A Review: Biological Importance of Mercapto Substituted 1,2,4-triazole Derivatives

 

N.S. Mahajan¹*, A.M. Manikrao¹, P.N. Shinde¹, R.D. Jawarkar¹, P.N. Khatale¹, S.C. Dhawale²

¹Department of Pharmaceutical Chemistry, Sahyadri College of Pharmacy, Methwade, Sangola, Solapur-413307, Maharashtra, India.

²Department of Pharmaceutical Chemistry, SRTM University, Nanded, Maharashtra, India.

*Corresponding Author E-mail: nsmahajan17@gmail.com

ABSTRACT:

Compounds containing 1,2,4-triazole moiety find wide range of applications and substituted 1,2,4-triazoles are becoming more prevalent in functional materials that are at the cutting edge of new technology. The biological activities of 1,2,4-triazole derivatives are well documented and  important discoveries in this area are continued, though the electron donor and coordinating ability of 1,2,4-triazoles has also seen an increase in their use as ligands, functional polymers, and industrial coatings. 1,2,4-triazole has shown its importance as antimicrobial, anti-inflammatory, hypoglycemic, antidepressant, antitubercular, analgesic, antimalarial and anticancer agents. This article is based on different pharmacological activities exhibited by the various compounds containing mercapto and/or thione substituted 1,2,4-triazole heterocyclic ring systems. This review highlighted the basic pharmacophoric requirements for the successful development in the designing of novel antibacterial, antifungal, antitubercular, and anti-inflammatory mercapto triazole agents.

 

 

INTRODUCTION:

In the last few decades, the chemistry of 1,2,4-triazoles and their derivatives has received considerable attention owing to their synthetic and effective biological importance. There are well known drugs containing the 1,2,4-triazole group e.g. Triazolam, Alprazolam, Etizolam, Furacyclin, Fluconazole, Itraconazole, Voriconazole, etc. Moreover, sulphur containing heterocycles represent an important group of sulphur compounds that are promising for use in practical applications. Among these heterocycles, the mercapto and thione substituted 1,2,4-triazole ring systems have been well studied and so far  variety of biological activities have been reported of  a large number of their derivatives.

 

In literature, large number of these triazole containing compounds  have been reported as antibacterial, antifungal, antitubercular, antiviral, antiparasitic, anticancer, anti-inflammatory, COX-2 inhibitor, carbonic anhydrase inhibitor, somatostatin agonists, anti-diabetic, anticonvulsant, anti-neuropathic, antihistaminic.

 

In addition to the important biological applications, mercapto-1,2,4-triazoles are also possess great utility in preparative organic chemistry, for example, in the presence of various reagents, undergo different types of reactions to yield other heterocyclic compounds, e.g., thiazolotriazoles, triazolothiadiazoles, triazolothiazines, triazolothiazepines and triazolothiadiazines [1]. In the present review the biological utility of most common and useful mercapto and thione substituted 1,2,4-triazole derivatives is compiled and discussed.

 

Antibacterial agents

Manikrao A. M. et al. [2] reported various3-(N-substituted carboxamidoethylsulfonyl)-(4H)-1,2,4-triazoles 1 active against E. coli, S. aureus, P. aeruginosa  bacterial strains. Out of the synthesized compounds, 1,2,4-triazole sulfone derivatives exhibited comparable activity with that of standard Norfloxacin.  However, biological results failed to draw any conclusion about SAR; hence more work is needed in this direction to get good clinical candidates.

 

Adhikari A.V. et al. [3] reported of novel quinoline derivatives 5-[4-aminosubstituted-8-(trifluromethyl)-quinoline-3-yl]-4-(un)substitutedphenyl-4H-1,2,4-triazole-3-thiols 2 carrying 1,2,4-triazole ring active against E. coli, S. aureus, P. aeruginosa and K. pneumoniae bacterial strains. Almost all compounds exhibited moderate to good antibacterial activity with MIC in between 6.25-50 μg/ml compared to the standard ciprofloxacin with MIC 6.25 μg/ml.

 

Structural activity relationship studies showed that the presence of –CF₃ at position 8, biologically active amines at position 4 of quinoline ring and bioactive moieties such as -SH, -CH₂CH₂OCH₃ and phenyl group at 1,2,4-triazole ring of title compounds were responsible for increased antimicrobial activity in newly synthesized compounds. This study also concluded that combination of two different heterocyclic systems quinoline and triazole were responsible for the enhancement of biological effect and hence ideally suited for the further development of novel antibacterial compounds.

 

Shivkumar B. et al. [4] reported 3-aryloxymethyl-4-[2-(benzimidazolyl-thio)-acetamido]-5-mercapto-1,2,4-triazole derivatives 3 active against the S. aureus and E. coil pathogens. Almost all the compounds exhibited moderate activity compared with standards procaine penicillin and streptomycin. The activity was attributed to substitution of bulkier groups on 3^rd and 4^th position of mercapto triazole ring.

 

Ulusoy N. et al. [5] reported series of new N-alkylidene/arylidene-5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoactetic acid hydrazides 4 active against S. aureus ATCC 6538, S. epidermidis ATCC 12228, K. pneumoniae ATCC 4352, P.  aerginosa ATCC 1539, E. coli and shigela. Compound with 5-nitro-2-furyl substitution showed good activity with MIC 2.4 μg/ml against S. aureus when compared with standard cefuroxime sodium (MIC 1.2 μg/ml). The substitutions which increase the lipophilicity were reported in the enhancement of activity.

 

Wadodkar K. N. et al. [6] reported novel heterocyclyl substituted s-triazoles, 3-(3-aryl-1H-pyrazol-5-yl)-4-substituted-5-mercapto-1,2,4-triazoles 5 active against pathogenic bacteria S. aureus, E. coli, S. dysentriae, S. typhi, K. pneumoniae, and   P. vulgaris. Majority of compounds were found highly active against P. vulgaris and moderately active against E. coli, when chloramphenicol was used as standard.  The activity observed was attributed to the union of triazole nucleus and pyrazole ring.

 

Rangappa K. S. et al. [7] reported condensed heterocyclic derivatives,4,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazoles 6 active against E. coli, P. fluorescens, B. subtilis, X. campestris and X. oryzae.  Compounds with electron releasing ethyl, phenyl, p-tolyl substitutions on the condensed ring showed the enhancement in activity while the electron withdrawing chlorine atom reduces the activity against said pathogens compared with standards, streptomycin and tetracycline.

 

Kaplancikil Z. A. et al. [8] reported new triazole and triazole fused with six membered ring systems, 4-arylideneamino-3-mercaoto-5-[(1H-indol-3yl)methyl]-4H-1,2,4-triazoles 7 and 3-[(1H-indol-3-yl)methyl]-6-aryl-7H-1,2,4-triazolo(3,4-b)-1,3,4-thiadiazines 8 active against S. aureus, and B. cereus. Compound 7 showed less activity than compound 8. Electron releasing substitution on phenyl ring showed good bacterial growth inhibition than electron withdrawing substitution. The screening also explained that hybrid derivatives were more active than simple molecules.

 

Tirlapur V. K. et al. [9] reported series of 5-[3-(amino-5-mercapto-4H-1,2,4-triazole-3-yl)-phenyl]-3-phenylcyxlohex-2-en-1-ones 9 active against E. coli, P. aeruginosa, S. epidermis and B. subtilis. All the compounds reported moderate to good activity against all the organisms when compared with standard ciprofloxacin. The results also concluded that, inductively electron withdrawing but mesomerically electron donating substituents on aryl group exhibited activity nearly equal to that of control.

 

EI Fttah M. E. et al. [10] reported novel compound, 5-(3,5-dibromo-2-hydroxyphenyl)-2,3,4-trihydro-1,2,4-triazole-3-thione 10 active against E. coli, P. aeruginosa, S. aureas, and B. subtilis. The activity was attributed to the inductively electron withdrawing but mesomerically electron donating substituent on phenyl group linked to triazole nucleus.

 

Aggrawal N. et al. [11] reported novel nalidixic acid analogs,3-(4-amino substituted-5-mercapto-4H-1,2,4-triazole-3-yl)-1-ethyl-7-methyl-1,8-naphthyridin-4(1H)-ones 11, active against S. aureus, B. subtilis, E. coli, K. Pneumonia and P. aeruginosa. Streptomycin and ciprofloxacin were used as standards. The observations concluded that, compounds with electron releasing substituents resulted into better activity than the compounds with unsubstituted phenyl ring.

 

Isloor A. M. et al. [12] reported a series of Schiff’s bases, N-[(4-{[(E)-substituted]-amino}-5-sulfanyl-4H-1,2,4-triazole-3-yl)methyl]-4-substituted benzamides 12 active against S. aureus, B. subtilis and E. coli, and P. aeruginosa. Compounds containing electron withdrawing chloro, methoxy and nitro group substitutions on phenyl ring reported good activity compared with standards streptomycin and ciprofloxacin.

 

Manikrao A. M. et al. [13] reported 3-(N-Substituted carboxamidomethylthio)-(4H)-1,2,4-triazole derivatives 13 active against S. aureus, E. coli, K. Pneumonia and P. aeraginosa. Streptomycin was used as a standard. Compounds with electron withdrawing chloro, methoxy and nitro group substitutions on phenyl ring exhibited powerful antibacterial activity. The results also concluded that, 1,2,4-triazole derivatives 13 may be considered as lead to develop a clinical candidate.

 

Antifungal agents

Rastogi S. et al. [14] reported various 5-(4’-chlorophenyl)-3-mercapto-4-[N-(2’-N-substitutedacetyl)]-amino-1,2,4-triazoles 14 active against T. rubum, E. floccosum and M. furfur.

 

Fig.1. Antibacterial agents

 

In the primary screening, compound with bulkier group at triazole nitrogen and inductively electron withdrawing but mesomerically electron donating substituent on phenyl group linked to triazole nucleus exhibited appreciable activity.

 

Dobosz M. et al. [15] reported series of 4-substituted-3-(thiophene-2-yl-methyl)-Δ²-1,2,4-triazoline-5-thiones 15 active against some species belonging to Trichophyton family. Compounds 15a-c with different substitutions recorded promising activity. Itraconazole and fluconazole were used as reference standards. These compounds reported total or partial inhibitory effects at concentrations of 250 or 500mg/L. The most effective derivative observed, contains the carbon ring substituted with methyl or methoxy group on the triazole nitrogen.

 

Yang G. F. et al. [16] reported 1,2,4-triazole[1,5-α]pyridine derivatives 16 active against R. solani. Carbendazim was used as control. After studying the QSAR analysis, compound having methyl, methyl and sec-butyl groups for R1, R2, and R3 positions respectively was synthesized and tested for its antifungal activity. EC₅₀ value of this compound observed 3.34μg/ml, which is much lower than standard carbendazim (EC₅₀-7.62 μg/ml) and hence more active. According to the CoMFA model R group of the target compound should have optimum steric effects. The results indicated that, in compounds 16 when R is substituted benzyl groups, 3^rd position of the benzyl ring should be unsubstituted and 4^th position should be substituted with an electron withdrawing group. It is also noticed that, when one of the ortho substituents is having electron withdrawing and other is having electron donating group, then this compound can exhibit good antifungal action.

 

Fig.2. Antifungal agents

 

Novel 5-[2-(substituted-sulfamoyl)-4,5-dimethoxybenzyl]-4-aryl-1,2,4-triazole-3-thiones 17 were designed with the aim of identification of good antifungal agents active against A. flavus, A. versicolor, A. ochraceus, A. niger, and P. funiculosum by Ezabadi et al. [17]. All compounds showed significant antifungal activity against all the micromycetes with MIC values in between 50.0-150 μg/ml compared to the commercial fungicide bifonazole (MIC 50-200 μg/ml). Differences in the activity among the prepared compounds were attributed to the different reactive group substitutions on triazole nitrogen. The best antifungal activity among synthetic analogues was observed of compound with N-dimethylsulfamoyl group substituted on the aromatic ring at the 5^th position of triazole nucleus.

Hussain S. et al. [18] reported various 4-amino-2-[4-(4-substituted-phenyl)-5-sulfanyl-4H-1,2,4-triazol-3-yl] and 4-amino-2-{4-amino-5-[(4-substituted phenyl)amino]-4H-1,2,4-triazol-3-yl} phenol derivatives active against A. niger. Compound, 4-amino-2-(4-(4-chlorophenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)phenol 18 containing a chloro group at para position of the phenyl ring exhibited very good activity. This observation led to conclude that, inductively electron withdrawing but mesomerically electron donating substituent on phenyl group linked to triazole nitrogen is primary requirement for good activity.

 

 

Fig.3. Antitubercular agents

 

Sztanke K. et al. [19] reported 7-(4-chlorophenyl)-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole-3-thiol 19 active against C. albicans. Miconazole was used as reference standard. This compound demonstrated a good activity with MIC value of 30.9 μM, superior than miconazole and hence may be considered as promising candidate for the development of new antifungal agents. The observations also shown that, union of 4,5-dihydroimidazole and [1,2,4]triazole nuclei resulted in bioactive molecule of high potency. The activity was further increased when the substituents designed with optimum toxophoric requirements.

 

Collin X. et al. [20] reported series of mono- and di-substituted 3-mercapto-1,2,4-triazoles 20 having substitutions at 3, 4 or 5 positions  on the triazole ring active against C. albicans and C. tropicalis. Alkylation of the thiol function by methylcyano group 20a resulted in increase in antifungal activity. Compound 20b with pyrole substitution did not favour the antifungal activity. Hence, it was revealed that presence of primary amine is necessary for the activity. Introduction of a chlorine atom in the para position on the aromatic ring of triazole 20c shown increase in activity to 50% compared with standard amphotericin.  This explained that,the balance of overall electron density present on the both aromatic and heterocyclic rings seems to be responsible for the activity.  

 

Manikrao A. M. et al. [21] reported various 3-(N-Substituted carboxamidoethylthio)-(4H)-1,2,4-triazole derivatives 21 moderately active against A. flavus, A. fumigatus, penicillium, and trichphyton spp. SAR studies explained that proper electron withdrawing or electron releasing substitutions on the correct positions of triazole nucleus is required for the design of good antifungal agent.

 

Antitubercular agents

Guzeldemirci N. U. et al. [22] reported a series of 4-alkyl/aryl-2,4-dihydro-5-((6-(4-bromophenyl)imidazo[2,1-b]thiazol-3-yl)methyl)-3H-1,2,4-triazole-3-thiones 22 active against M. tuberculosis H37Rv (ATCC 27294). Various derivatives showed antitubercular action with MIC of 6.25 μg/ml which is weaker than clinical drug rifampicin (MIC= 0.25 μg/ml).

 

Suresh Kumar G. V. et al. [23] reported series of 2-substituted-5-isopropylthiazole fused with 1,2,4-triazoles active against  M. tuberculosis H37Rv strain. Compound   4-(2-chlorobenzylideneamino)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazole-3-thiol 23  exhibited significant anti-tubercular activity with MIC 8μg/ml compared with isoniazide (MIC 0.25 μg/ml). The activity was attributed to the union of thiazole and triazole rings.

 

Vagdevi H. M. et al. [24] reported 4-amino-5-(4-pyrrol-1-y1-phenyl)-2,4-dihydro-1,2,4-triazole-3-thione derivative 24 active against M. tuberculosis H37RV. Compound exhibited comparable activity with that of standard Isoniazide. The results concluded that, optimization of the structure is necessary for the development of powerful antitubercular agent.

 

Shiradkar M. R. et al. [25] developed S-derivatives of clubbed triazolyl-thiazoles, N-{4-[(4-N-substituted-5-s-substituted-4H-1,2,4-triazol-3-yl)-methyl]-1,3-thiazol-2-yl}-2-substituted amides 25-27 in search of powerful antimicobacterial agent active against M. tuberculosis. None of these compounds showed better activity than its precursor indicating that free amino group is the primary requirement for the activity. It was also observed that, highly electronegative part at sulfhydryl group is essential for antimycobacterial activity.

 

Thiozolyl derived triazole-thiol compounds 27 showed significant antitubercular activity with MIC value 0.39 µg/ml, which is equal to the MIC value of standard rifampicin. Isopropylthiazole clubbed triazole compound 28a exhibited two fold enhanced potency than precursor carbohydrazide [26]. Compound 29 reported good antitubercular action with MIC value 8 µg/ml. This value is considerably greater than that of its precursor without triazole ring, suggesting that the triazole moiety plays an important role in enhancing the antitubercular activity [27].

 

Klimsova V. et al. [28] reported 1,2,4-triazole-3-benzyl sulfonyl derivatives 30 and its sulfide analogs active against various mycobacterium species. Sulfone was prepared with the understanding that sulfide moiety is generally activated in-vivo through oxidation of sulfur to sulfoxide and sulfone. The antimycobacteriological assessments revealed that the triazole derivatives possess only a moderate or slight activity. By comparing their MIC values of the compound prepared with Isoniazide, triazole derivatives found less active against M. tuberculosis and M. kansasii. Enhancement in activity was seen in triazole compound with electron withdrawing substituents especially nitro, trifluromethyl and thioamide.

 

Antiviral agents

Girardet J. L. et al. [29] reported series of novel 3,4,5-trisubstituted-1,2,4,-triazoles 31 significantly active against Efavirenz and Nevirapine – resistant viruses, containing K103N and/or Y181C mutation or Y188L mutation. The observations concluded that, electron releasing substitutions at R position resulted into good antiviral agent. A number of derivatives of the above category are considered for clinical evaluation.

                                       

    Fig.4. Antiviral agents

 

Antiparasitic agents

Saadeh H. A. et al. [30] reported many 1,2,4-triazole-3-thiol metronidazole derivatives 32a-c active against pathogenic species E. histolytica and G. intestinalis. Compound 32a showed better activity than standard metronidazole (IC50-5.03 µmol/L) with IC50 value ranging from 1.10 to 1.53 µmol/L. Additionally, compound 32b reported most potent derivative against G. intestinalis with IC50 value 0.76 µmol/L.  The IC50 values of compounds 32b and 32c recorded much lower than that of metronidazole against E. histolytica. These novel compounds proved good drug candidates to treat parasite infections.

 

Anticancer agents

Xiang J. et al. [31] registered substituted phenyl-1,2,4-triazole-3-thione analogues, N-2,3,4,6-tetra-o-acetyl-σ-D-glucopyranoyl-4-(arylmethylideneamino)-5-phenyl-2H-1,2,4-triazole-3(4H)-thiones 33 as a powerful cytotoxic agents active HHagainst human malignant cell lines (MCF-7 and bel7402).

 

 

Fig.5. Antiparasitic agent

 

Fig.6. Anticancer agents

 

The glycosyl esters 33 showed significant activity compared with 5-flurouracil (IC₅₀- 5µM) against human MCF-7 and Bel-7402 malignant cell lines with IC₅₀ values in the range of 9-18 µM. SAR studies revealed that, introduction of 2,3,4,6-tetra-o-acetyl-D-glucopyranoyl bromide into 1,2,4-triazole-3-thione system is potentially responsible for the cytotoxic activity of this series.

 

Mavrora A. T. et al. [32] reported 4,5-substituted-1,2,4-triazole-thione derivatives 34(a-b) and 35(a-b) which possess high cytotoxicity in-vitro against thymocytes. The corresponding IC₅₀ values were 0.46µM, 0.0012µM and 1.0×10⁶µM. The observations shown that, introduction of 5-phenylthiophene-2 or 4,5,6,7-tetrahydrobenzothiophene-2 substitutions at the 5^th position of 3-mercapto-1,2,4-triazole is necessary for the interaction with the biological target.

A series of novel aniline-1,2,4-triazole compounds reported good human methionine aminopeptidase-2 (MetAP2) inhibitory activity. The observations resulted that, the activity is due to the interaction of triazole nitrogen and the active site of MetAP2. Compounds 36a and 36b with furanyl methyl side-chain substitutions on the triazole ring resulted into the potent inhibitors of human endothelial cell proliferation [33].

 

Anti-inflammatory agents

Kacukguzel S. G. et al. [34] reported compounds derived from difiunisal hydrazide, 5-(2’,4’-difluoro-4-hydoxybiphenyl-5-yl)-4-substituted-1,2,4-triazoline-3-thiones 37 active against carrageen induced rat paw edema. The percentage inhibition of inflammation by synthesized compounds was observed in the range from 3.34-73.03%. The standard drug used was diflunisal showed 24.16% inhibition. Compound 37b showed highest anti-inflammatory activity (73.03% inhibition). The replacement of carboxylic acid function by heterocyclic moieties shown increase in anti-inflammatory activity.

 

Amir M. et al. [35] reported novel 1,2,4–triazole derivatives of biphenyl-4-yloxy acetic acid, 5-[(biphenyl-4-yloxy)methyl]-4-alkyl/aryl-3-mercapto-(4H)-1,2,4-triazoles 38. Compounds 38a-c showed inhibition of inflammation in the range of 18.18% to 81.81% compared with standard ibuprofen. The highest activity was observed of compound 38a bearing n-butyl group at position 4. Moreover, compound 38a exhibited maximum reduction in ulcerogenic activity. The results conluded that, when carboxylic group of biphenyl-4-yloxy acetic acid cyclized to 1,2,4-triazole ring, then significant anti-inflammatory and analgesic activity along with reduced ulcerogenic potential can be achieved.

 

Palaska E. et al. [36] reported 1,2,4-triazole-3-thione derivatives, 5-(2-naphthyloxyacetyl)-4-substituted-1,2,4-triazole-3-thiones 39, actively inhibit carrageenan-induced foot paw edema (CPE) with percentage inhibition in the range of 43 to 61%. Allyl and phenyl analogs significantly inhibited edema when compared with standard phenylbutazone. Compound 39a with methyl substitution exhibited superior anti-inflammatory profile and low gastric ulceration incidences.

 

Shanker K. et al. [37] reported indolylmethyl-4H-1,2,4-triazole-3-thiols 40-41 active against inflammation. Compound 40 showed 31.03% inhibition while compound 40 exhibited 38% inhibition of inflammation after oral administration. It was noted that, substitution of acid functionality by heterocyclic moiety i.e. triazole, resulted in enhancement of activity.

 

Labanauskas L.  et al. [38] reported 5-(2, 3 and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives 42-43 showing carrageenin- and bentonite-induced foot paw edema inhibition. Aspirin and ibuprofen were used as standards. The smaller differences in activity of the synthesized compounds were made it difficult to predict the effect of substituent on the activity.

 

Tozkosparan B. et al. [39] reported 5-aryl-3-alkylthio-1,2,4-triazoles, 44-45 and corresponding sulfones 46 significantly active against inflammations.  In regard to the structure, the most important variable affecting the activity was oxidation of sulfur to sulfone. Alkyl sulfone derivatives were found much more potent analgesic and anti-inflammatory agents than the corresponding alkyl thio analogs. When compared the effect of substitution on the phenyl ring a chlorine substituent resulted in good activity irrespective of its position, whereas replacing the chlorine by bromine produced inactive compounds with side effects. Compounds 44 and 45 were observed the most active in both analgesic and anti-inflammatory activity tests. In contrast to reference compound acetyl salicylic acid, these compounds did not induce gastric lesion in experimental animals at the doses that exhibited analgesic and anti-inflammatory activity.

 

Noyalnalpan N. et al. [40]  designed novel 3-[2-(2-oxobenzothiazoline-3-yl)ethyl]-4-substituted-1,2,4-triazol-5-thione analogs 47, in which position 4 of the triazole ring is substituted by cyclohexyl, methyl, allyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-nitrophenyl, benzyl, and phenylethyl group as a possible anti-inflammatory agents. These compounds exhibited lower analgesic and anti-inflammatory activity than the reference compounds, aspirin and indomethacin, when assessed using the p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model. It was also noticed that, carbon chain length between the two ring systems, 1,2,4-triazoline-5-thione and the 2-oxobenzothiazoline played an important in exhibiting analgesic and anti-inflammatory activity. When the distance is increased by two carbon atoms, the activity of these compounds gets further diminished.

 

Kalluraya B. et al. [41] developed series of 1,2,4-triazole Schiff bases, 4-[(4-aryl)-methylidene]-amino-2-(substituted-4-ylmethyl)-5-{1-[4-(2-methylpropyl) phenyl] ethyl}-2,4-dihydro-3H-1,2,4-triazole-3-thiones 48 to get active anti-inflammatory drug. These molecules exhibited much better anti-inflammatory activity, and similar analgesic activity compared with standard diclofenac sodium. Compounds recorded percentage of inflammation inhibition ranging from 56 to 74%, whereas standard drugs diclofenac and ibuprofen showed 65% and 42% inhibition. The results concluded that, replacement of the carboxyl function of ibuprofen by certain bulkier heterocyclic moieties generally improves the pharmacological profile of the parent compound. It was interesting to note that all the non-carboxylic test compounds exhibited anti-inflammatory activity greater than ibuprofen.

 

Goekhan-Keleskci N. et al. [42] reported 3-[(5-Methyl-2-benzoxazolinone-3-yl)methyl]-4-alkyl/aryl-1H-1,2,4-triazole-5(4H)-thione derivatives 49 possessing analgesic activity at 100 mg/kg dose against acetic acid induced writhing test. All compounds exhibited activity comparable with or higher than that of aspirin. Compounds 49a-c showed moderate to good anti-inflammatory effects. Compound 49c with N-phenyltriazole moiety was observed as the most active derivative with percentage inhibition of 79.8% at 100mg/kg dose level, and also found safe in ulcer incidence.

 

Tozkoparan B. et al. [43] developed novel 3,6-disubstituted-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines 50 in the search of potent anti-inflammatory agent. The results shown that, there was no noticeable increase in analgesic and anti-inflammatory activity when 3-substituted-4-amino-5-mercapto-1,2,4-triazoles were condensed with the 1,3,4-thiadizine ring. Among the condensed derivatives, the compounds, carrying either a 4-chloro or 4-fluoro substituent on the phenyl ring at the 6^th  position of the heterocyclic compound exhibited better analgesic and anti-inflammatory activities and less ulcerogenic risk, along with minimum lipid peroxidation activity in both carrageenan-induced oedema and acetic acid induced writhing tests.

 

Manikrao A. M. et al. [44] reported newer series 3-(N-substituted carboxamidoethylthio)-4H-1,2,4-triazoles 51 active against inflammation produced by CPE. Diclofenac sodium was used as standard (23.14% inhibition). These newly synthesized compounds showed inflammation inhibition ranging from 25.94 - 44.44%. Compound bearing phenyl substitution showed equipotent activity while incorporation of chloro, nitro, methyl and methoxy groups into phenyl ring enhanced the anti-inflammatory activity considerably. It was also noted that, the derivative having substitution at para position found more active than the derivative with substitution at ortho and/or meta positions.

Cyclooxygenase 2 (COX 2) Inhibitors

Shafiee A. et al. [45] designed substituted 3-alkylthio-4,5-aryl-4H-1,2,4-triazoles,3-alkylthio-5-(4-methylsulfonylphenyl)-4-aryl(or-cyclohexyl)-4H-1,2,4-triazoles 52-53 in search of potent COX-2 enzyme inhibitor. The results concluded that, COX-2 selectivity and potency was dependent on the steric properties of C-3 thio or alkyl thio substituent on the central triazole ring and electronic properties of the C-4 phenyl ring substituent. It was also observed that, SO₃Me or SO₂NH₂ substituent at the para position of a phenyl ring and p-F substituent on non sulfonyl vicinal phenyl ring improved the in-vivo activity.

 

Fig.7. Anti-inflammatory agents

 

Fig.8. COX 2 inhibitor

 

Carbonic anhydrase inhibitors

Supuran C. T. et al. [46] designed 1,2,4-triazole-3-thione derivatives 54 in search of newer drug active against enzyme carbonic anhydrase. The experimental results shown that, thiol moiety present in 54 may lead to effective carbonic anhydrase inhibitors targeting isozyme-I. The deprotonated sulfonamides/sulfamates moiety which is also present in 54 directly bind to catalytically critical Zn(II) ion of the enzyme active site and participated in a multitude of polar and hydrophobic interactions with amino acid residues for the effective activity.

 

Fig.9. Carbonic anhydrase inhibitor

 

Somatostatin subtype II/V (SSt₂/SSt₅) Agonists

Contour Galcero M. O. et al. [47] developed novel 3-thiol-1,2,4-triazoles 55-56 to identify possible effective sst₂/sst₅ agonist. In results, it was noticed that, butylamine group substituted at 4^th position and indole group substituted at the 3^rd position on 1,2,4-triazole nucleus shown higher binding affinities with human somatostatin receptor subtypes II and V.

 

Antidibetic agents

El Ashry E. H. et al. [48] reported the in-vitro and in-vivo effects of 5-(2-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thiol 57a and 4,5-Diphenyl-1,2,4-triazole-3-thiol 57b on α-glucosidase and α-amylase. Compound 57a exhibited reversible inhibition of the competitive and non competitive types, with Ki value of 10^-5 mol/L magnitude, for α-glucosidase and α-amylase. On the other hand, compound 57b did not display an inhibitory effect towards α-amylase but showed a potent inhibitory effect of the competitive type for hepatic α-glucosidase with Ki 10^-5 mol/L. The difference in the degree of inhibition of α-glucosidase and α-amylase by compound 57b and the inhibition of α-glucosidase by compound 57a rather than α-amylase may be attributed to the interaction of these compounds with the active site of each enzyme.

 

Anticonvulsant agents

Siddiqui N. et al. [49] reported new series 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-4-(substitutedphenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones 58a-b effective against seizures. These thiazolyl containing triazoles showed comparable anticonvulsant activity and higher protective index than the standard drugs phenytoin, ethosuximide and phenobarbital. Compound 58a possessed strong anti-maximal electroshock seizure (MES) activity with effective dose (ED)₅₀ of 13.4mg/kg which is close to the dose of phenytoin and carbamazepine and better than phenobarbital and valproate.

 

Siddiqui N. et al. [50] reported various indolyl-substituted triazoles 59a-c with more potent activity than carbamazepine after 4h in the MES model. These novel compounds also displayed lower neurotoxicity than standard drug phenytoin.

Fig.10. Somatostatin agonists

 

 

Fig.11. Antidibetic agent

 

Kucukguzel I. et al. [51] reported series of novel 3-{[(substitutedphenyl)-methyl]thio}-4-alkyl/aryl-5-{[(substitutedphenyl/5-nitro-2-furyl)methylene]amino]-phenyl}-4H-1,2,4-triazoles 60  effective against epilepsy. The observations revealed that, small alkyl moieties at N-4 of triazole ring resulted in anticonvulsant activity; whereas aryl substitution at the same position completely blocked activity using both maximal electric shock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. This may be due to the fact that, steric influences of aryl function at triazole ring restrict the nucleus to reach to the binding site. Therefore alkyl substitution at the triazole ring appeared to be preferable over aryl functions.

 

Antineuropathic agents

There are several literatures reported that, many triazoles have potential activities for treating Alzheimer’s disease (AD). Triazolyl-thiophene derivatives 61a-b were reported as good inhibitors of cdk5/p25 with the IC50 values of 32 and 0.035 mol/L. The results was also revealed that, an ideal cdk5/p25 inhibitor with minimal toxicity and potential activity can be designed using the structural transformation to a 2-position of thiophene core and amino and sulfhydryl groups in triazole core [52].

 

Antihistaminic agents

Sander K. et al. [53] reported human Histamine H₃ Receptor (hH₃R) antagonistic activity of 1,2,4-triazole derivative 62, the first metal containing H₃R ligand, synthesized by the incorporation of a ferrocene unit using 1,2,3-triazole linker to the basic H₃R antagonist pharmacophore.  The triazole moiety is a qualified extension of the hH3R pharmacophore offering improved pharmacodynamic properties. The substitution pattern on the azole rings showed an essential impact on the hH3R affinities. Substitution of the ferrocene unit by an aromatic pyridyl moiety, compound 63, resulted in high affinity with a Ki value of 0.018 μmol/L.

 

Fig.12. Anticonvulsant agents

 

 

Fig.13. Antieuropathic agent

 

Fig.14. Antihistaminic agents

 

Other medicinal agents

In addition to the above accounts, triazole compounds also exhibited potential applications in other medical fields, such as antioxidant [54], anti-gout and hyperuricemia, Ghrelin receptor regulator [55], antihypertensive, ion channel blocker [56-60] and so on. Triazole compound trapidil is an important hypotensive drug widely used in clinic. A series of triazole incorporated pyridazinones were synthesized and their bioactive evaluation showed that compounds 64a-c gave appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol [61].

 

Fig.15. Antihypertensive agent

 

CONCLUSION:

Among a great deal of various researches having been done in the whole range of triazole-based derivatives as medicinal drugs, the most important and successful development is mainly occurred in the designing of novel antibacterial, antifungal, antitubercular, and anti-inflammatory agents. The basic pharmacophoric requirements for these activities are observed as shown in figures 16, 17 and 18.

 

Presently, with increasing researchers being engaged in the research and development of triazole drugs, in near future more triazole chemical drugs with good curative effects, low toxicity and superior pharmacokinetics properties will be launched as novel molecules that could be used in clinic. And, it is all possible that, this will be proved remarkable contribution in prevention of diseases and protection of human’s health with utmost priorities.

 

Fig.16. Ideal requirements for mercapto triazole

 

Fig.17. Ideal requirements for mercapto triazole antibacterial and antifungal agents. antitubrcular agents.

 

Fig.18. Ideal requirements for mercapto triazole anti-inflammatory agents.

 

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Accepted on 05.04.2012      © RJPT All right reserved