A brief study of various synthetic methods of triazoles derivatives and their biological potential

136

A brief study of various synthetic methods of triazoles derivatives and their biological potential

Mohammad Asif

Department of Pharmacy, GRD(PG)IMT, Dehradun, (UK), 248009, India

* Corresponding author: [email protected]

Received 09 June 2014, Revised 16 July 2014, Accepted 17 July 2014.

Abstract

In the last few years, heterocyclic compounds have attracted strong interest and a lot of work has been done on triazole ring. Many different derivatives have been prepared from it which possesses useful pharmacological activities. Different pharmacologica l activities of triazole ring and its derivatives possess a wide range of pharmacological activities such as anticancer, anticonvulsant, antimicrobial, anti-inflammatory, antioxidant, antitubercular, antimalarial, antinociceptive etc. In triazole ring, substitution at 1,4 and 1,3 positions of a more electronegative group will possess more active analogues. Various pharmacological activities of triazole in one place and it is also the milestone for the new research towards this moiety. The triazole moiety has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. A literature survey of procedures for the preparation of 1,2,4-triazole and 1,2,3-triazoles is presented by generalized synthetic method.

Key words: Heterocyclic, Biological activities, triazole, synthesis.

Introduction

The chemistry of N-bridged heterocycles derived from 1,2,4-triazole has received considerable attention in recent year due to their usefulness in different areas of biological activities and as industrial intermediates. 1,2,4-triazole moiety appears frequently in the structure of various natural products¹ and the synthesis of compounds incorporating this moiety has attracted widespread attention of chemists as well as biologists, mainly due to their diverse biological activities in pharmaceutical and agrochemical fields. 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

137 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 (A and B) 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 (Saini and Dwivedi. 2013). Its diversity in showing the pharmacological activities is mind blowingly identified well by the medicinal chemists as;

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], analgesic, anti-inflammatory [15], antitubercular [16], anti-convulsant [17], anticancer [18], antimalarial [19], antiviral [20], analgesic [21] and antimigrain [22] CNS stimulants, sedatives, antianxiety activities. Now a day’s research is concentrated towards the introduction of new and safe therapeutic agents of clinical importance. The triazoles are said to be the isosters of imidazoles in which the carbon atom of imidazole is isosterically replaced by nitrogen. Triazoles nucleus have been incorporated into a wide variety of therapeutically interesting drug candidates. They are used as optical brightening agents, as antioxidants, as corrosion inhibitors and as additives with a variety of other functions. Many dye stuffs and pigments have heterocyclic. The Triazole derivative possess a wide a range of pharmacological activities. The importance of triazole derivatives lies in the field that these have good position in heterocyclic chemistry, due to its various biological activities [23].

N N H N

N N H N

1, 2, 4 triazole (A) 1,2,3 triazole (B) Figure 1: Triazoles

Other heterocyclic moiety with triazole ring: Schiff bases are considered as a very important class of organic compounds which have wide applications in many biological aspects [24] Many

138 Schiff bases containing 1,2,4-triazole moiety exhibit antibacterial, antifungal [25] and antitumoral activities [26] The substituted nicotinic acid is among the various heterocycles that have received most attention during last three decades as potential biomolecules. Nicotinic acid derivatives exhibit antibacterial, antioxidant, anti-inflammatory and anticarcinogenic activities. It is seen from the current literature that pyridine congeners are associated with different biological properties like pesticidal [27,28], insecticidal and antifungal activities. A large number of antibiotics contain amide linkage. Several derivatives of amides were prepared and found to possess antimicrobial activities. Literature survey reveals that various drugs e.g. penicillin (antibacterial), pyrazinamide (antitubercular), indinavir, ritonavir. (Protease inhibitors as anti- AIDS) etc contain their particular activities due to the amide linkage present in their structure.

Chemistry: Triazole, also known as pyrrodiazole is one of the classes of organic heterocyclic compounds containing a fivemembered diunsaturated ring structure composed of three nitrogen atoms and two carbon atoms at non-adjacent positions. The simplest form of the triazole family is triazole itself. Triazole is a white to pale yellow crystalline solid with a weak, characteristic odour; it is soluble in water and alcohol, melts at 120°C and boils at 260°C. It occurs as a pair of isomeric chemical compounds 1,2,3-triazole, and 1,2,4-triazole, with molecular formula C₂H₃N₃, and a molecular weight of 69.06 . The two isomers are 1,2,3 and 1,2,4-triazole [29,30].

Table-1. Chemical characteristics of 1,2,3 and 1,2,4-triazole

Properties of 1, 2, 3-triazole Properties of 1, 2, 4-triazole Molecular formula C₂H₃N₃ Molecular formula- C₂H₃N₃

Molar mass 69.0654 Molar mass - 69.0654

Boiling point 203 °C Boiling point- 260

Melting point 23-25 °C Melting point - 120-121°C

Density 1.192 g/cm-3 Density - 1.394 g/cm-3

Appearance colourless liquid Appearance white solid

Solubility in water very soluble Solubility in water very soluble Basicity (pKb) 9.4 Basicity -(pKb) 10.3

Acidity (pKa) 1.2 Acidity -(pKa) 2.2

Vapour Pressure 0.4 mmhg (25oc) Vapour Pressure 0.02 mmhg (25oc)

Biological profile of triazole derivatives: Triazole refers to either one of a pair of isomeric chemical compounds, having a five membered ring of two carbon atoms and three nitrogen atoms. The two isomers are: 1,2,3-triazole and 1,2,4-triazole. 1,2,4-Triazole and its derivatives represent one of the most biologically active class of compounds and are associated with diverse pharmacological activities [31-35]. The substituted 1,2,4-triazole nucleus is particularly common and can be found in marketed drugs such as fluconazole, terconazole, rizatriptan, alperazolame and triazolame [36]. A large variety of 1,2,4-triazole derivatives possess antibacterial antifungal,

139 antiviral, anti-inflammatory, anticonvulsant, antidepressant, antitubercular, antitumoral, antihypertensive, analgesic, enzyme inhibitor, hypoglycemic, sedative, hypnotic, antiparasitic, herbicidal, insecticidal and plant growth activities [37-42]. Thus several potent drugs possessing triazole nucleus have been applied in medicine like, alprazolam (anxiolytic, tranquilizer), anastrozole, letrozole, vorozole (antineoplastics, non-steroidal competitive aromatase inhibitors), estazolam (hypnotic, sedative, tranquilizer), etoperidone (antidepressant), fluconazole, itraconazole, terconazole (antifungl agents), ribavirine (antiviral agent), benatradin (diuretic), rilmazafon (hypnotic, anxiolytic, used in the case of neurotic insomnia), nefazodone (antidepressant, 5-HT2 A-antagonist), rizatriptan (antimigrain agent), trapidil (hypotensive), prazodone (antidepressant, anxiolytic, selectively inhibits central serotonine uptake) and triazolam (sedative and hypnotic). The triazole antifungal drugs include fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, and posaconazole. The triazole plant protection fungicides include epoxiconazole, triadimenol, propiconazole, metconazole, cyproconazole, tebuconazole, flusilazole and paclobutrazol [43-48].

Biological activity of 1,2,4-triazole derivatives: Various work are available with regard to the study of 1,2,4-triazoles. The literature revealed that the compound containing 1,2,4-triazole are reported to possess diverse biological activities. Some 1,2,4-triazole fused acyclic and membered macro cyclic compounds (1) with potential antimicrobial activity[49]. The 1,2,4-triazoles derivative (2) with antibacterial activity against Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli and Pseudomonas aeurogenosa using cup-plate method [50]. Some 1,2,4- triazole analogues (3) for evaluation of their antifungal activity against C. albicans, A. niger [51]. Some new 1,2,4-triazoles and their Mannich and Schiff bases (4) and screened for their antimicrobial activity against E. coli, Y. pseudotuberculosis, P. aeriginosa, Enterococcus faecalis, S. aureus, B. cereus, C. tropicalis and C. albicans [52]. Some 1,2,4-triazole derivatives (5) and have shown the activity against E. Coli, klebsiella pneumonia, Yersinia pseudotuberculosis, Enterobacter aerogenes, P. aeurogenosa, staphylococcus aureus, E.

faecalis, Bacillus cereus, Candida tropicalis, C. glabrata [53]. Some new 1,2,4-triazole derivatives (6) and screened for their biological activity in vitro against Gibberella zeae, Alternatia solani [54]. Some 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones (7) has described activity as anti-inflammatory by carrageenan Paw Edema Test (CPE) method [55]. Some 1,2,4-triazoles (8) starting from isonicotinic acid hydrazide and evaluation of their antimicrobial activities against E. coli, Y. pseudotuberculosis, P. aeruginosa, Enterococcus aureus, Bacillus cereus, C. tropicalis and C. albicans, by Agar-well diffusion meyhod [56]. The 5-aryl-3-alkylthio-1,2,4-triazoles (9) and sulfones with anti- inflammatory activity and also analgesic activity [57]. The 1-acylthiosemicarbazides, 1,2,4- triazole-5(4H)-thiones (10), 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2- benzoxazolinones showed analgesic activity, anti-inflammatory activity and also antimicrobial

140 activity against Candida krusei, Candida albicans and Candida parapsilosis. The 4H-1,2,4- triazole derivatives (11) which have shown analgesic activity [58].

Compounds (1) Compounds (2) Compounds (3)

Compounds (4) Compounds (5) Compounds (6)

Compounds (7) Compounds (8) Compounds (9)

Compounds (10) Compounds (11)

N H N

N S

N N

O

CH₂

N N

N H

S

NH CH₃ O

N N N H

S N

N R H

O

N N N N

S NH

O

N R

N N

N Cl

O N

O CH₃ N N

O SH N N

N O

CH₃

O N

N N

N

N N

F S

N N

CH₃

N H N

N S

N N

O

CH₂

N N H N

Ar^- S O O R

N N H N

CH₂ S C H₃ N

C O O

C

H₃ N

N N

R SH

N N N

R'

R"

141 N

N N S N

N N

CH₃

O NH Cl

N S N N N

^{O O O}

CH₃

N N

N

Compound (12) Antibacterial [59] (13) Antimicrobial [60] (14) Antibacterial [61]

S N N

N CH₃

S O O

Br

O

(15)Antifungal [62]

N N N HS

F

N N HN

N Br

N N

N

O CH₃

(16) Anticonvulsant [63] (17) Antibacterial [64]

N N NH

S Cl

Br

(18) Anti-inflammatory[65].

N NH

N S

O O

CH3

Cl

(19) Anti-inflammatory [66].

Figure 1. Structure of some 1,2,4-triazole derivatives.

Recent Advancements

Recent literature survey demonstrates that the 1,2,4-triazoles are becoming of great practical significance. 1,2,4-triazole derivatives possess analgesic, antipyretic and antiphlogistic properties. A group of 1,2,4-triazole-5-ones and their mannich bases have shown antitubercular activity [67] and have been investigated with regard to their mode of action.

Anticancer activity: A series of compound 3-(2,4-dichloro-5-fluorophenyl)-6-(substituted phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (19) compounds were tested for their antitumor activity. Among the compounds, compound 19a, 19b and 19c exhibited most potent activity against sixty cancer cell lines of leukemia, non-small cell lung cancer, melanoma, ovarian cancer, prostate and breast cancer [68].

A series of novel alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives (20). These derivatives were then screened for their in-vitro anticancer activity against three cancer cell lines such as U937, THP-1 and Colo205. Compounds 20a and 20b showed potent anti-cancer activity against the respective cell lines [69].

142 N

N N

N S

Cl Cl F

R

N N

N R CF3 O

N N N

R₁

R= 19a; 4-Cl, 19b; 2,4-Cl 19c ; 2,4Cl -5-F 20a: R= H, R1= CH3-(CH2)8-CH2; 20b: R= CH₃, R1= CH₃-(CH₂)₈-CH₂ Anticonvulsant activity

A series of 6-alkoxy-[1,2,4] triazolo [4,3-b] pyridazine derivatives (21) and screened them for anticonvulsant activity. In all synthesized derivative, 6-(2, 4-dichlorophenoxy)-[1,2,4] triazolo [4, 3-b] pyridazine 8 was found to be most active and exhibiting the lowest toxicity [70] A series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one (22) compounds and screened them for their anticonvulsant activity. Compounds 22a, 22b, 22c-g were exhibited potent anticonvulsant activity in all the four animal models of seizure which are maximal electroshock seizure (MES), subcutaneous pentylenetetrazole, subcutaneous strychnine, and subcutaneous picrotoxin -induced seizure threshold tests [71].

N N N

N

O

Cl Cl

HN N N

O

R

R₂ R₁

21 22

R, R1, R2 22a: H, 2-CH3, 4-CH3; 22b: H, 2-CH3, 5-CH3; 22c: NO2, H, 4-F; 22d: NH2, H, 4-F;

22e:CH₃, H, 4-F; 22f: H, H, 4-F; 22g: OH, H, 4-F

Antimicrobial activity: A series 5-(4-amino substituted-8-(trifluoromethyl) quinolin-3-yl)-4- (un) substituted phenyl -4H-1,2,4-triazole-3-thiols (23) from derivatives of 4-hydroxy-8- (trifluoromethyl) quinoline-3-carbohydrazide and screened for their antimicrobial activity against E. coli, S. aureus, P. aeruginosa, K. neumonia. The activity of these compounds was compared with ciprofloxacin as standard drug. The compounds 23a, 23b and 23c showed comparatively very good activity against all the bacterial strains [72]. A series of novel sulfanilamide-derived 1,2,3-triazole compounds (24 and 25) via 1, 3-dipolar cycloaddition and screened them in vitro for their antibacterial and antifungal activities against S. aureus, E. typhosa, P. aeruginosa, S.

143 dysenteriae, B. subtilis, E. coli, as well as C. albicans and C. mycoderma. The activity of the synthesized compounds was compared with the reference drug chloramphenicol. The compounds 24, 25a and 25b bearing dodecyl, 2,4-dichlorobenzyl and 2,4-difurobenzyl group, respectively, showed the most potent antibacterial activities against all tested bacterial strains with the MIC values ranging from 32 to 128 μg/mL[73].

N CF3

R2

N N N R1 SH

R1= Ph, -CH2Ph, -CH2CH2OMe; R2= substituted amines; 23a: cyclopropyl amine, 23b: cyclohexyl amine, 23c: 3,3 Dimethyl butylamine. 23d: Piperidine-4- propanol, 23e:Morpholine, 23f: 4- Piperidine morpholine

NH₂ S

HN O

O N

N

N (CH2)11CH3

NH₂ S

H O N

O N

N N R₃

R₂ R₁

Figure 24 Figure 25 25a R₁ = Cl, R₂ =H, R₃ = Cl;

25b R1 = F, R2 = H, R3 = F

Anti-inflammatory activity: A series of several new 6-alkoxy (phenoxy)-[1,2,4]triazole [3,4-a]

phthalazine-3-amine derivatives (26). All synthesized derivative further screened for their anti- inflammatory activity. The compounds 26a and 26b possess highest anti-inflammatory activity in comparison to the reference drug Ibuprofen [74].

Anti-oxidant activity: A series of 4-(3,4-dihydroxyphenethyl)-5-methyl-2H-1,2,4-triazol 3(4H)- one derivatives (27 and 28) which were then screened for anti-oxidant activity. It was found that compounds 27a-d and compound 28 possess highest degree of antioxidant activity [75].

N N

N N O R

NH₂ N

HN

N O

(Ar)R

OH OH

N HN

N O

HO HO

OH OH

26a: R = -C6H4 (o-Cl); 27a-d 28 26b: R = -C6H4 (p-NH2)

144 4-(2,3-dihydroxyphenethyl)-5-(3,4-dihydroxybenzyl)-2H-1,2,4-triazol-3(4H)-one

Compound: 26a 26b 26c 26d Ar: -CH3 -CH2CH2CH3 -C6H5 S

A series of 3-alkyl (aryl)-4-(3,4-dihydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (29) and were evaluated for their antioxidant activity by DPPH free radical scavenging method.

Among the compounds 29a, 29b shows more potent antioxidant activity.

Anti-malarial activity: A series of chalcone and dienone hybrid compounds (30) containing aminoquinoline and nucleoside templates which were then screened for in-vitro antimalarial activity. Amongst the compounds, three compounds were found to be most active that is compounds 30a, 30b and 30c, compound 30a was the most active and potent against D10, Dd2 and W2 strains of P. falciparum compared with the standard drug chloroquine [76].

Anti-tubercular activity: Various derivatives of substituted 1,2,4-triazol-(3-yl) benzene-1,2,3- triol derivative (31) and screened them for anti-TB activity. It was found that compounds 31a and 31b possess comparable activity with that of standard drug Rifampicin against M.

tuberculosis. The remaining compounds are found to be less active than standard [77].

N HN N

O N

OH OH R

N Cl

N N N O

O

H3CO

R

HO HO

HO

N N N

HN

R

29a:R=CH3; 29b:R=CH2C6H5 R 30a: 2,4-diOMe; 30b: 2,3,4-triOMe; 31a: NO2; 31b: OH 30c: 2, 3, 4-triOMe

Anti-nociceptive activity: A series of 1-[2-(1H-tetrazol-5-yl) ethyl]-1H-benzo-1,2,3 triazole derivative (32) were screened for anti-nociceptive and anti-inflammatory activity. It was found that compounds 32a and 32b possess significant anti-nociceptive activity while compounds 32c and 32d possess significant anti-inflammatory activity [78,79].

145 N

N N

N N N N

R

32a R=

O

NH₂, 32b

O

OH, 32c^H3C

OSO

,32d^H2N

OSO

From the above discussions it may be concluded that the modifications in triazole moiety displayed valuable biological activities and these modifications can be utilized to develop potentially active agents for future investigations.

In the last few years, heterocyclic compounds have attracted strong interest and a lot of work has been done on triazole ring. Many different derivatives have been prepared from it which possesses useful pharmacological activities. In the present review, we have compiled the different pharmacological activities of triazole ring and its derivatives. It has been observed that triazole derivatives possess a wide range of pharmacological activities. In triazole ring, substitution at 1,4 and 1,3 positions of a more electronegative group will possess more active analogues. This review contains various pharmacological activities of triazole in one place and it is also the milestone for the new research towards this moiety. Medicinal chemistry is an aspect of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design and identification of biologically active compounds. It also involves study of metabolism, interpretation of mode of action at the molecular level and the development of structure activity relationship (SAR) of the active nuclei. It is devoted to the discovery and development of new agents for treating diseases. Inorganic compound continue to be important in therapy, for example, antacids, mineral supplements and radiopharmaceuticals, but organic molecules with increasingly specific pharmacological activities are clearly dominant. Heterocyclic compounds are cyclic compounds with at least two different elements as ring member atoms. They are the counterparts of homocyclic compounds, which have only ring atoms from the same element.

Although heterocyclic compounds may be inorganic, most contain at least one carbon atom, and one or more atoms of elements other than carbon within the ring structure, such as sulfur, oxygen or nitrogen. In organic chemistry noncarbons which replace carbon atoms are called heteroatoms [80-84]. Triazole and its derivatives possess a great significance in medicinal chemistry and numerous heterocyclic compounds containing triazole with different biological activities can be synthesized from them. Triazole has a basic, five membered, heterocyclic ring containing two carbon and three nitrogen atoms. It forms a pair of isomeric chemical compounds [85]. Out of these two, 1, 2,4-triazole possess significant and wide variety of activity in comparison to 1,2,3- triazole. 1,2,3-triazole is considered to be the most stable organic compound in comparison to all other organic compounds possessing three adjacent nitrogen atoms. Aziridine was formed by flash vacuum pyrolysis from 1,2,3-triazole at 500°C which leads to loss of molecular nitrogen (N2). Certain triazoles undergo cleavage very easily due to socalled ring-chain tautomerism such as in the Dimroth rearrangement. 1,2,3-triazole is considered to be the most useful component, widely used in research purpose as a building block for complex chemical compounds such as

146 pharmaceutical drugs like tazobactam. 1,2,4-Triazole is a basic aromatic heterocycle and its derivatives posses a wide variety of pharmacological activities. Some of the marketed preparation which contains triazole ring is fluconazole and itraconazole. The attachment of quinoline ring to triazole ring is responsible for producing anti-bacterial effect and further modifications can be made on it to enhance its pharmacological effect. Substitution at 3rd position may also increase the pharmacological activity of a compound for e.g.:- 3-Amino-1,2,4 triazole is a competitive inhibitor of the production of HIS3 gene, imidazoleglycerolphosphate dehydratase. It is an enzyme catalyzing the sixth step of the histidine production and is also a non selective systemic triazole herbicide used on non food crop land to control annual grasses and broad leaf and aquatic weeds [88].

F

F

O O

N N N N

N

N N N O

CH₃ H₃C

OH

Posaconazole (Antifungal)

Cl

Cl O O N

O

N N N

N

N N N O

CH₃ H₃C

Itraconazole (Antifungal)

N O

Cl N N

O

NH₂ N

O H₃C

CH₃

Cl

Rilmazafone (Anxiolytic)

Cl N N

N N

N

H₃C O

O

Nefazodone (Antidepressant)

N OH N N

N

N N F

F

Fluconazole (Antifungal)

HO O

HO OH

N N

N

NH₂ O

Ribavirin (Antiviral) ^N

N N N H₃C

N CH₃ H₃C

Trapidil (Anti-hypertensive Vasodilator)

147 N

N N

N Cl H₃C

Alprazolam (Tranquillizer)

H3C

CH₃ CN

H₃C H₃C NC

N N

N

Anastrozole (Antineoplastic)

F

F OH

CH₃ N N N

N N

F

Voriconazole (Antifungal)

N N

N N

Cl

Estazolam (Sedative-Hypnotic)

F N N N

F

O NH₂

Rufinamide (Antiepileptic)

N N

N O

N N

Cl

Trazodone (Antidepressant)

Figure 2. Some triazole based drugs available in clinical Uses [89-100].

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. Einhorn-Brunner [101-104]

reported synthesis of a mixture of isomeric 1,2,4-triazoles from the reaction of imides with alkyl hydrazines in presence of acyl hydroxide (Scheme 1). The synthesis of substituted 1,2,4-triazole by the reaction of an amide and a hydrazide [105] (Scheme 2).

R₁ H

N R₂

O O

R₃ NH₂ N H

N N R₃ N R₁

R₂

R₃ R₂ R₁

AcOH

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

R' H N

NH₂ O

R NH₂ O

N N N

H

R' R

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

148 A highly regioselective one-pot process provides rapid access to highly diverse 1,3,5- trisubstituted 1,2,4-triazoles from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines [106].

R OH2

O

R₁ NH₂ NH

R N

O

NH₂

R1 N

N N R'

R

R'' H₂NNH-R''

R, R’R’’=alkyl, aryl

Scheme 3

An effective 1,3-dipolar cycloaddition for the synthesis of 1,3,5-trisubstituted 1,2,4-triazole derivatives 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 [107].

R H

NO.HCl

Cl COOCH₃ N.HCl

N N N R'

COOCH₃ ArHN

NEt₃

Ar

R= alkyl, aryl

Scheme 4

The 3-N, N-Dialkylamino-1, 2, 4-triazoles 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 [108].

N N

SCH3

H₂N R'' O

N N N

N

R''

R'''

R' NH₂ R'

R R

R''' R,R’, R”’ = alkyl, R’’= alkyl, aryl

Scheme 5

The [1,2,4] Triazolo[1,5-a]pyridines have been prepared in good yields from 2-aminopyridines by cyclization of N-(pyrid-2-yl) formamidoximes under mild reaction conditions with trifluoroacetic anhydride [109].

149 HN N

OH

N N N

R R

TFAA THF

Scheme 6

The 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 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 [110].

Scheme 7

Compound triazole derivatives as synthesized as below [111];

R-CH=NNH-CO-NH₂

Br₂/ gl. CH₃COOH ^N O N

NH2

R

Formamide Ethylene glycol

N NH N

NH2

R

Scheme 8

The 1-monosubstituted aryl 1,2,3-triazoles 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 [112].

ArN₃ CaC₂ CuI / Na ascorbate CH₃CN / H₂O (2:1)

N N N

Ar

Scheme 9

Pd-catalyzed synthesis of 1H-triazoles from alkenyl halides and sodium azide represents a completely new reactivity pattern in the context of Pd chemistry [113].

NaN₃ ^{N NH}

N Ar Br

Ar

Scheme 10

Cycloadditions of copper (I) acetylides to azides and nitrile oxides provide ready access to 1,4- disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively [114].

150

R-N₃ R

CuSO4.%H2O Sod. Ascorbate

N N R N

R' R= alkyl R’=PhCOOH Scheme 11

Synthesized 1,2,3-Triazoles 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 [115].

R-N_{3 H}

3CO

R'

N N

N R

R' OCH3

N N

N R

R'

Scheme 12

Pellizari Reaction: The synthesis of 1,2,4-triazole derivatives by the mixture of amide and acyl hydrazide is generally referred to as the Pellizzari reaction. It has been reported that heating the mixture of formamide and hydrazine hydrochloride with KOH yield of 1,2,4-triazole. For example benzamide and benzoyl hydrazide gave 3,5-diphenyl-1,2,4-triazole [116].

NH₃ O

N H O

NH₂

N HN N

140^oC

Scheme 13

Einhorn-Brunner Reaction: The synthesis of 1,2,4-triazoles by condensation between hydrazines or mono substituted hydrazine and diacylamines in the presence of weak acid is known as the Einhorn–Brunner reaction. For example N formyl benzamide and phenyl hydrazine gave 1,5-diphenyl-1,2,4-triazole [117].

NH O

CHO

C₂H₅OH _O

HN N HN HN

NH2

N N N

Scheme 14

151 1,5-Diarylsubstituted 1,2,3-triazoles are formed by aryl azides and alkynes in DMSO in the presence of a catalytic amount of tetra alkyl ammonium hydroxide. The reaction is simple, does not require a metal catalyst [118].

Ar-N₃ Ar' _CH N(CH₃)₄OH

DMSO ^N _N^N

Ar

Ar'

Scheme 15

Thiosemicarbazide on cyclization in alkaline medium afford 1,2,4-triazoles [119,120].

HN NH S O

NH R

N N N

R

SH N

N NH

R S NaOH

R = Phenyl, 4-Methoxy phenyl, 3-methyl phenyl, 2-Flouro phenyl Scheme-16

Thiosemicarbazides on heating with triethylamine in ethanol cyclizes to give 1,2,4-triazoles [121].

O N

O NH O

HN H N

S R

N(C₂H₅)₃

O N

O

N NH N

R S

Scheme-17 R =substituted Aryl

Thiosemicarbazide on refluxing with 1,1 cyclopropane dicarboxylic acid and SOCl₂ in alkaline medium cyclizes to give 1,1-bis(3-thio-1,2,4-triazol-5-yl) cyclopropane [122].

O O

HO OH

N N

NH N

H N N

HS SH

i. SOCl₂, NH₂NNCSNH₂ ii. NaOH

Scheme-18

2-Chloro-6-methoxy-4-phenyl-quinoline on refluxing with substituted acylhydrazides in a nitrogen atmosphere yield 7-Methoxy-1-(4-methoxyphenyl)-5-phenyl-1,2,4-triazolo[4,3-a]

quinoline [123].

152 N

H₃CO

Ph

Cl

N N N

OCH₃ H3CO

i. RCONHNH₂Ph ii. n-butanol

Scheme-19

(2E)-4-phenylquinolin-2(1H)-one hydrazone when refluxing with formicacid in ethanol yield 5- phenyl-3,3a-dihydro [1, 2, 4]triazolo[4,3-a]quinoline [124].

HN H₂N N

N i. HCOOH

ii. C₂H₅OH

HN N

Scheme-20

1,2,4-Triazole-3,5-diamine derivatives were synthesized in moderate to high yields in one-pot reaction from the corresponding isothiocyanates, monosubstituted hydrazines, and sodium hydrogen cyanamide in the presence of 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride. Typically, two target compounds were obtained, but high regioselectivity to one isomer was observed when aromatic and sterically bulky hydrazines were used. Examples with a detailedrepresentative procedure are given below [125,126].

R₁NCS

i.NaNHCN ii.R₂NHNH₂

EDC

N N

N NH

R₁

R₂ NH₃

N N N

N H R₁

NH₂ R₂

R₁/R₂ = Alkyl, Aryl

Scheme-21

The N-(4-methylsulfonylphenyl)aryl carbohydrazonamides undergoes a ring closure using 1,1 - thiocarbonyldiimidazole and subsequent alkylation to afford 5-(4-halophenyl)-4-(4- (methylsulfonyl)phenyl)-2H-1,2,4-triazole-3(4H)-thione [127].

153 N

HN

NH₂ S H₃C O

O

X

N N H₃C SO

O

X

HN S 1,1'-thiocarbonylimidazole

Scheme-22

The reaction of N, N-dimethylformamide azine with primary amines mediated by p-toluene sulfonic acid gives the triazole as shown in scheme-9. The driving force of this reaction is the release of dimethyl amine as well as the stability of the triazole formed [25].

N H₃C

H3C

N

CH₃ CH₃

NH3-R ^{p TosOH}

N N

N R -2 HN(CH₃)₂

R = Alkyl/Aryl Scheme-23

1,3,4-oxadiazole on reaction with the primary amines gives 3,5-disubstituted 1,2,4-triazole [128].

N N H₃C O R₁

NH₂ p TosOH

-H₂O

N N N

R₁

CH₃ R₂

R₂

Scheme-24 R₁/R₂ = Alkyl/Aryl

(Z)-4-chloro-N'-(ethoxy(p-tolyl)methylene)benzohydrazide undergoes cyclization in presence of hydrazine monohydrate to produce 4-amino-3-(pchlorophenyl)-5-p-tolyl-4H-1,2,4-triazole [129,130].

H₃C

N N H O

CH₃

O

Cl

H₃C

N N

N Cl

H₂N

i. Propanol ii. R₂NHNH₂

Scheme-25

Reaction of resin bound S-methyl isothiourea with carboxylic acids yielded resin-bound S- methyl-N- acylisothiourea which reacted with hydrazines under mild conditions to afford the corresponding resin-bound 3-amino-1,2,4-triazoles with regioselectivity [131].

154 i. DMF

ii. R₂NHNH₂ iii.TFA/DCM O

NH S H₃C

O N

H R₁

O N

N N

R1

H2N

R2

Scheme-26

When substituted phenylthiourea is refluxed with 2-(aryloxy)alkanoic hydrazides in presence of pyridine, it gave 1,2,4-triazole. The completion of the reaction was assured by the ceasing of the methylmercaptane evolution [132].

O

HN NH₃ O

R

O NH NH₂

Pyridine

O N NH

S R

Scheme-27 R=CH_3, Cl, Br,

Triazole synthesis using microwave: Microwave synthesis reduces the reaction time resulting in more decision point per unit time rather then days. The short reaction time provided by microwave synthesis makes it ideal for rapid reaction scouting and optimization of reaction conditions, allowing very rapid. In order to fully benefit from microwave synthesis one has to be prepared to fail in before succeeding. While failure could cost a few minutes, success would gain many hours or even days. The 4,5-Disubstituted-1,2,4-triazole-3-thiones have been prepared in one stage from the reaction of acid hydrazide with alkyl or aryl isothiocyanate in the presence of a KOH (10%) solution on the surface of silica gel as well as on the surface of montmorillonite K10 under microwave irradiation. These triazoles have also been prepared from the reaction of 4-substituted-1-aroyl thiosemicarbazides, with a KOH (10%) solution on the surface of silica gel under microwave irradiation [133].

O NH

NH₂

R₁ R₂NCS

O NH

HN R₁

S HN

R₂ N

N

N CH3

R₂ S

R₁ 10%KOH MW

, SiO3

MW

montmo rillonite

K10

Scheme 28 R₁ -CH₃, C₆H₅, 4-Cl-C₆H₅, 4-NO₂-C₆H₅; R₂ –CH₃, C₆H₅

Different types of 4,5-disubstituted 1,2,4-triazole-3- thiones by microwave irradiation as well as by a classical method. The beneficial effect of microwave irradiation on the dehydrative cyclization of thiosemicarbazides in different reaction media is described. The results show that

155 the effect of microwave irradiation on the reaction studied was the shortening of reaction times (from 2–9 h to 2–4 min) and a minor decrease (1–4%) of yields [134].

R H

N N H

S NH

R₁ O

MW

R₁

R SH

Scheme 29 R- Benzyl, 2- methyl phenyl; R1–2-pyridyl ,3-pyridyl, 4-pyridyl

Synthesized 3,5-disubstituted-4-amino-1,2,4-triazoles from the reaction of aromatic nitriles with NH₂NH₂·2HCl in the presence of NH₂NH₂·2H2O excess in ethylene glycol under microwave irradiation [135].

Ar-CN Ethylene glycol NH₂NH_2.2H₂O

NH₂NH_2.H₂O ^{N N}

N Ar Ar

NH2

Scheme 30

A novel one-step synthesis of thiazolo-[3,2-b]-1,2,4-triazoles were reported from the reaction of chalcones with bis-(1,2,4-triazolyl)-sulfoxide [136].

O

R₁ R₂ N

N N S

O N

N N

N N

N S

R₁ O

R1

Toluene

Scheme 31

Symmetrical 3,5-substituted-4-amino-1,2,4- triazoles are quickly prepared from aromatic aldehydes via nitriles by two-step reactions without any separation under microwave irradiation for several minutes [137].

ArCHO NH₂OH.HCl

NCH₃ O

ArCN ^NH2NH2.H2O HO(CH₂)OH

MW

N

N NH NH Ar

Ar

N Ar Ar

NH₂ NH₂NH_2.HCl

Scheme 32

4.6.Condensation of acid hydrazide with S-methylisothioamide hydroiodide and ammonium acetate on the surface of silica gel under microwave irradiation afforded 1,2,4-triazoles [138].

O NH

NH₃ R1

S NH₂ R₂

H3C

I^-

NH₄OAc Et₃N, MW

N N HN R₂ R1

156 Scheme 33

An efficient microwave-assisted one-pot and three-component synthesis of substituted 1,2,4- triazoles has been achieved utilizing substituted primary amines [139]. A efficient one-step, basecatalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles by the condensation of nitriles and hydrazides under microwave irradiation [140].

R₂ N H O

NH2

K₂CO₃, n-BuOH

MW _N ^N

HN R2

R₁

R₁CN

Scheme 34

Under the reaction conditions, a diverse range of functionality and heterocycles are tolerated.

The reactivity of the nitrile partner is relatively insensitive to electronic effects. A new protocol for Biginelli reaction microwave irradiation in the synthesis of some 1,2,4-triazoles as a potential antifungal agents against C. albicans and A. niger has been reported recently [141].

R1

HN

N N NH

S

R₂

Synthesized new antifungal azoles including 1,2,4-triazole derivatives from substituted hydrazide using various solid supports under microwave irradiation [142].

NH O NH

HN O

R

NH₄SCN

Basic/neutral alumina MW ^NH O NH N N

R

S

Scheme 35

A simple and fast synthesis of 6-aryl-3-substituted 5H-[1,2,4]-triazolo-[4,3-b][1,2,4]- triazoles in high yields has been developed by microwave aided heterocyclization of N-(3- methylthio-5- substituted 4H-1,2,4-triazol-4-yl)-benzenecarboximidates [143].

157 HN

NH N

N N R

S CH₃

N N HN N

N R

Scheme 36

Discussion

In the previous years the synthesis of high nitrogen containing heterocyclic systems has been attracted to many pharmaceutical and agrochemical industries. Triazole is a five member heterocyclic nucleus has attracted a wide attention of the Chemist in search for the new therapeutic molecules. The triazole nucleus is one of the most important heterocycles which is a feature of natural products and medicinal agents. Triazole nucleus is enjoying their importance as being the center of activity. The nitrogen containing heterocyclics are found in abundance in most of the medicinal compounds. The triazoles are said to be the isosters of imidazoles in which the carbon atom of imidazole is isosterically replaced by nitrogen. Triazole and its derivatives have a wide range of application and play vital role in biological fields [144-146]. These Skeletons have its multiple potential against several activities. In the last few decades, the chemistry of triazoles and their fused heterocyclic derivatives has received considerable attention owing to their synthetic and effective biological activities. Also, there are known drugs in market containing the triazole group e.g. fluconazole, intraconazole, voriconazole, Triazolam, Alprazolam, Etizolam and Furacylin. This review includes the Microwave synthesis of triazoles and its reported derivatives. The derivatization of Triazole ring is based on the phenomenon of bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen triazole analogue. This review provides a brief summary of the medicinal chemistry of triazole system and highlights some examples of recent drug containing this moiety in the current literature.

Triazole is a unique moiety that is responsible for various biological activities. This article highlighted research work of many researchers reported in literature for different pharmacological activities on synthesized triazole compounds.

This review has presented comprehensive details of triazole analogues, potent compounds reported for particular pharmacological activity and the method or technique involved in evaluation process [147,148]. More investigations must be carried out to evaluate more activities of triazole for many diseases whose treatment are difficult in the medical sciences.

This has been noticed so far, that modifications on triazole moiety results in the formation of compounds with valuable biological activities. It will be interesting to observe that these modifications can be utilized as potent therapeutic agents in future. Thus many more

158 modifications on triazole moiety can be possible and needs to be continued for the use of mankind.

Conclusion

1,2,4-Triazoles have attracted considerable attention in the fields of medicine and agrochemical research as well as in materials science, due to their unique structures and properties. 1,2,4- triazole and its derivatives belong to a class of exceptionally active compounds possessing many pharmacological properties.Some of the derivatives of triazoles are also known to exhibit anticancer activity. 1,2,4-Triazoles have clinched much importance as they have also been investigated for their CNS depressant, pesticidal, anti-mycobacterial, hypoglycemic, diuretic, insecticidal and herbicidal effects. Sulfonamide drugs (sulfa drugs) were the first antimicrobial drugs that paved the way for the antibiotic revolution in medicine. From a structural point of view, sulfonamides are interesting because of their tendency to form different hydrogen bonded systems in the solid state by introducing various hydrogen-bond donors and acceptors as substituents into simple sulfonamide molecules. 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 a variety of biological activities have been reported for a large number of their derivatives. It is well established that various derivatives of triazole exhibit broad spectrum of pharmacological properties. The 1,2,4-triazole moiety present in the various natural products and the synthesis of compounds. This moiety has attracted attention of chemists as well as biologists. The compounds containing different heterocyclic moiety would be tested for antimicrobial activity against different strains of pathogenic organisms. Similarly few of the compounds would also be screened for anti-inflammatory and analgesic activities. Many of the available therapeutically important medicines such as ketoconazole, itraconazole, voriconazole and fluconazole contain this heterocyclic nucleus. In view of the above mentioned facts and in continuation of interest in the heterocycles containing 1,2,4-triazole moiety to identify as new molecule that may be value in designing new, potent, selective and less toxic antimicrobial agents. This combination is thought in an attempt to investigate the influence of structure variation on the anticipated biological activities, hoping to add some synergistic biological significance to the target molecules.

REFERENCES

[1]. Ragenovic KC, Dimova V, Kakurinov V, Molnar DG, Buzarovska A. Molecules 2001; 6:

815‐824.

[2]. Kartritzky AR, Hand Book of Heterocyclic Chemistry, 1st edition. Pergamon Press Oxford 1985; 87.

[3]. Y.A. Al‐Soud, N.A. Al‐ Masoudi. Arch. Pharm. Pharm. Med. Chem. 1999; 332:143–144.

[4]. Y.A. Al‐Soud, N.A. Al‐Masoudi, I.M. Lagoja. Carbohydr. Res.1999; 318: 67–74

159 [5]. Y.A. Al‐Soud, N.A. Al‐Masoudi, A.E.‐R.S. Ferwanah. Bioorg. Med. Chem. 200311: 1701- 1708.

[6]. Y.A. Al‐Soud, R.F. Halah, N.A. Al‐Masoudi. Org. Prep. Proced. Int. (OPPI) 2002; 34:

648–664.

[7]. Y.A. Al-Soud, N.A. Al‐Masoudi. Heteroatom. Chem.2003; 14: 298–303.

[8]. Varvarason A, Tantili-Kakoulidou A, Siatra-Papastasikoudi T, Tiligada E. Arzneim Forsch 2000; 50: 48-54.

[9]. Gokce M, Cakir B, Earl K, Sahin M. Arch Pharm 2001; 334: 279-283.

[10]. Pintilie O, Profire L, Sunel V, Popa M, Pui A. Molecules 2007; 12: 103-113.

[11]. Zan XI, Lai LH, Ji GY, Zhon ZX. J Agric Food Chem 2002; 50: 3757-3760.

[12]. Chem H, Li Z, Han Y. J Agric Food Chem 2000; 48:5312-5315.

[13]. Passannanti A, Diana P, Barraja P, Mingoia F, Lauria A, Cirrincione G.

Heterocycles.1998; 48: 1229.

[14]. Hosur MS, Talwar R. Ind J Pharm Sci 1993; 55: 86.

[15]. Udupi RH, Kulkarni VM, Purushottamachar P, Srinivasalu NJ. Indian Chem Soc 2002; 79:

381.

[16]. Ilkay K, Sevim R. Farmaco. 2004; 55(11): 893.

[17]. Holla SB, Veerendra B, Shivananda MK. Eur J Med Chem. 2003; 38: 759.

[18]. Jilino M, Stevens FG. J Chem Soc Perkin Trans1 1998; 1677.

[19]. Diana GD, Nitz J. J EP 566199, 1993.

[20]. Shenone S, Bruno O, Ranise A, Bondavalli W, Falcone G, Giordano L, Vitelli M et al.

Bioorg Med Chem. 2001; 9: 2149-2153.

[21]. Hart C. Am Chem Soc. 1999; 2: 20‐31.

[22]. Zech, B., Croetz, H. J. Indian chem. Soc, 1981, 280, 2923- 2926.

[23]. Witkop B, Ramachandran LK. Metabolism, 1964, 13(10), 1016-1025.

[24]. Rao G, Rajasekaran S, Attimarad M. Indian J Pharm Sci, 2000, 62(6), 475-477.

[25]. Kane JM, Baron BM, Dudley MW, Sorensen SM, Staeger MA, Miller FP. J Med Chem, 1990, 33(10), 2772-2777.

[26]. Clereq D. Clin Microbial Rev, 1997, 10, 674-93.

[27]. Alterman M, Samuelsson B. J Med Chem, 1998,41, 3782-92.

[28]. Khalil SA. Eur J Med Chem, 2010, 45, 5265-5277.

[29]. Saini MS, Dwivedi J. Inter J Pharm Sci and Res, 2013; Vol. 4(8): 2866-2879.

[30]. Gupta S, Kumar D. Inter J Med and Pharm Res, 2013, 1(2): 250-257

[31]. Jones, D. H., Slack, R.; Squires, S. and Woolridge, K. R. H., J. Med. Chem., 1965, 8, 676.

[32]. Goswami, B. N., Kataky, J. C. S. and Baruah, J. N., J. Het. Chem., 1984, 2, 225.

[33]. Holla, B. S., Kalluraya, B. and Sridhar, K. R., Curr. Sci., 1987, 56, 236.

[34]. Abdon, N. A., Amin, F. M. and Mansoura, A., J. Pharm. Sci., 1990, 6, 25.