SYNTHESIS AND BIOLOGICAL SIGNIFICANCES OF 1, 2, 4-TRIAZOLE AND ITS DERIVATIVES: A REVIEW

SYNTHESIS AND BIOLOGICAL SIGNIFICANCES OF 1, 2, 4-TRIAZOLE AND ITS DERIVATIVES: A REVIEW

Mukhtyar S. Saini*¹ and Jaya Dwivedi ²

Department of Chemistry, Government G.M. Science College ¹, Jammu-180 001, Jammu and Kashmir, India

Department of Chemistry, Banasthali University ², Jaipur- 304 022, Rajasthan, India

ABSTRACT: In the last few decades, to synthesize the different new heterocyclic compounds along their derivatives which were evaluated for their biological activities as antimicrobial, antiviral, antitumor, anticonvulsant, antifungal, the triazole moiety seems to be very small but in the biological profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. In this review we provides a brief response of the medicinal chemistry of 1, 2, 4-triazole and its derivatives. A literature survey of procedures for the preparation of 1, 2, 4-triazole and 1, 2, 3-triazoles is presented by generalized synthetic method.

Triazole, Heterocyclic, Antifungal, Anticancer Activity, Anti-Inflammatory Activity, Antiviral,  Anticonvulsant Activity

INTRODUCTION:Triazoles are the class of heterocyclic compounds ¹ which are under study since many a years. 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 azole ring are readily able to bind with a variety of enzymes and receptors in biological system via diverse non-covalent interactions, and thus display versatile biological activities.

In recent years, the chemistry of triazoles and their fused heterocyclic derivatives has received considerable attention owing to their synthetic and effective biological importance.

The derivatization of Triazole is considered to be based on the phenomenon of bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen atom yields triazole analogue. There are two possible isomers of triazole (1, 2) depending on the position of nitrogen atom in the ring and are numbered as shown in Fig. 1. Out of the two triazoles, 1, 2, 4- triazole have drawn great attention to medicinal chemists from two decades due to its wide variety of activity ², low toxicity and good Pharmacokinetic and Pharmacodynamic profiles. Its diversity in showing the pharmacological activities is mind blowingly identified well by the medicinal chemists as;

1, 2, 3-TRIAZOLE             1, 2, 4-TRIAZOLE

FIGURE 1: TRIAZOLES

Pyrimidines ³, D‐manno‐pentitol‐1‐yl‐1, 2, 4‐ triazoles ⁴, benzotriazoles ⁵, indoles ⁶, quinolones ⁷, triazolo thymidines ⁸, are in record. Literature survey reveals that 1, 2, 4-triazole derivatives exhibit wide range of biological activities including antibacterial ^9-11 antifungal ^12-13 antitumour ¹⁴, anti-inflammatory ¹⁵, antitubercular  ¹⁶, anti-convulsant ¹⁷, anticancer ¹⁸, antimalarial ¹⁹, antiviral ²⁰, analgesic ²¹and antimigrain ²².

Synthesis of 1, 2, 4-triazole backbone: There are various methods for synthesis of 1, 2, 4-triazole are available in literature which involve conventional one pot, multi-components, microwave assisted, under free condition, regioselective, These methods can be summarized as below.

Einhorn-Brunner ^23-26reported synthesis of a mixture of isomeric 1, 2, 4-triazoles (4) from the reaction of imides (3) with alkyl hydrazines in presence of acyl hydroxide (Scheme 1). Pellizzari ²⁷ reported synthesis of substituted 1, 2, 4-triazole (7) by the reaction of an amide (5) and a hydrazide (6) (Scheme 2).

      3                                                                                                               4

SCHEME 1: Synthesis of a mixture of isomeric 1, 2, 4-triazoles using imides with alkylhydrazines in presence of acyl hydroxide

  5                                      6                                                                       7

SCHEME 2: Synthesis of a substituted 1, 2, 4-triazole from amide and a hydrazide

G.M. Castanedo et al, ²⁸ have synthesized a highly regioselective one-pot process provides rapid access to highly diverse 1, 3, 5-trisubstituted 1, 2, 4-triazoles (8) from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines.

8

SCHEME 3

L.Y. Wang et al, ²⁹ have synthesized an effective 1, 3-dipolar cycloaddition for the synthesis of 1, 3, 5-trisubstituted 1, 2, 4-triazole derivatives (9) by reaction of oximes with hydrazonoyl hydrochlorides using triethylamine as a base gave the desired 1, 3, 5-trisubstituted 1, 2, 4-triazoles in good yields.

The reaction was applicable to aliphatic, cyclic aliphatic, aromatic and heterocyclic oxime substrates.

SCHEME 4

D.V. Batchelor et al, ³⁰ have synthesized 3-N, N-Dialkylamino-1, 2, 4-triazoles (10) can be prepared from S-methylisothioureas and acyl hydrazides in good yields. The reaction conditions are relatively mild and tolerate a broad range of functional groups.

SCHEME 5

E. Huntsman et al, ³¹ have synthesized [1, 2, 4] Triazolo[1, 5-a]pyridines (11) have been prepared in good yields from 2-aminopyridines by cyclization of N-(pyrid-2-yl) formamidoximes under mild reaction conditions with trifluoroacetic anhydride.

SCHEME 6

Olcay Bekircan et al [32] have synthesized new bis-1, 2, 4-Triazole derivatives by the reaction of 3-Aryl-5-phenyl-4-amino-4H-1, 2, 4-triazoles and bis-aldehydes to yield 1,2/1,3-bis[o-(N-methylidenamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane, derivatives. Compounds (12) were reduced with NaBH4 to afford the corresponding 1, 2/1, 3-bis [o-(N-methylamino-3-aryl-5-phenyl-4H-1, 2, 4-triazole-4-yl)phenoxy]ethane/propane derivatives (13)

SCHEME 7

V. Ram et al, ³³ have synthesized (14) triazole derivatives as below;

14

Y. Jiang et al, ³⁴ have synthesized 1-monosubstituted aryl 1, 2, 3-triazoles (15) was prepared in good yields using calcium carbide as a source of acetylene. The copper-catalyzed 1, 3-dipolar cycloaddition reactions were carried out without nitrogen protection and in a MeCN-H₂O mixture.

J. Barluenga et al, ³⁵ have synthesized (16) a Pd-catalyzed synthesis of 1H-triazoles from alkenyl halides and sodium azide represents a completely new reactivity pattern in the context of Pd chemistry.

F. Himo et al, ³⁶ have synthesized, Cycloadditions of copper(I) acetylides to azides and nitrile oxides provide ready access to (17) 1, 4-disubstituted 1, 2, 3-triazoles and 3, 4-disubstituted isoxazoles, respectively.

D. R. Rogue et al, ³⁷ have synthesized   1, 2, 3-Triazoles (18), were prepared in good to modest yields by cycloaddition of alkyl azides onto enol ethers under solvent-less conditions. The reaction can access ring-fused triazoles that are unavailable by azide-alkyne cycloadditions and is easily scalable. The 1, 2, 3-triazole products bear functionality that may be readily derivatized.

Rebecca Hluhanich et al, and Ilkay kucukguzel et al, summarized acetylation reactions: N, N’- bis(3-alkyl-4, 5-dihydro-1, 2, 4-triazol-5-on-4-yl)-1, 4-xylenediimines undergoes acetylation reaction in presence of acetic anhydride to form N, N’- bis(1-acetyl-3-alkyl-4, 5-dihydro-1, 2, 4-triazol-5-on-4-yl)-1,4-xylenediimines [62], methyl 5-amino-1H-[1, 2, 4] triazole-3-carboxylate undergoes acetylation in presence of acetic anhydride (AC₂O) to form two isomeric diacetylated products [63].

19

BIOLOGICAL SIGNIFICANCES:

Antibacterial activity:

Antibacterial: Bacteria are the simplest and smallest unicellular organisms found individually or in clusters. The multitude of highly effective and relatively non-toxic drugs available for the treatment of bacterial infections has provided tough competition for the medicinal chemist, attempting synthesis of new antibacterial agents. The medicinal chemistry is towards its advancement, many antibiotics are now chemically modified from original compounds present naturally e.g. beta lactams ³⁸ and named as amino glycosides and a lot more are synthetically derived as sulfonamides ³⁹, the quinolones and the oxazolidinones.

They are classified in two types based on their mode of action as bactericidal agents and bacteriostatic agent ⁴⁰. Among various triazole derivatives, base and sugar modified nucleoside derivatives reflect a potent anti‐microbial activity resulting in its application in the chemotherapy of cancer and viral infection.

The inhibitory effect of N‐glucosides (1), (3) and those of S‐glucosides (2)are manipulated by changing the position of substituent on aromatic ring.

V. Ram et al, ⁴¹ have synthesized triazole substituted triazolo-pyrimidine derivatives and found antibacterial activity. In compound (1), R= pyridyl

Westerman et al, ⁴² have prepared 6, 7-dihydro-1, 3, 4-triazolo[ 1, 5-a ]-1, 3, 5-triazin-2-Sulfonamides (2) and found them as agents with herbicidal and plant growth regulting activity. In compound 2, Ar=(un) / substituted Ph, naphthyl, pyridyl; R=H, acyl, alkyl,phenyl-alkyl,(un) substituted carbonyl etc.R₁,R₂= phenyl; X=O,S.

(2)

Katica Colanceska-Ragenovic et al,⁴³synthesized a few 4-allyl/amino-5-aryl-1, 2, 4-triazoles (3) and tested for antibacterial and antifungal effects against Escherichia coli, Bacillus subtilis, Salmonella enteritidis, Staphylococcus aureus, Aspergillus niger and Candida albicans.

Freddy H. Havaldar et al, ⁴⁴ have synthesized 3-[4-(4-substituted phenyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4 triazol-3-ylmethoxy)-phenyl]-2-phenyl-3H-quinazolin-4-one (4) and were evaluated in vitro for their antibacterial activity.

R.K. Mali et al, ⁴⁵have synthesized5-(N-substituted carboxamidomethylthio)–3-(3'-pyridyl) - 1, 2, 4-triazole derivatives and were evaluated in for their antibacterial activity.

Anti-inflammatory Activity: Mohammad et al, ⁴⁶ synthesized a series of 1, 3, 4-oxadiazole [6a-6b] and 1, 2, 4-triazole [6c] derivatives of 4-hydroxyphenyl acetic acid and evaluated for their anti-inflammatory activity by carrageenan induced rat paw edema method. The compounds, which showed good anti-inflammatory activity, were screened for their ulcerogenic and lipid peroxidation activities.

Birsen Tozkoparanet al, ⁴⁷ synthesized triazoles (7-8) showed anti‐inflammatory activity.

 8

Abbaset al ⁴⁸ synthesized substituted (9-10). Triazoles showed anti‐inflammatory activity.

9

Radhakrishana T.R.et al, ⁴⁹ synthesized triazoles (11).showed anti‐inflammatory activity.

R.H.Udupiet al,⁵⁰synthesized triazoles derivative (12).showed anti‐inflammatory activity.

Antifungal activity:  Antifungals are the class of drugs that are used to eradicate fungal infections from the human body. Fungi are heterotropic microorganisms that are distinguished from algae by lack of photosynthetic ability. Fungi include both yeast and moulds. The former are spherical, oval and mucosid colonies in agar medium and the latter consists of elongated cells that usually reproduce by budding and forming branches of cells.

Ahluwalia et al, ⁵¹ have synthesized (13). 5-(3', 4'-dihydro-2', 2', 8'-trimethyl-2'H-1'-benzopyran-7-yloxymethyl)-4-phenyl-1, 3, 4-triazole-3(4H)-thiol (III) which shows significant antifungal activity. R=C₆H₅, mcl-C₆H₄, pcl-C₆H₄,m-or pCH₃- C₆H₄, pCH₃O- C₆H₄.R₁=CH₃, C₆H₅,R₂=H,CH₃.

R.K. Mali et al, ⁵²synthesized 5-(N-substituted carboxamidomethylthio)–3-(3'-pyridyl) - 1, 2, 4-triazole (90) derivatives (14). Anti-fungal activity was carried out against C. albicans and A. niger at the concentrations of 50 and 100 μg/mL using Fluconazole as the standard.

K. Ilango et al, ⁵³synthesized a new series of 3, 6-disubstituted-1, 2, 4-triazolo-[3, 4-b]-1, 3, 4- thiadiazoles. The compounds (15) were screened for antifungal activity against Candida albicans and Aspergillus niger using Ketoconazole as standard.

Nilkanth G. Aher et al, ⁵⁴Candida fungal pathogens were impinged by the new triazole derivatives (16), analogous to the fluconazole both by in vivo and in vitro. The easily accessible molecules, 1, 4‐disubstituted‐1, 2, 3‐triazole compounds with long alkyl chains displayed a good antifungal activity.

It was more potent than the standard drugs namely ketoconazole, amphoterecin B and fluconazole. The enantiomers are still under process as they are supposed to have more potent activity than the racemic compounds.

Xiaoyun Chai, et al, ⁵⁵   fumigatus was impinged by nearly all type of synthesized compounds and showed broad spectrum activity. The compound (17) showed 128 times more activity against Candida albicans.

Mitscher LA et al, ⁵⁶ reported a novel 2‐substituted‐5‐[isopropylthiazole] clubbed 1, 2, 4‐triazole were synthesized as potent antifungal agent. The activity was shown by the compound (18), named 3‐(4‐Isopropylthiazol‐2‐yl)‐ 6‐(4‐nitrophenyl)‐[1, 2, 4]triazolo[ 3, 4‐b][1, 3, 4]thiadiazole.

Todoulou O.G et al, ^{57 and 58-60} have evaluated the compounds (19-22) as below and found antifungal activity.

Antiviral activity: HIV (retrovirus) is a virus resulting in the slow depletion of immune system of the affected human beings resulting in opportunistic infections.

Some new compounds were synthesized by P. Selvam et al, ⁶¹ and evaluated for the anti‐HIV activity. 4‐[(1, 2‐dihydro‐2‐oxo‐3H‐indol‐3‐ ylidene)amino]‐N (4, 6‐ dimethyl ‐2‐pyrimidinyl) ‐benzene sulphonamide and its derivatives (23) were prepared and they were found active against replication of HIV‐1 and HIV‐2 in MT‐4 cells.

Rebecca Hluhanich et al, ⁶² synthesized Various derivatives of trisubstituted triazoles (24) were prepared as inhibitors of reverse transcriptase and the two derivatives with difference in thio group position were found out to be most active compounds .

Ilkaykucukguzel et al, ⁶³prepared as the novel thiourea derivatives obtained from 5‐[(4‐amino phenoxy)methyl]‐ 4‐alkyl/aryl‐2, 4‐dihydro‐3H‐1, 2, 4 triazole‐3‐ thiones (25) which proved to be having a good activity against cox sacie virus B4, also active against the thymidine kinase positive Varicella zoster Virus.

Alessandro K. et al, ⁶⁴prepared (26) N‐amino‐1, 2, 3‐triazole and evaluated for Antiviral activity against cantalago virus.

Krzysztof Sztanke et al, ⁶⁵reported synthesis of (27). ethyl 1-(7-phenyl-2H-3, 5, 6, 7- tetrahydro-imidazo [2, 1-c] [1, 2, 4]triazol-3-yl)formate The influence of the ethyl 1-(7- phenyl-2H-3, 5, 6, 7- tetrahydro-imidazo[2,1-c][1,2,4]triazol-3-yl) formate on human adenovirus5 (Ad-5) and human enterovirus (Echo-9) replication has been investigated. For this compound, the activity against the selected DNA (Ad-5) and RNA (Echo-9) viruses and the cytotoxicity towards normal GMK (Green Monkey Kidney) cells were determined. Ethyl 1-(7-phenyl-2H-3,5,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazol-3-yl)formate

Anticancer activity: Mohammad Al-Amin et al, ⁶⁶synthesized a series of bis–[4-N-amino-5-mercapto-1, 2, 4-triazol-3-yl] alkanes and and bis–[1, 2, 4-triazolo[3, 4-b] - 1, 3, 4-thiadiazol-4-yl] alkanes  derivatives (28).

H. Mujagic et al, ⁶⁷ synthesized Compound 1‐(6, 7, 8, 9‐Tetrahydro‐5H‐[1, 2, 4]‐triazolo[1, 5,‐a]‐ azepine‐2‐yl)benzyl]indole (32), was prepared and evaluated for anticancer activity against human tumour cell lines derived from nine cancer cell lines . The anticancer activity was moderate or weak in comparison to other lead series of compounds namely vincristine and vinblastine.

Laura B. Peterson et al, ⁶⁸ synthesized triazole analogues (33) where triazole moiety is analogy to amide moiety of natural products. The SAR suggest that the sterically demanded side chains consisting of biaryl, indole or homologated aryl groups showed better activity than substituted aryl compounds

Zhi‐Yi Cheng et al, 69 synthesized 4‐aryl‐5‐ cyano‐2H‐1, 2, 3‐triazole were synthesized and found to have HER2 tyrosine kinase inhibitors. The lipophilicity of the substituting groups in (34) is the main bioactivities which is rational by the IC₅₀ value. 4 Phenyl position on the triazole is the best substituting position for inhibitory activity.

Kristin Odlo et al, ⁷⁰ synthesizeda compound named 2‐methoxy‐5‐(1‐(3, 4, 5‐ trimethoxyphenyl)‐1H‐1, 2, 3‐triazol‐5‐yl) aniline showed potent cytotoxic activity. Molecular modelling supported that the activity of (35) was most likely due to binding site of α, β‐tubulin in the β subunit. They were represented as cis restricted analogue of combresatin.

Anticonvulsant agents: Seizures initiate by the rapid and excessive firing of neurons and is controlled by the class of drugs called Anticonvulsant.

Hong Guang Jin et al, ⁷¹ reported the synthesis of 7-alkoxy-4, 5- dihydro[1, 2, 4]triazolo[4, 3-a]quinoline1(2H)-ones (36) and investigated for anticonvulsant activity and neurotoxicity

S. Moreau et al, ⁷²reported the synthesis of 3-amino-7- (2, 6-dichlorobenzyl)-6-methyl triazolo[4, 3-b]pyridine derivatives (37) of amide and carboxylic acid and investigated for their anticonvulsant potency

Dayanand Kadadevar et al, ⁷³ reported the synthesis and evaluation of N-(substituted phenyl)-2-[5-phenyl-2H-1, 2, 4-triazol-3-yl-amino]acetamide (38) for their anticonvulsant activity

Liu Xin et al, ⁷⁴ recently anticonvulsant activity of clubbed Thiazolidinone-barbituric acid and Thiazolidinone-triazole derivatives have been reported (39).3-(2-chloroacetyl)-2-arylimino-5-[(Z)-arylmethylidene]-1, 3-thiazolan-4-ones on treatment with 5-(1-phenoxyethyl)-4H-1, 2, 4-triazole-3-thiol in identical conditions provided a set of bulkier derivatives which have also shown the anticonvulsant potential.

M. Shalini et al, ⁷⁵ synthesized and anticonvulsant activity of 4,5‐diphenyl‐2H‐1,2,4‐ triazole was carried out on four animal models of seizures namely , viz. Maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)‐ induced seizure threshold tests. The various substituted compounds (40) showed the anticonvulsant activity

Ilkay Kucukguzel et al, ⁷⁶ synthesized a Novel series of 3‐{[(substituted phenyl) methyl] thio} ‐4‐alkyl/aryl‐5‐(4‐aminophenyl)‐ 4H‐1, 2, 4‐ triazoles (41), was synthesized which were similarly evaluated by the above said technique and the two active compounds were evaluated and was concluded that the alkyl substitution or primary amino group were essential for the compound to show an activity.

Nadeem Siddiqui et al, ⁷⁷ synthesized a new class of drug (42) incorporating triazoles to thiazoles 3‐[4‐(substituted phenyl)‐1, 3‐thiazol ‐2‐ ylamino] ‐4‐(substituted phenyl)‐4, 5‐dihydro‐1H‐1, 2, 4‐ triazole‐5‐thiones were synthesized and found to have anticonvulsant activity which was designed as keeping in view the structural requirement of pharmacophore model. The figures of Protective index (PI), Median Hypnotic Dose (HD₅₀), and Median lethal dose were higher than the standard drugs.

Li‐Jun Guo et al, ⁷⁸ synthesized 5‐hexyloxy‐[1, 2, 4] triazolo [4, 3‐a] quinoline (43) and evaluated, found potent anticonvulsive in nature with low level of neurotoxicity. All the possible mechanism of anticonvulsive activity was done in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3‐mercaptopropionic acid and strychnine test.

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    Saini MS and Dwivedi J: A Review: Synthesis and Biological significances of 1, 2, 4-triazole and its derivatives. Int J Pharm Sci Res 2013: 4(8); 2866-2879. doi: 10.13040/IJPSR. 0975-8232.4(8).2866-79

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