Triazole analogues as potential pharmacological agents: a brief review

Background A large number of studies have recently reported that, because of their significant biological and pharmacological properties, heterocyclic compounds and their derivatives have attracted a strong interest in medicinal chemistry. The triazole nucleus is one of the most important heterocycles which has a feature of natural products as well as medicinal agents. Heterocyclic nitrogen is abundantly present in most medicinal compounds. The derivatization of triazole ring is based on the phenomenon of bio-isosteres in which substituted the oxygen atom of oxadiazole nucleus with nitrogen triazole analogue. Main text This review focuses on recent synthetic procedure of triazole moiety, which comprises of various pharmacological activities such as antimicrobial, anticonvulsant, anti-inflammatory, analgesic, antitubercular, anthelmintic, antioxidant, antimalarial, antiviral, etc.. Conclusion This review highlights the current status of triazole compounds as different multi-target pharmacological activities. From the literature survey, triazole is the most widely used compound in different potential activities.


Background
In the field of research and the synthesis of new bioactive molecule, heterocyclic chemistry plays the most important role. Medicinal chemistry is a part of the medical and pharmaceutical sciences, is concerned with the development and design, and credits the significant biologically active drug molecule. The most active biological activities have been shown among these heterocyclic molecules containing nitrogen and oxygen. Many different compounds have been prepared and exhibit different types of useful pharmacological activity [1].
To investigate a new agent is one of the most difficult tasks for the medicinal chemist. Synthesis of heterocyclic systems consisting high nitrogen has been rising over the past decade owing to their usefulness in different applications such as propellants, explosives, pyrotechnics, and especially chemotherapy. In recent years, considerable attention has been received by the chemistry of triazoles and their fused heterocyclic derivatives because of their synthetic and effective biological importance [2].
Azolic derivatives such as thiazole, triazole, oxadiazole, and thiadiazole are pharmacologically active compounds and, due to their effective use in medicinal chemistry, have been intensely studied for various biological activities [3].

Main text
Triazole Triazole is a five-member heterocyclic ring containing two carbon and three nitrogen atoms with molecular formula C 2 H 3 N 3 [4]. And it is found in two isomeric forms, 1,2,3triazole and 1,2,4-triazole, which are also known as pyrrodiazole. (Fig. 1).

Synthetic approaches of triazoles
The article gives a brief review of the synthetic procedure and characterization of triazole and its pharmacological activity.
Lu yang et al. reported 4-acyl-NH-1,2,3-triazole synthesis by the use of water-mediated cycloaddition reactions of enaminone and tosilazide, requiring both a mild condition (40°C) and practical scalability, when using the water as sole medium without any catalyst (Scheme 1) [22].
Shelke et al. had synthesized and found that, in the absence of a catalyst, the substitution of 1,2,4 triazole from hydrazine and formamide under microwave irradiation and this reaction effectively indicates excellent functional group tolerance (Scheme 2) [23].
Yin et al. synthesized a substituted triazole by one pot cyanoimidation of aldehydes where cyanamide as nitrogen source and the NBS as an oxidant in high yield without any catalyst. The substituted product N-cyanobenzimidate may also be subjected to a cyclization reaction to produce a high yield of 1,2,4-triazole derivative (Scheme 4) [25].
Faldiman et al. reported 1,4 disubstituted 1,2,3 triazoles from azides. These are obtained with excellent yield from aromatic and aliphatic halides that are easily available without formation of potentially unstable organic azide intermediates (Scheme 5) [26].

Pharmacological activities of triazole derivatives
This article presented discusses a brief description of the various triazole activities, and the recent studies have showed the wide range of pharmacological activities available for triazole derivatives which may be divided into the following categories:
Wujec et al. synthesized the ten compounds which contain the manic base-1,2,4 triazole. The broth microdilution technique was used against Grampositive and Gram-negative bacteria to evaluate antimicrobial activity of these compounds. The phenyl ring present in the 4-position of piperazine appears essential for antibacterial action. Compound 2a showed the potent activity with MIC value 30 μg/mL against M. luteus and 60 μg/mL against three different bacterial strains (B. subtilis, S. aureus, and S. epidermidis) [30].
Lipeeva et al. synthesized and investigated a novel series of 1,2,3-triazole-substituted coumarins and tested their in vitro antimicrobial activity against four different bacterial strains. Result showed that compounds 3a, 3b, and 3c showed potent activity against S. aureus strains with MIC values ranging between 0.16 and 0.41 μg/mL as compared with the reference drug ceftriaxone and streptomycin. The structure activity relationship of compound (carboxamidotriazolylbenzoic acid) substitution at position C-6 of coumarin core displayed promising activity towards A. viscosus as compared with compound 3b. The compound 3b with triazolylbenzoic acid substitute in the C-7 position exhibited highest activity towards the bacterial strains of S. aureus "Viotko", and compound 3c with the substitution of 3-ethynylcoumarin with methylanthranilate exhibited remarkable antibacterial activity against the strains of S. aureus [31]. Tingjunhong Ni et al. synthesized twenty-seven triazole derivatives containing alkynyl side chains, and their antifungal activity towards Cryptococcus and Candida species were evaluated as compared with reference drugs. The results showed that the compounds 5a and 5b demonstrated in vitro activity towards all fungi with MIC 80 values in range between 0.0156 and 0.5 μg/mL, higher than ravuconazole and fluconazole. Structural relationships showed the introduction of fluoro, chloro, and cyano groups at p-position of phenyl alkynyl or pyridinyl alkynyl side chain enhances their antifungal activity [33].
Rezki et al. reported and investigated a novel series of 2,5-disubstituted thiadiazole clubbed 1,2,4-triazole as a potential antimicrobial agent. All derivatives were characterized by IR, 1 H-NMR, 13 C-NMR, MS, and elemental analysis. In vitro inhibitory growth activities of three Gram-positive (+) bacteria, three Gramnegative (-) fungi, and three strains of normal pathogenic microorganism strains were tested of all these compounds. SAR studies revealed the presence of phenyl or alkyl substitution at N-4 has enhanced their antimicrobial activity towards strains of bacteria and fungi with MIC values of 8-16 μg/mL, where ciprofloxacin and fluconazole are the reference drugs (Table 1). Compounds 7a-7c were found to be the most potent antimicrobial agent [35].
Han et al. reported a new series of triazole derivatives containing different ester skeletons and evaluated as antifungal agents. The antifungal activity was investigated by utilizing the microdilution broth method. In all the synthesized compounds, compounds 11a and 11b showed the most significant activity against four important fungal pathogens (MIC 80 = 2-8 μg/mL). Molecular docking studied revealed the target compounds interact with CYP51 mostly by Van der Waals and hydrophobic interactions [39].
Al-blewi et al. synthesized a novel series 1,4-disubstituted-1,2,3-triazole-sulfonamide hybrids and evaluated for their antimicrobial activity. All the synthesized hybrids were verified by mean of spectroscopic analysis. From the result, only compound 12a showed the most significant activity with MIC value range between 32 and 64 μg/mL as compared with the standard drug [40].

Antitubercular activity
Ramprasad et al. reported nineteen derivatives of quinoline-triazole hybrids and screened their antitubercular activity against Mycobacterium bovis. Result revealed that two derivatives, 13a and 13b, showed the potent antitubercular activity with MIC values 31.5 μm and 34.8 μm. SAR studies revealed that these compounds are essential for their activity due to n-octyl and 3-fluorophenyl groups presented on 1,2,3-triazole ring [41].  [2,3-d]pyrimidine-1,2,3-triazole derivatives for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. All synthesized hybrids exhibited significant antitubercular activity. Among these series, compounds 15a and 15b showed the remarkable MIC value 0.78 μg/mL. The molecular docking results to the exhibition of high Moldock score of these compounds. SAR studies showed that the triazole ring substituted with heteroaryl compound containing highly electronegative atoms also enhance their activity [43]. significant activity (MIC = 1.56 μg/mL), in contrast with its antimicrobial activity [45].

Anthelmintic activity
Kharb et al. investigated fifteen novel imidazolecontaining triazole derivatives and screened their anthelmintic activity towards Pheretimaposthuma at concentrations of 0.150% and 0.300% w/v respectively as compared with the albendazole as positive control. Result revealed that, the compound 18a displayed significant anthelmintic activity as compared with the reference drug [46].
Gupta et al. reported five derivatives and evaluated for their anthelmintic activity against P. posthuma. From the result, compound 19a showed the potent vermicidal activity, and it exhibited the maximum paralysis time and 37.33 min of death time at 20 mg/mL concentration [47,48].
Satyendra et al. synthesized novel di-chloro substituted benzoxazole-triazolo-thione derivatives, and their anthelmintic activities were evaluated. Among them, the compound 20a exhibited the potent anthelmintic activity against P. posthuma as compared with the reference albendazole at 1% concentration [49].

Anticonvulsant activity
Verma et al. reported a series of novel 4,5-disubstituted-2,4dihydro-3H-1,2,4-triazole-3-thione derivatives for anticonvulsant activity. Anticonvulsant activity of compound wastes by maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ) test in mice and rat and neurotoxicity screened at 30, 100, and 300 mg/kg dose and was suspended in 30% PEG 400 by an oral route to the mice. Among all these compounds, only compound 21a exhibited significant anticonvulsant activity at 300 mg/kg at a 4-h duration [50]. Zhang et al. synthesized a new series 3,4-dihydroisoquinolin containing 1,2,3-triazole compounds and investigated their anti-epileptic activity by using MES (maximal electroshock) and PTZ (pentylenetetrazole)induced seizure test. Among the synthesized compound, only compound 23a showed excellent antiepileptic activity with ED 50 value 48.19 mg/kg. It was found to be more active than valproate but less active than carbamazepine [52]. Siddiqui et al. synthesized various triazoles containing thiazole derivatives. The two most active compounds 47 and 48 were tested in the Phase II anticonvulsant study for their anticonvulsant activity (ED 50 ) and neurotoxicity (TD 50 ). And anticonvulsant action was carried out by two methods mostly using the electroshock (MES) and chemo shock (scPTZ) models. From the result, compounds 28a and 28b exhibited the potent anticonvulsant activity [57].
Zheng et al. synthesized a novel series of 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazole-5(4H)-one derivatives and evaluated their anticonvulsant activity. All the synthesized derivatives were characterized by NMR, IR, and mass spectroscopy. Among the series, compound 29a was found to have the most promising activity with ED 50 value of 25.5 mg/kg [58]. Syed Shaf et al. reported a novel series of bis-hetero cycles containing 2-mercapto benzothiazole-based 1,2,3triazole and screened their anti-inflammatory activity. From the result, compound 37a display the significant selective COX-2 inhibition activity as compared with the standard drug and compound 37b also exhibited the comparable analgesic activity [66].
Tozkoparan et al. synthesized a novel series of 5-aryl-3alkylthio-1,2,4-triazole derivatives and screened their antiinflammatory activity. All the synthesized derivatives were characterized by spectral and elemental analysis. Among the series, compounds 39a and 39b exhibited potent analgesic and antiinflammatory activities with no ulcerogenic effect [68].
Kaur et al. described a novel series of 1,4-diaryl-substituted triazoles was synthesized and evaluated for their COX-2 inhibition. From the result, only compound 40a displayed excellent COX-2 activity [69].

Anticancer activity
Mahanti et al. reported a series of fused acridine containing 1,2,4-triazole derivatives. And screened their anti-proliferative activity towards several human cell lines including, MCF7 (Breast), A549 (Lung), A375 (Melanoma), and HT-29 (Colon). The IC 50 value of target compound in range between 0.11 ± 0.02 and 13.8 ± 0.99 μM as compared with the standard range 0.11 ± 0.02 to 0.93 ± 0.056 μM. Result revealed that the compounds 41a-41c exhibited the excellent anticancer activity. SAR investigations of this series revealed that introduction of 4-chloro, 3,4,5-(CH 3 O) 3 , and 4-CF 3 CH 3 groups at para-position of the phenylring displayed the significant anticancer activity [70]. Ma et al. reported a novel series of 1,2,3-triazole-pyramidine hybrid derivatives and screened their cytotoxic potential towards several tumour cell lines. Among these synthesized compounds, the compound 44a exhibited the potent and selective anti-proliferative activity with IC 50 values in range between 1.42 and 6.52 μM. Particularly, studies revealed that the compound 44a also inhibit the growth of EC-109 cancer cells via apoptosis-inducing activity and cell cycle arrest at G2/M phase [73].
Duan et al. synthesized a new series of 1,2,3-triazole-dithiocarbamate hybrids and screened their anticancer activity against four different selected human cancer cell lines including MCF-7, PC-3, MGC-803, and EC-109. Among these, the compounds 45a and 45b showed significant wide-spectrum activity. Compound 45a was found to be most potent towards selected four different human cancer cell lines as compared with 5-fluorouracil [74].
Aouad et al. reported a novel series of benzothiazolepiperazine-1,2,3-triazole hybrids and investigated their anti-proliferative activity against different human cancer cell lines. Some hybrid molecules showed significant antiproliferative activity. ADME and clog P analysis method confirmed the biological profile. From the result, compound 46a exhibited the remarkable antiproliferative activity [75].
Ashwin et al. reported a novel series of 1,2,3-triazole derivatives and screened their anticancer activity against acute myeloid leukemia cell lines. Result revealed that, compound 47a exhibited the significant anticancer activity with an IC 50 of 2 μM towards MV4-11 cells [76]. different tumour cell lines. From the result, compound 49a with the shortest alkyl substituent at the triazole ring showed significant inhibitory activity against the CaCo-2 cell line but low cytotoxic effect on normal MDCK I cells [78].

Antidiabetic activity
Saeedi et al. reported the quinazolinone-1,2,3-triazole hybrid derivatives and screened their in vitro αglucosidase inhibitory activity as leading to an effective antidiabetic agent. All these derivatives displayed excellent antidiabetic activity with IC 50 values ranging between 181.0 and 474.5 μM and were found to be more potent than reference drug acarbose (IC 50  Avula et al. synthesized a class of novel 1,2,3-triazole analogues were synthesized and evaluated their αglucosidase inhibitory activity in ranges between 14.2 and 218.1 μM. Result revealed that the compound 51a exhibited the most effective antidiabetic activity as compared with the reference drug. And the activity of this compound is 67 times better than the reference due to the presence of the methoxy phenyl group [80].
Wang et al. synthesized a novel series of triazinetriazole derivatives and evaluated their antidiabetic activity. All these derivatives exhibited the potent antidiabetic activity. Out of all synthesized compounds, compound 52a showed potent α-glucosidase inhibitory activity [14].
Gonzaga et al. synthesized 1-phenyl-1H-2-phenyl-2H-1,2,3-triazol derivatives and screened their α-glucosidase and porcine pancreatic α-amylase activity. All compounds tested at 500 μM, only compound 54a was found to have the most significant antidiabetic activity with 54 μM as compared with acarbose [82]. Kucukguzel et al. investigated a new series of novel thiourea containing triazole derivatives and tested their anti-HIV activity. Structures of synthesized derivatives were confirmed by elemental and spectral analysis. Result revealed that the compound 57a exhibited the significant anti-HIV activity towards Coxsackie virus B4. SAR studies revealed that, the presence of the allyl group at N-4 of the 1,2,4-triazole ring and phenyl ring at terminal nitrogen of thioureas enhanced their activity [85].

Antiviral activity
Wang et al. reported a novel series of sulfanyl-triazole derivatives as an HIV-1 non-nucleoside reverse transcriptase inhibitor by using high throughput screening. It exhibited significant activities against the selected resistant mutants. From the result, compound 58a exhibited excellent anti-HIV activity [86].
Karypidou et al. synthesized a series of fused 1,2,3triazole derivatives as potential antiviral agent. All the derivatives were screened against some variety of viruses (HIV-1, HIV-2, vaccinia virus, adenovirus-2, and coronavirus) in HEL cells and their inhibitory activity was compared with standard drugs. Among all the tested series, compound 59a (EC 50 = 8.95 μM) and 59b (EC 50 = 8.90 μM) exhibited the moderate activity against human coronavirus [87]. Cao et al. synthesized novel triazole derivatives for in vitro antiviral activity against EV71 and CVB3 in cellbased assay. All the synthesized derivatives were characterized by various spectroscopic methods including 1 H NMR, 13 C NMR, and mass spectroscopy. Among the result, only compound 60a exhibited remarkable antiviral activities against EV71 and CVB3 virus with the EC 50 value of 5.3 ± 0.7 and 10.1 ± 3.8 μg/mL as compared with the control ribavirin [88].

Antimalarial activity
Oramas-Royo et al. reported and investigated a new series of 1,2,3-triazole-napthaquinone derivatives. Several of these compounds were tested for their in vitro antimalarial activity towards Plasmodium falciparum strains. From the result, compounds 62a and 62b exhibited potent antimalarial activity with IC 50 values of 0.8 and 1.2 μM. SAR studies revealed that the compound 62a bearing a fluoro group at C-3 and a methoxy group at C-4 and compound 62b with an unsubstituted phenyl ring enhanced the antimalarial activity [90].
Thakkar et al. reported new ten compounds containing 1,2,4-triazole and evaluated their in vitro antimalarial activity against P. falciparum strain. All these synthesized derivatives were characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy, and elemental analysis. From the result, compounds 64a, 64b, and 64c exhibited the potent antimalarial activity with IC 50 values 0.282, 0.245, and 0.230 μM as compared with the reference drug chloroquine Pyrimethamine. SAR studies revealed that introduction of 4-OH, 3-NO 2, 4-CL in the phenyl group enhance activity [92].
Joshi et al. synthesized a novel series of quinoline triazole amide analogues and screened for their antimalarial activity against different strains (CQS D10 and CQR K1). It was concluded that the compounds 65a, 65b, and 65c showed most potent activity towards P. falciparum CQS D10 strain with IC 50 values in the range between 349 and 1247 μM, and these compounds also exhibited similar activity against CQR K1 strain of parasite [93].
Guantai et al. synthesized a new triazole-linked chalcone and dienone hybrids and evaluated in vitro antimalarial activity. From the result, compound 66a was found to have the most significant activity against D10, DD2, and W2 strains of P. falciparum as compared with the reference drug chloroquine [94]. Tarawneh et al. synthesized a novel series of isoxazole and triazole derivatives and evaluated for their anti-infective agent. All the compounds were screened against P. falciparum D6 and W2 strains. From the result, the only compound 67a exhibited the most potent activity with IC 50 values of 0.70 and 0.59 μM against D6 and W2 strains [95].

Miscellaneous activities
In spite of all these activities, triazoles are also active as antihypertensive agent 68a, neuroprotective agents 68b and 68c, and diuretic 68d (Table 3). Triazole nucleus was found to possess significant atypical behaviour and good potency to block 5-HT receptors and good ability of selective antagonists towards the human vasopressin V 1A receptor [96][97][98][99].

Conclusion
This review article highlights research work of many researchers reported in literature for different pharmacological activities on triazole compounds. Triazole has unique moiety that is responsible for various biological activities. The importance of triazole moiety can be magnified by carrying out further studies on its possible substitution and thus to synthesize better agents that can have strong future commitments. 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. More investigations must be carried out to evaluate more activities of triazole for many diseases whose treatment are difficult in the medical sciences.

Authors' contributions
We declare that this work was done by the authors named in this article: SLK conceived and designed the study. SK carried out the literature collection of the data and writing of the manuscript. AY and SK assisted in the data analysis and corrected the manuscript. The authors read and approved the final manuscript.

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