Abstract
Among the nitrogen-embedded heterocycles, 1,2,3-triazoles derivatives are widely explored and earned considerable attraction in pharmaceutical industry and academics. 1,2,3-Triazoles have attracted significant consideration during the last few years due to widespread implementation in synthetic organic chemistry, drug discovery process, supramolecular chemistry, chemical biology, polymer chemistry, fluorescent imaging as well as materials chemistry. Even though absent in nature, these N-heterocycles have a wide spectrum of medicinal applications against several malignant cells, microorganisms, viruses and their preclusive actions are resistant to various enzymes. Moreover, 1,2,3-triazoles-based scaffolds have been extensively immersed as a linker and a functional moiety, mainly owing to the fact that their processing simplicity, orthogonality development and attractive “Click” properties. This chapter highlights the recent developments on diversified biological efficiencies of 1,2,3-triazoles and their approach in the progress of novel bioactive as well as pharmacoactive entities in future.
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1 Introduction
1,2,3-Triazoles and their derivatives are among the topmost immense N-heterocyclic scaffolds because of the widespread spectrum of pharmacological and biological activities [1,2,3,4]. Triazoles are the five-membered heterocycles embedded with three consecutive nitrogen-atoms that can be synthesised simply utilizing ‘click’ chemistry through ruthenium- or copper-catalysis between azides and terminal alkynes by cycloaddition reactions [5]. However, the ‘linker’ feature of 1,2,3-triazoles was established and distinct 1,2,3-triazole-based conjugates and hybrids were prepared and appraised as prime compounds for various biological and pharmacological targets due to their specificity, reliability and biocompatibility [6].
Furthermore, 1,2,3-triazole-based scaffolds have several convenient attributes such as immense chemical reliability (generally inactive to basic or acidic hydrolysis and reducing and oxidizing reactions even at higher temperature), effective dipole moment (4.8–5.6 Debye), capability of hydrogen bonding and aromatic character, which enhances their aptitude and solubility to interact with biomolecular targets as well as highly stable to metabolic degradation [7]. 1,2,3-triazole and its derivatives exhibit numerous biological activities such as anti-proliferative, anti-HIV, anti-inflammation, antimicrobial, anticonvulsant, anti-leishmanial, anti-trypanosomal, etc. [8,9,10,11,12,13,14,15]. Moreover, these motifs are usually steady for hydrolysis in both acidic and basic conditions along with oxido-reductive environment, making them steady to metabolic deterioration and designates upraised aromatic compensation. Furthermore, these enormous properties reveal the functionalised 1,2,3-triazoles skeletally appearing the amide bond and capable toward mimicking an E or a Z amide bond. Several well-known pharmacophore that possesses 1,2,3-triazole motif are existing in the market as an anticancer medication carboxyamidotriazole, wide spectrum cephalosporin antibiotic cefatrizine, β-lactam antibiotic tazobactam and anticonvulsant drug Rufinamide, etc. [5]. In this chapter, modern advancements in the improvement of 1,2,3-triazole-based pharmacologically active molecules are highlighted (Fig. 1).
1,2,3-triazoles are the bioisosteres of amide bonds because of their electronic and structural resemblance and possess higher stability towards metabolic degradation. The pharmacological activities exhibited by 1,2,3-triazoles are anticancer, antimicrobial, anti-HIV, antimalarial, anti-inflammatory, antifungal, antiallergic, antiepileptic, anti-leishmanial, antituberculosis and anthelmintic activities [16]. They are proficient in forming hydrogen bonding interaction, enhancing their solubility and capacity to combine with biomolecular targets [17].
Few of the FDA approved 1,2,3-triazole containing drugs are listed in Table 1 [2].
2 Anticancer Activity of 1,2,3-Triazole Derivatives
Cancer is the principal health threat around the globe and affects a wide majority of the global community. In this contrast, several anticancer agents conveyed for medication of diverse types of cancers act through distinct mechanisms [18]. Nevertheless, the main side effect related to these anticancer agents is cytotoxicity towards the healthy cells because of inadequacy in specificity for the abnormal cells. 1,2,3-Triazoles have been investigated for the last 30 years as well as inspected mostly for the chemotherapeutic potential. However, numerous scientists and researchers all over the world have accomplished intensive exploration in this specific field. In this portion, we highlight modern advancements in the progress of 1,2,3-triazole-based pharmacologically active antineoplastic compounds (Fig. 2) [19,20,21,22].
Interestingly, the heterocyclic triazole such as 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3- triazol-5-yl)aniline 1, repressed tubulin polymerization. In addition, to explore the mechanism of cell death, DNA fractionation methodology was enrolled which exposed that the triazole-based compounds 2 and 4 encouraged DNA impair via apoptosis due to the biochemical ambience for these moieties and exceptional cytotoxic activity [23]. Additionally, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo [d]isoxazole (PTB) (compound 3) was establish as atop most efficient antineoplastic agent against MV4-11 cells [24]. In addition, 4-[phenyl-1-(1-phenyl–ethyl)]-1H-1,2,3-triazole analogue 8 exhibited decent cytotoxicity counter to HL 60 cells. In continuation, two triazole-based compound, 3{1 N(2-cyanophenyl)-1H- 1,2,3-triazol-4yl}methyloxy betulinic acid 6 and 7{1 N(5- hydroxy-naphth-1-yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid 5 showed remarkable anticancer activity against leukaemia cell line HL-60 [25]. In addition, compound, 7 displayed as the most effective derivative against K562 and A431 human tumour cell lines [26]. In continuation, compound 9 was found vastly effective to the leukaemia K-562 cell line and SK-MEL-5, which is one of a series of melanoma cell lines [27]. Additionally, compound 10 showed huge potential in counter to Hs578T triple-negative breast cancer cell lines (TNBC) as well as showed the most powerful inhibition against tubulin polymerization [28]. In continuation, a series of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)acrylamide (compound 11), which encouraged M-phase (mitosis) arrest in immortal HeLa cells. Remarkably, among the series of 1,2,3-triazole-dithiocarbamate-urea hybrids, scaffolds 12 and 13 exhibited a wide range of anticancer activity against MGC-803 cells [29].
Quinazoline-4(3H)-one linked to 1,2,3-triazoles were assessed in contrast to various malignant cell lines; namely, three are human breast cancer cell lines (MDA-MB-231, MCF-7, T-47D), human lung carcinoma (A549) and prostate cancer cell lines (PC3). Three compounds have exhibited a potent anticancer activity compared to the reference drug, Etoposide in the cell line MDA-MB-231 with the IC50 values of 12.05 µM, 15.62 µM and 13.47 µM respectively whereas Etoposide IC50 values are 23.56 µM. Two compounds showed potency against A549, non-small cell lung cancer (NSCLC), in comparison to erlotinib. Docking study clearly indicates that 1,2,3-Triazole moiety executes a vital responsibility in suppressing activities of EGFR active site [30].
ErbB is a transmembrane glycoprotein with a molecular weight 170 KDa to 185 KDa. It consists of ErbB1/EGFR/HER1; ErbB2/HER2 Neu; ErbB3/HER3 and ErbB4/HER4. Quinazoline-4(3H)-one related to 1,2,3-triazoles inhibits the Endothelial growth factor receptor (EGFR). It is composed of three fragments: (a) extracellular N-terminal, (b) transmembrane domain and (c) intracellular tyrosine kinase. The extracellular N-terminal comprises four domains- I, II, III and IV. It binds to several ligands but the intracellular tyrosine kinase is highly preserved [31]. with the presence of Leucine, the domain I and III of extracellular N-terminal are rich whereas, in the presence of Cysteine, the domains II and IV are extremely observed [32].
EGFR (Endothelial growth factor receptor) can be found in two states, i.e. the Open state which is active and closed state which is inactive. Until a ligand is bound, both these states exist in equilibrium and it stabilises the open state, once the ligand is bound. For the Closed state; The domains II and IV have interaction in between them, existing on the extracellular N-terminal; however, any interaction with the ligand is not shown by the domains I and III. In open state, the domains I and III interact with the ligand when the domains II and IV move away (Fig. 3) [31].
In homodimerization and heterodimerization of the receptors on the extracellular N-terminal of EGFR, domain II is involved. The formation of dimer is asymmetric as well as characteristic, the small N-lobe of the one kinase binds with the large C-lobe of the other kinase domain. The activation of CDKs (cyclin-dependent kinases) and Src family kinases leads to this dimer formation [32].
All the series of the compounds occupied the active site of EGFR. The hook shape conformation in the binding model of inhibitors is because of the existence of triazole rings. The 1,2,3-triazole ring interacts with the amino acids present in the active site of EGFR receptors involves various interactions like electrostatic interaction, Pi- anion interaction, H-bonding and Van der waals interaction [30].
Novel bis alkynes with di-substituted triazoles were synthesised and they were evaluated for the anticancer activities and identified that the bis alkynes themselves have some anticancer activity. In order to increase their anti-proliferative activity, many substitutions were done on the bis alkyne. The introduction of one triazole moiety in the bis alkyne has shown the deleterious effect on its anti-proliferative activity but introduction of one more triazole moiety makes it a good anticancer exhibiting compound. One of the bis triazole moiety is highly potent which exhibits the anti-proliferative activity in nanomolar range [33].
3 Anti-inflammatory Activity of 1,2,3-Triazole Derivatives
Amongst all biological processes, inflammation is the most important part of the immune system’s response to infection and injury. It Comprises The release of arachidonic acid (AA) from phospholipids (are main components of the plasma membrane), sustaining additional bioprocessing through 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) pathways. Previously we have discussed the activity of many NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen, indomethacin and naproxen, which suppress arachidonic acid (AA) metabolism via inhibition of cyclooxygenase (COX). In this section of the chapter, modern advancements in the development of triazole-based pharmacologically active anti-inflammatory compounds are listed (Fig. 4).
In addition, to evaluate the anti-inflammation and antineoplastic action against various cancer cell lines, 1,2,3-triazole-embedded N-alkyl nitrone derivatives and N-phenyl nitrone derivatives were investigated. However, the measure of anti-inflammatory activity compounds 14 and 15 showed noteworthy inhibitory effect on Interleukin-1β (IL-1β) secretion [34]. In addition, compound 16 improved TNFα-enhanced cyclooxygenase-2 expression by Western blot analysis and showed to be extremely good on the molecular level, related to diclofenac, the standard drug [35]. In continuation, the compound 17 displayed good inhibitory effect on Glycogen Synthase Kinase-3β (GSK-3β) and also effective to prevent the inflammatory cytokines TNF-α (Tumour Necrosis Factor-α), IL-1β and Interleukin-6 (IL-6) extensively, related to standard anti-inflammatory drug, indomethacin, as well as a GSK-3β inhibitor, SB216763 [36]. Furthermore, compounds 18, 19 and 20 show substantial inhibitory activity on Interleukin-1β (IL-1β) secretion, a scope of anti-inflammatory action [34]. In addition, greater specificity towards the cyclooxygenase -2 (COX-2) binding site were showed by a series of 1-{4-[(1H-1,2,3- triazol-4-yl)methoxy]-2-hydroxyphenyl}-2-phenylethanone derivatives 21, an efficient anti-inflammatory compound [37]. In continuation, the protein–ligand relations between COX-2 (PDB code 4PH9) and desired compounds were availed for docking investigations and compound 22 anticipated the extremely good binding attitude to the active site of 4PH9 protein [38]. Additionally, a noteworthy anti-inflammatory activity showcased by betulonic conjugate 23, suggested at the highest dose in comparison to the reference drug indomethacin. However, from the SAR study, upon altering of hexyl substitution at the triazole scaffolds onto a benzyl moiety and to a higher extent such as methoxyphenyl and acetyl phenyl substitution, revealed the possibility of enhancing the anti-inflammatory activity in triazoles [39]. In addition, compound 24 established good potential for the selective cyclooxygenase-2 (COX-2) inhibitory strain with COX-2/COX-1, however, the compound controlled major anti-inflammatory action is associated with the reference drug ibuprofen [40]. In continuation, 1-[2-(1H-tetrazol-5-yl)ethyl]-1H-benzo[d][1,2,3]triazoles were anticipated to the effective anti-inflammatory as well as anti-nociceptive activities. The related compounds 25 and 26 produced greater anti-inflammation compared to reference drugs [41]. However, new 1,2,3-triazole-based phthalimide analogues were investigated for anti-inflammatory activities and the compounds 27 and 28 exhibited best activity [42].
Ibuprofen, an NSAID containing free carboxylic group, is responsible for some side effects like inhibition of Prostaglandin synthesis in GIT. So, modifications were done to the carboxyl group of the Ibuprofen. One of the modifications is the introduction of the five-membered heterocycle, 1,2,3-triazole. These novel triazole-containing compounds were synthesised and their anti-inflammatory movement was evaluated.
The anti-inflammatory actions of these molecules were monitored at the dose of 10 mg/kg body weight by a suitable method; namely, carrageenan-induced rat paw edema model and their obtained outcomes are correlated with the standard drug, Ibuprofen. One of these compounds has exhibited potential actions 94.01% after 3 h, 96.35% after 4 h, 95.62% after 5 h and 94.17% after 6 h when compared with the standard drug in 3 h 93.16%, in 4 h 95.62%, in 5 h 95.62% and in 6 h 94.70%. The other molecules have exhibited comparable to moderate anti-inflammatory activity. The side effects of the Ibuprofen compounds were reduced [38].
The 4,5-Dihydro-1H-1,2,3-triazoles were prepared and their activity was evaluated against standard drug, Ibuprofen. The anti-inflammatory activity was observed at various hours and the percentage inhibition was calculated. Two compounds have exhibited good anti-inflammatory activity with the % inhibition of 63.28% at 1 h and 67.12% at 3 h; 63.43% at 1 h and 68.07% at 3 h respectively and the Ibuprofen activity was 64.06% at 1 h and 68.10% at 3 h [43].
4 Anti-tubercular Activity of 1,2,3-Triazole Derivatives
Over the last few decades, there has been considerable growth in occurrences of tuberculosis specifically, via drug-resistant Mycobacterium tuberculosis (M. tb), a species of pathogenic bacteria. Anti-tubercular medications such as rifampicin, pyrazinamide, isoniazid, streptomycin and ethambutol (known as antibiotics) are very often inadequate. Hence, there is a need for developing more advanced anti-tubercular compounds, in this context, here we are providing few active compounds against tuberculosis (Fig. 5) [44,45,46,47,48,49,50,51,52,53,54].
In exploration of novel potent molecules in contrast to M. bovis BCG and M. tuberculosis (MTB) H37Ra, interestingly 1,2,3-triazoles-based benzothiazinone (compounds 29 and 34) were exhibit maximum potential against M. bovis BCG and MTB [44]. In addition, for the inhibition of H37Rv strain, an approach was bashed by employing 1,2,3-triazoles including fluorine-embedded benzimidazole series. Additionally, these compounds were potentially valuable for the anti-tubercular activity and mostly the compounds 30, 31 and 32 displayed better activity associated with standard rifampicin [45]. In continuation, compound 33 exhibited two-fold greater competence than the reference drug econazole, signifying that the scaffold is expected to be improved for the anti-tubercular activity [46]. Furthermore, N-substituted-phenyl-1,2,3,-triazole-4-carbaldehydes were screened and the compounds 35 and 36 exhibited the best inhibition [47]. In continuation, 1,2,3-triazole conjugates of 2-mercaptobenzothiazole were considered and screened to the M. tuberculosis H37Rv strain for anti-tubercular activity. The related compounds 37, 38 and 39 inhibited the growth of M. tuberculosis H37Rv strain [48]. In addition, compound 40 was exposed as an effective compound counter to M. tuberculosis (MTB) [49]. Furthermore, compound 41, i.e. 1-dodecyl-4-phenethyl-1H-1,2,3-triazole exhibited inhibition against M. tuberculosis H37Rv [50]. Additionally, compound 42 showed a harmonious activity in combining studies with no CYP-inhibition and first line-TB drugs [51]. In continuation, quinoline-derived triazole sugar hybrid, 43 showcased potential as an effective compound in contrast to M. tuberculosis H37Rv strain through LRP (Luciferase Reporter Phage) assay [52]. Additionally, 5-nitrofuran–triazole conjugates screened for antibacterial as well as anti-tubercular action. In continuation, amidst all the tested scaffolds, 44 exhibited auspicious bioactivities against tuberculosis [53]. However, compound 45 inhibited M. tuberculosis H37Rv. The SAR was proposed that electrostatic interactions and hydrogen bonding interaction of polar functional groups of anti-mycobacterial compounds and amino acids of ATP-synthase of bacteria, which might be the plausible incentive for the potent activity [54].
Some 1,2,3-triazoles were prepared and these molecules were evaluated for anti-tubercular action in contrast to a virulent strain of MTB (MTB H37Ra; ATCC 25,177). The parameter taken into consideration was inhibition of growth of the virulent strain. Many compounds have exhibited the activity against MTB with the MIC range of 5.8–29.9 μg mL-1. These compounds showed movement with the IC50 of 0.2 μg/mL to 8.3 μg/mL. But these compounds have not exhibited the comparable activity with Rifampicin. Antioxidant activity is important for anti-tubercular drugs because of oxidative stress, which can lead to chronic inflammation. So, the antioxidant properties for these compounds were evaluated by employing 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Five compounds have exhibited excellent antioxidant activity when compared to BHT and vitamin C (ascorbic acid) with the IC50 values of 10.1 μg/mL, 10.9 μg/mL, 12.1 μg/mL, 11.0 μg/mL and 11.4 μg/mL whereas the IC50 values of the standard drugs were 16.5 μg/mL and 12.7 μg/mL respectively.
The reported mechanism of 1,2,3-triazole derivatives showed inhibition to the DprE1 (decaprenylphosphoryl-β-D-ribose-2′-epimerase) enzyme of MTB and it is involved in the biosynthetic pathway of an important component of mycobacterial cell wall, i.e. decaprenyl phosphoryl-D-arabinose (DPA). These compounds were docked with the enzyme DprE1. The docking studies have revealed that the triazole ring exhibits various interactions by virtue of the amino acid residues present in the active site of DprE1 through hydrophobic bonds and Vander Waals interactions and they have shown the binding energy of −77.97 kcal/mol, −73.79 kcal/mol and −66.58 kcal/mol. The compounds with the triazole ring exert a good anti-tubercular activity [55].
5 Anti-leishmanial and Anti-trypanosomal Activity of 1,2,3-Triazole Derivatives
Trypanosomatids are protist protozoan parasites that affect millions of people all over the world and cause many significant human and animal diseases. Leishmania which is a genus of trypanosomes, thus blameworthy for leishmaniasis diseases. According to WHO, more than 0.9–1.6 million new cases arise every year and 21 species are well-known sources for disease in people. In several countries, kinetoplastids, a ubiquitous group of flagellated protozoa, cause trypanosoma cruzi (chagas’ disease), Leishmania species (leishmaniasis) and African trypanosomes (African sleeping sickness). These tropical diseases are specifically injurious in susceptible populations, predominantly amidst immunocompromised people or children which forcefully diminish human potential, moreover keeping people in poverty [56,57,58,59,60,61,62,63,64,65,66,67,68].
In briefly, 1,4-diaryl-1,2,3-triazole scaffolds were investigated in contrast to Leishmania amazonensis promastigotes and the analogues 46 and 51 exhibited extreme potency counter to Leishmania amazonensis (L. amazonensis) and Leishmania infantum (L. infantum) [56]. Additionally, triazolopyridopyrimidines 47 and 48 were discovered as more effective and screened against L. infantum amastigotes, related to the reference drug miltefosine [57]. In continuation, compounds 49 and 50, related to the alkyltriazoles, exhibited dynamic activity counter to promastigote and amastigote forms in comparison with standard pentamidine and amphotericin B [58]. In addition, the 4-(3-nitrobenzyl)-1,2,3-triazole 5’-substituted guanosine analogue 52 displayed extreme potential on axenic amastigotes [59]. Furthermore, 1,2,3- triazole-derived O-benzylquercetin glycoconjugates were screened for anti-leishmanial action and among all the investigated analogues, 53 exhibited potent effectiveness related to leishmaniasis [60]. In continuation, N-[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl] moiety, functionality on the C-2 amine of thiadiazole screened for anti-leishmanial action counter to the standard promastigote and 4-methylbenzyl analogue 54 was found to be the most effective compound against promastigotes [61]. Additionally, 1,2,3-triazolylsterols were screened against L. donovani and compound 55 was found to be potent against Leishmania donovani (L. donovani) and showed 5-times potent than the reference drugs [62]. Furthermore, it was established that diamidines 56 showed good potential against anti-trypanosomal activity than the standard melarsoprol, curing all infected mice [63]. Additionally, difluoromethylene 1,2,3-azole derivative 57 exhibited inhibition against the parasite growth expressively [64]. In addition, compound 58 contrary to the anti-parasite infections; exhibited promising effects [65]. In continuation, 5’-aryl-5’-deoxyguanosine analogues screened against L. donovani and compound 59 was found to be the most effective in the series without cytotoxicity [66]. In addition, 1,2,3-triazoles-linked 1,4-naphthoquinones based on nor-α-lapachone and nor-β-lapachone, moreover among the screened naphthoquinone analogues, nor-α-lapachone derivatives (compounds 60 and 61) exhibited the highest anti-leishmanial activity [67]. However, sialic acid-6-O-galactose coupled to 1,2,3-triazole and the sialic acid galactopyranoside analogue 62 exhibited potential effect on Trypanosoma cruzi trans-sialidase (TcTS) inhibition (Fig. 6) [68].
However, the new analogues of long-chain alkyl [1,2,3-triazoles] and two alkylphosphocholine derivatives comprising azide scaffold and some peptide-based triazoles were screened for the inhibition of cysteine protease rCPB2.8. rCPB2.8 is one of the targets for anti-leishmanial drugs [69].
Oyelere et al. reported that aryltriazolylhydroxamates with 1,2,3-triazole as a surface-recognition cap-group-linking and spacer-group chain lengths exhibited their potency as histone deacetylase (HDAC) inhibitors. Nevertheless, the addition of 1,2,3-triazole enhanced anti-leishmanial as well as antimalarial activities [70].
6 Antimicrobial Activity of 1,2,3-Triazole Derivatives
Antimicrobial resistance (AMR) is one of the top 10 worldwide public health emergencies, in agreement with the World Health Organization (WHO). It causes more than 23,000 deaths and 2 million infections per year [71]. It has been reported globally, the struggle of pathogenic bacteria (which are capable of causing infections when entering into the body through water, air or physically) regarding available drugs. Furthermore, because of imperceptive antifungal activities, the occurrence of fungal infections improved swiftly as well as increased resistance. Therefore, scientists and researchers have mainly been focused on the improvement of novel antimicrobial agents for bacterial infections [72]. In this regard, diverse 1,2,3-triazole-based analogues display auspicious antimicrobial activities. However, molecules containing 1,2,3-triazole ring systems as novel antimicrobial agents has been described in this section [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91].
The recently prepared scaffolds were investigated toward the antibacterial efficacies against gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Shigella boydiias well as gram-positive bacteria like Staphylococcus aureus, Enterococcus faecalis and showed antifungal action in contrast to pathogenic yeast such as Candida albicans, C. tropicalis, C. Parapsilosis, Cryptococcus neoformans, Dermatophyte as well as Aspergillus, the moulds (a type of fungus) like Aspergillus niger, A. fumigates. Among these investigated compounds, compound 63 exhibited auspicious antifungal activity as well as potent antibacterial action [74]. In addition, spirocyclic triazolyl derivatives keep noteworthy biological activities and compound 64 screened against six diverse microbial strains and showed decent antimicrobial activity [75]. In continuation, compounds 65 and 66 were exhibited antibacterial and antifungal activity and this is mostly because of existence of halo-substituted phenyl rings and a piperazine ring in the frame [76]. Additionally, triazole-based moieties, i.e. compound 67 and 68 displayed important minimum inhibitory concentrations (MIC) and exhibited dynamic potential against several gram-positive and gram-negative bacteria like Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa [77]. Indeed, compounds 69 and 70 exhibited enhanced antibacterial activity [78]. In addition, compound 71 exhibited more potency than the standard ampicillin counter to gram-positive (Staphylococcus aureus) and gram-negative bacteria (Escherichia coli) and exhibited considerable cytotoxicity and antifungal activities [79]. In continuation, 3,4-dichlorobenzyl analogue 72 and consistent hydrochloride 74 exposed potent activity against anti-E. coli compared to reference drugs Norfloxacin and Chloromycin. In addition, it was proved by initial data that, compound 72 could efficiently interpolate into calf thymus DNA to form 828-DNA conjugate by blocking DNA replication and establishing antimicrobial actions [80]. Indeed, compound 73 evaluated towards anti-bio-film, antimicrobial and bactericidal actions and showcase maximum potency and as well as promising cytotoxicity (Fig. 7) [81].
In addition, compounds 75 and 76 seemed more auspicious antibacterial agents against gram-positive bacteria (S. aureus, S. epidermidis and B. subtilis) as well as gram-negative bacteria (E. coli, P. aeruginosa, S. typhi and K. pneumoniae) [82]. Further, coumarin-based triazole derivatives (compound 77) exhibited comparable antifungal activity in comparison with reference drugs [83]. In addition, compounds 78 and 79 displayed decent potency in contrast to bacteria and fungi [84]. In continuation, compound 80 (with 4-pentylphenyl substituent), showed durable inhibitory action counter to bacteria and 85 (with 4- bromophenyl substituent) has a greater antifungal potency. Additionally, the above-mentioned analogues displayed a decent cytotoxic activity against a number of verified tumour cell lines, nevertheless non-toxic to the non-tumour liver cells [85]. Indeed, compound 81 exhibited outstanding antibacterial strain related to the standard drug Vancomycin, whereas 88 displayed better potency contrary to yeast [86].
In continuation, compounds 82 and 87 resulted in a stimulating antimicrobial strain in contrast to the screened bacteria and fungi omitting E. coli, which displayed slight counter action [87]. In addition, compounds 90 and 89 were exhibited effective antibacterial and antifungal strain respectively [88]. Indeed, compound 90 drew two-fold more antifungal activity than the standard miconazole, as well as extremely potent to diverse bacterial strains [89]. In addition, compound 86 showcased an extremely good discriminatory toxicity contrary to microorganisms [90]. However, 1,2,3-triazole attached carboxylic acid, bromoquinoline analogues were investigated and among all compounds, 89 displayed effective potential to antimicrobial and antifungal strains (Fig. 8) [91].
7 Anti-viral Activity of 1,2,3-Triazole Derivatives
Viral toxicities are regarded as leading precarious infections, as they kill over million people yearly around the globe. Recently, coronavirus disease (COVID-19), an extremely infectious disease, killed more than 4 million people all over the world. In contrast, recent developments of anti-viral drugs show that there is a public health crisis to discover the extremely potent and ingenious agents. With this intent, several 1,2,3-triazole-based compounds were produced and evaluated for anti-viral action [92,93,94,95,96,97,98].
The compound 91 exhibited potency against influenza A replication which was higher to the standard drug ribavirin in terms of anti-viral activity as well as displayed human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) activity [92]. Indeed, analogue 92 showed powerful inhibitory action against the replication of H5N1 (RG14) (influenza a virus), amantadine-resistant A/WSN/33 (H1N1) and oseltamivir-resistant A/WSN/1933 (H1N1, 274Y) virus strains. In addition, 5-ethynyl nucleoside 93 showed anti-viral activities counter to most of the viruses [93]. In continuation, the interactivity of circulating tumour DNA (CT-DNA) with the sugar-triazoles was screened, revealed that the compound 94 can interrelate via groove binding with circulating tumour DNA (CT-DNA) [94]. In addition, longer alkyl chain compound 95 potentially abridged RNA copies multiplication, with 10 μM treatment diminish viral RNA [95]. Furthermore, phosphonate 96, exhibited anti-viral action in MDCK (Madin Darby canine kidney cell cultures) counter to Influenza A H3N2 subtype [96]. Additionally, compounds 97 and 98 exhibited high selectivity indices (polymerase chain reaction (PCR) method) for the cytotoxic activity and anti-EBV activity [97]. However, compounds 99 and 100 exhibited diffident inhibition in contrast to respiratory syncytial virus (RSV) and compound 101 showed uncertain inhibition counter to Coxsackievirus B4 (Fig. 9) [98].
8 Summary/Conclusion
1,2,3-triazole and its derivatives are recognised as prosperous motifs in medicinal chemistry and biosciences. Moreover, excellent features of 1,2,3-triazole accelerate its broad spectrum of implementation from bioconjugation to material science. However, among the synthesised triazoles they resemble properties in which these scaffolds act as a linker, displaying CH-π interaction with enzymes. Nevertheless, the unique features of these moieties in the hybrid molecules make them a remarkable motif, a significant aspect in drug delivery and design. Scientists and researchers around the globe make continuous efforts to improve and increase the 1,2,3-triazole-based chemistry, enabling the advancement of 1,2,3-triazoles derivatives with higher selectivity and lesser toxicity in future.
Abbreviations
- NSAID:
-
Non-steroidal Anti-inflammatory Drugs
- HIV:
-
Human Immunodeficiency Virus
- RSV:
-
Respiratory Syncytial Virus
- DNA:
-
Deoxyribonucleic Acid
- EGFR:
-
Endothelial Growth Factor Receptor
- COX:
-
Cyclooxygenase
- AA:
-
Arachidonic Acid
- U.S. FDA:
-
United State Food and Drug Administration
- ADP:
-
Adenosine di-phosphate
- LOX:
-
Lipoxygenase
- TNF-α:
-
Tumour Necrosis Factor Alpha
- RNA:
-
Ribonucleic Acid
- SAR:
-
Structure–Activity Relationship
- MTB:
-
Mycobacterium Tuberculosis
- DPPH:
-
2,2-Diphenyl-1-picrylhydrazyl
- TcTS:
-
T. cruzi trans-sialidase
- WHO:
-
World Health Organization
- HDAC:
-
Histone Deacetylases
- COVID-19:
-
Coronavirus Disease-2019
- MDCK:
-
Madin Darby Canine Kidney
- EBV:
-
Epstein-Barr Virus
- UV:
-
Ultraviolet
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Kabi, A.K. et al. (2022). An Overview on Biological Activities of 1,2,3-Triazole Derivatives. In: Swain, B.P. (eds) Nanostructured Biomaterials. Materials Horizons: From Nature to Nanomaterials. Springer, Singapore. https://doi.org/10.1007/978-981-16-8399-2_11
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