d) [5] (Scheme 14).

Scheme 14: Methyl/ethyl-4-amino-5-mercapto-l,2,4-triazole.

5a R₁= C₆H₅ R₂= C₆H₅

5b R₁=CH₃ R₂=C₆H₅

5c R₁= C₆H₅ R₂= CH₃

5d R₁=CH₃ R₂= C₆H₅

All the compounds exhibited significant anti-inflammatory activity in comparison to ibuprofen at 50mg/kg body wt.

Antibacterial activity: The antibacterial activity of pyrazole and 1,3,4-oxadiazole derivatives of 2-phenyl-1,8- napthyridine (6,7) [6] (Scheme 15).

Scheme 15:The antibacterial activity of pyrazole and 1,3,4-oxadiazole
derivatives of 2-phenyl-1,8- napthyridine (a, b) [6].

6a Ar=C₆H₅

6b Ar=p-CH₃C₆H₄

6c P-CH₃OC₆ H₄

6d Ar=p-ClC₆H₄,

6e Ar=p-BrC₆H₄

6f Ar=o-HOC₆H₄

6g Ar= 2,4 -(HO)₂ C₆H₃

6h Ar=m- NO₂-C₆H₄

6i Ar=p-NO₂C₆ H₄

6J Ar=2-Napthyl

7a Ar=C₆H₅

7b Ar=p-CH₃C₆H₄

7c P-CH₃OC₆ H₄

7d Ar=p-ClC₆H₄,

7e Ar=p-BrC₆H₄

7f Ar=o-HOC₆H₄

7g Ar= 2,4 -(HO)₂ C₆H₃

7h Ar=m- NO₂-C₆H₄

7i Ar=p-NO₂C₆ H₄

7J Ar=2-Napthyl

Compounds 6b, 6c, 6d, 6b, 7d and 7e were most effective while 6h, 6i, 7a, 7g and 7h were found to have low activity. The remaining conipounds were moderate activity. Antibacterial activity of 1, 3, 4-oxadiazoles (8) [7] (Scheme 16).

Scheme 16: Antibacterial activity of 1, 3, 4-oxadiazoles.

R₁= C₆H₅XCH₂

R₂= C₆H₅, H, NH₂

8a X=S R₁=Ph

8b X=SO₂ R₁= Ph

8c X=S, R₁=H-

8d S O₂ R₁=H

Antibacterial activity of these compounds against E. coli and B. Cirroflagellous are decreases in the order like 8a>Sb>8c>8d. Antibacterial activity of coumarin incorporated 1,3,4-oxadiazoles (9ad) [8] (Scheme 17).

Scheme 17: Antibacterial activity of coumarin incorporated 1,3,4-oxadiazoles.

9a R₁= CH₃ R₂ =C₆H₅

9b R₁= CH₃ R₂=P-OH-C₆H₄

9c R₁= CH₃ R₂=p-CH₃C₆H₄

9d R₁= CH₃ R₂ =p-OCH₃C₆H₄

All the compounds were screened for their antibacterial activity against E. coli and Staphylcoccus using ciprofloxacin as std. drug. The compound 9d showed 80% inhibition against S. aureus while, 9a showed 80% inhibition against E. coli. The 3-aryloxy methyl/pheny! ethyl-4-phenyl-5-(-(5’inercapto-4’-phenyl-1,2,4 thiazol-3’-yl-methyI mercapto)-l,2,4triazoles (l0a-c) for evaluating antibacterial activity [9] (Scheme 18).

Scheme 18:Ethyl-4-phenyl-5-(5’inercapto-4’-phenyl-1,2,4 thiazol-3’-yl-methyI
mercapto)-l,2,4triazoles.

10a R₁=2-CH₃ R₂=5-CH₃

10b R₁=4-CH₃, R₂=5-CH₃

10c R₁=H R₂=H

All these compounds exhibited promising antibacterial activity against E. coli and S. aureus. Antibacterial activity of 4-(psubstituted phenyl)-3-niercapto-5-[2’-morphoiino)quinoxalinol-l,2,4triazoles (lla-c) at a concentration of 2, 3 and 5 mg/ml, against S. aureus, S. typhi, E. coli and B. subnlis [10] (Scheme 19).

Scheme 19: Antibacterial activity of 4-(psubstituted phenyl)-3-niercapto-5-[2’-
morphoiino)quinoxalinol-l,2,4triazoles.

11a, R = p-chlorophenyl

11b, R = p-methoxy phenyl

11c, R = phenyl

Compound l1b was found to inhibit all the test organisms whereas 11a was totally inactive against all the organisms. A series of substituted 2-(5’-inercapto-4’-phenyl-1’,2’, 4’-triazole-3’-yl)indoles (12a-k) [11] (Scheme 20).

Scheme 20: Substituted 2-(5’-inercapto-4’-phenyl-1’,2’, 4’-triazole-3’-yl)
indoles (12a-k).

12a R₁=Cl R₂=H R₃= H

12b R₁= Cl R₂=H R₃=CH₃

12c R₁=Cl R₂=H R₃= Ph

12d R₁=Cl R₂=H R₃=Br

12e R₁=OCH₃ R₂= H R₃=H

12f R₁=CH₃ R₂=H R₃= CH₃

12g R₁=OC₂H₅ R₂=H R₃=H

12h R₁=CH₃ R₂=Br R₃=H

12i R₁=Br R₂=H R₃= H

12j R₁=Br R₂=H R₃=Ph

12k R₁=CH₃R₂=HR3=CH₃

All these compounds were found to possess significant against E. coli, S. aureus and antifungal activity against C. utilis and S. cerevisiae. Antibacterial activity of 3-(-aryl ethyl)-4-phenyI-5-mercapto-l, 2,4, triazoies (13a-c) [12] (Scheme 21).

Scheme 21: Antibacterial activity of 3-(-aryl ethyl)-4-phenyI-5-mercapto-l, 2,4,
triazoies (13a-c) [12].

All these compounds were active against S. aureus, E. coli, S. typhi, and P. aeruginosa except 13b, which was inactive against Pseudmonas.

Anticonvulsant activity: Anticonvulsant activity of some new 1,3,4-oxadiazoie derivatives (14) [13]. Anticonvulsant activity of 2,4-dihydro-3H-1,2,4 triazol-3-ones (15) (Schemes 22 and 23).

Scheme 22: Anticonvulsant activity of some new 1,3,4-oxadiazoie derivatives.

Scheme 23: Anticonvulsant activity of 2,4-dihydro-3H-1,2,4 triazol-3-ones.

15a Ar=C₆H₅ R₁=H R₂= H

15b Ar=C₆H₅R1=CH₃ R₂=H

15c Ar=C₆H₅R1=H R₂=CH₃

15d Ar=C₆H₅R1=H R₂=C₂H₅

The anticonvulsant activities of the triazoles were tested against maximal electroshock and pentylene tetrazole-induced seizures in mice. The compounds having monohalogenated aryl substituents were found to be most active.

Antifungal activity: Most of the recent clinically used anti-fungal drugs contain triazoie nucleus, none of the drug used today are from other azoles like oxadiazole, pyrazine, and triazine. The main drawback of triiizoles is CYP₄₅₀ Isoform inhibition selectivity. This results in many drug interactions when given concomitantly with certain medications also metabolized by this CYP Isoform. For example, fluconazole inhibits the metabolism of warfarin leading to increase in bleeding time. Fluconazole also decrease the metabolism of the CYP_2C9 substrate phenytoin, an anti-epileptic drug with a narrow therapeutic index. On the basis of above facts, different types of azoles are still in progress to get a better drug, some are given as follows. Antifungal activity of 2-aryl-5-(3,5-diphenylpyrazole4-yl oxymethyl)-1,3,4-oxadiazoles (16ac) [14] (Scheme 24).

Scheme 24: Antifungal activity of 2-aryl-5-(3,5-diphenylpyrazole4-yl
oxymethyl)-1,3,4-oxadiazoles (16a-c).

Compound 16b show promising antifungal activity against fungi as compared to 16a and 16c. Fungicidal activity of 3,6,9-triaryl-2- thioxothiazolo[4,5-d]-[l,3,4]oxadiazolo[2,3-b]pyrimidines (17) [15] (Scheme 25).

Scheme 25: Fungicidal activity of 3,6,9-triaryl-2-thioxothiazolo[4,5-d]-[l,3,4]
oxadiazolo[2,3-b]pyrimidines (17).

17a R=H R’= H

17b R=4-Cl R’=H

17c R=2-CH₃, R’=H

17d R=H R’=2-Cl

17e R= 4-Cl R’=2-Cl

17f R=2-CH, R’=2-Cl

I7g R=H R’=4-OCH₃

17h R=4-Cl R’=4-OCH₃

17i R=2-CH₃ R’=4-OCH₃

Compounds 17b, 17e and 17h have very strong activity against Aspergillus niger and Peuicilliiini cilrimun at 1000, 100 and l0 ppm concentration. All these three compounds have either 2-Cl. 4-Cl or 4-OCH₃ groups (electron donar group) in their structure.

Thus, it can be concluded that Cl-group imparts much towards fungicidal activity of this series of compounds. Antifungal activity of oxadiazoles (18) [16], Good anticonvulsant activity is shown by 18b and 18c. Moderate activity produced by compound 18a (Scheme 26).

Scheme 26: Good anticonvulsant activity is shown by 18b and 18c.

Fungicidal activity of some 5-methylene-2-[5’-aryl-1’,3’4’-oxadiazol- 2’-yI]amino-4-thiazolones (19) against A. niger [17] (Scheme 27).

Scheme 27: Fungicidal activity of some 5-methylene-2-[5’-aryl-1’,3’4’-oxadiazol-
2’-yI]amino-4-thiazolones (19) against A. niger.

Among tested compounds 19a is more active against A. niger then 19b and 19c. Activity is decreases on dilution to 100 and 10 ppm. The fungicidal activity of 2’-substituted spiro[indoline-3,5’- [5H][l,3,4]-oxadiazolo[3,2-C]-thiazol]-2-ones against H. oryzae (20) [18] (Scheme 28).

Scheme 28: The fungicidal activity of 2’-substituted spiro[indoline-3,5’-[5H]
[l,3,4]-oxadiazolo[3,2-C]-thiazol]-2-ones against H. oryzae.

20a R=H

20b R= 2-CH₃

20c R=4-CH₃

20d R=3-CH₃

20e R=4-Cl, 3-CH₃

Among these compounds 20e was the most active. It inhibited 90% growth of fungus. This compound has a -CH₃ group along with a chloro function on the phenyl ring which probably enhances fungitoxicily. Antifungal activity of 4-substituted-3,7-dimethyl-pyrazolo[3,4-e] [l,2,4]triazine (21) [19] (Scheme 29).

Scheme 29: Antifungal activity of 4-substituted-3,7-dimethyl-pyrazolo[3,4-e]
[l,2,4]triazine (21).

The antifungal activity of tiie compounds was carried out by the poison food technique. Tiie compounds used were tested in potato dextrose broth in concentration of l0mg/ml, 5mg/ml, 2.5 mg/ml and 1 mg/ml. Compounds 21a and 21d are more active against fungus strain, because of presence of acidic group in these compounds. The fungitoxicity of 1,2,4-triazolo and thiadiazolo[3, 2-b]-l,3,4-oxadiazoles (22, 23) [20] (Scheme 30).

Scheme 30: The fungitoxicity of 1,2,4-triazolo and thiadiazolo[3, 2-b]-l,3,4-
oxadiazoles (22, 23).

23a R=2-F R’=2-Cl; 23b R=4-F R’=2-Cl; 23c R=3-F R’=2-Cl

23d R=2-F R’=4-Cl; 23e R=3-F R’=4-Cl; 23f R=2-F R’=4-CH₃; 23g R=4-F R’=4-CH₃; 23h R=3-F R’=4-CH₃

Compound 22c, 23a, 23e and 23g showed full activity against fungus at l0ppm. The fungicidal data indicate that the presence of toxophoric group -Cl, -OCH₃ on phenyl ring enhances the activity. Antifungal activity of some 1,3,4-oxadiazoie derivatives (24, 25) [21] (Scheme 31).

Scheme 31: Antifungal activity of some 1,3,4-oxadiazoie derivatives.

R₁=C₆H₅,

4-CI-C₆H₄,

4-CH₃C₆H₄,

4-OCH₃C₆H₄

R₂=R3=CH₃.C₂H₅

R₂=H, R₃=C₆H₅

X=O, CH₂; Y=CH₂, (CH₂)₂

The maximal antifungal activity was observed with the compounds having dimethyl/ aniline/ morpholino/ piperidino moieties at the 2^nd position of 1,3,4-oxadiazole. Antifungal activity of 5-substituted - I, 3, 4- oxadiazoIine-2-thiones (26) [22] (Scheme 32). Among the compounds tested, compound (26h), carrying a morpholino methyl substituent possess highest degree of antifungal activity.

Scheme 32: Antifungal activity of 5-substituted - I, 3, 4- oxadiazoIine-2-thiones.

The antifungal activity of 5-arylidene-2-aryl-3-(1,2,4- triazoloacetamidyl)l,3-thiazol-4-ones (27). Compounds 27a, 27b and 27d showed good antifungal activity (Table 1) [23] (Scheme 33).

Scheme 33: Antifungal activiity of 5-arylidene-2-aryl-3-(1,2,4-triazoloacetamidyl)
l,3-thiazol-4-ones (27).

Table 1: The antifungal activiity of 5-arylidene-2-aryl-3-(1,2,4-triazoloacetamidyl) l,3-thiazol-4-ones (27). Compounds 27a, 27b and 27d showed good antifungal activity.

The antifungal activity of 7/9-substituted-4-(3-alkyl/aryl-5,6- dihydro-s-triazoio[3,4-b]thia-diazol-6yl)-tetrazolo [1.5-a] quinolines (28) (Table 2) [24] (Scheme 34).

Scheme 34: Antifungal activity of 7/9-substituted-4-(3-alkyl/aryl-5,6-dihydro-striazoio[
3,4-b]thia-diazol-6yl)-tetrazolo [1.5-a] quinolines (28).

Table 2: The antifungal activity of 7/9-substituted-4-(3-alkyl/aryl-5,6-dihydro-striazoio[ 3,4-b]thia-diazol-6yl)-tetrazolo [1.5-a] quinolines.

The compounds 28a and 28c showed significant antifungal activity against A. niger and C. albicans at 1000 g/ml concentrartion. The fungicidal activity of 3-aryloxy/arylmethyI {-4-aryl-5-mercapto- 1,2,4triazoles (29a-f) (Table 3) [25] (Scheme 35).

Scheme 35: The fungicidal activity of 3-aryloxy/arylmethyI{-4-aryl-5-mercapto-
1,2,4triazoles (29a-f).

Table 3: The compounds 28a and 28c showed significant antifungal activity against A. niger and C. albicans at 1000 g/ml concentration. The fungicidal activity of 3-aryloxy/arylmethyI {-4-aryl-5-mercapto-1,2,4triazoles.

Against A. niger and H. oiyzae by agar plate technique at 1000, 100, 10 ppm concentration. The highest activity was shown by compounds having 3,4 dichlorophenyl moieties.

Some cyclic analogs of SM 8668, compound (30), these thiolene triazole derivatives had 4-chloro or 2,4-dichlorophenyl substituents (X=4C1 or 2,4Cl₂) instead of 2,4-difluorophenyl moiety of SM 8668 (Scheme 36).

Scheme 36: Thiolene triazole derivatives having 4-chloro or 2,4-dichlorophenyl
substituents (X=4C1 or 2,4Cl₂).

30a, n = 1; X=2,4-Cl₂

30b, n = 1; X=4-CI

(30c), n =2; X=2,4 CI₂

These compounds were tested in-vitro and in-vivo antifungal activity, out of which 30a, 30b, and 30c showed promising antifungal activity.

Antitubercular activity: Antituberculosis activity relationship study in a series of 5-(4-amino phenyl)-4-substituted-2,4-dihydro- 3H-l,2,4-triazole-3-thiones, some of the compounds give moderate activity [26].

Anticancerous activity: The cytotoxic/antiproliferative effects of (1,2,4)-triazolo(4,3-c) quinazolines in tumor cell lines hela and B16. Some of the compounds produced moderate activity [27] (Figures 1-4).

Figure 1: Antifungal drugs possessing azole nucleus.

Figure 2: Antifungal agents under clinical trial.

Figure 3: Orally acting triazole, which is completing phase-I clinical trials.

Figure 4: Wide spectrum orally acting antifungal agent.

Ravuconazole: It is found to be more potent thati flucofiazole and itraconazole aginst clinical isolates of Crypiococciis deofonnans.

Triazoles have been reported to possess wide variety of biological activity [28,29].