Triazoles- A paradigm shift in drug discovery: A review on synthesis and therapeutic potential

1.1. Importance of triazoles and paradigm shift in drug discovery in medicinal chemistry

Triazoles have become very important in pharmaceutical chemistry, helping to develop a wide range of treatments [15]. The structure of triazoles is highly stable and better at interacting with biological targets, making them highly effective in treating conditions like fungal/bacterial infections and cancer [16]. Triazoles and their derivatives are utilized as therapeutic agents, as illustrated in Figure 1.

Close

Figure 1.

Triazoles as potential active agents against different diseases.

Export to PPT

The nitrogen atoms in triazoles allow them to form strong bonds with target proteins, making these compounds versatile and powerful [17]. This has led to the synthesis of effective triazole-based drugs, such as fluconazole, a common antifungal, and letrozole, employed to treat breast cancer. These drugs are not only effective but also set high standards in their fields, demonstrating the influence of triazoles on modern medicine [18]. The use of triazoles in drug design has brought significant changes to the way new drugs are discovered. Triazoles have not only transformed the field of medicinal chemistry but also opened the door to future drug discoveries, establishing themselves as essential tools in the pharmaceutical industry [19]. The structures of Triazoles-based medicines have been exhibited in Figure 2.

Close

Figure 2.

Pharmaceutical active compounds used in medicines.

Export to PPT

1.2. Chemistry of triazoles

Several features characterize the chemistry of triazoles, and the arrangement of atoms in a triazole ring not only provides rigidity to the molecule but also endows it with a lot of chemical reactivity that makes triazoles suited for several chemical and pharmaceutical uses [20]. Triazoles are present in two primary isomeric forms (Figure 3), and the distinction is made depending on the position of the nitrogen atoms within the ring. The 1,2,3-triazole isomers are synthesized by the Huisgen 1,3-dipolar cycloaddition reaction [21]. The reaction involves the coupling of an azide with an alkyne to form triazoles with excellent regioselectivity and high efficiency. This method has marked the advancement in synthetic chemistry, particularly in triazole derivatives, since it makes the production of accurate synthetic structures possible [22]. The electron-rich nature of the nitrogen atoms in triazoles affects their moderate electron density and allows them to undergo various reactions, including nucleophilic substitutions, electrophilic aromatic substitutions, and other reactions involving transition metals [23]. Triazoles are also aromatic; the presence of the aromatic ring provides stability to the ring and determines its reactivity. The delocalization of its π-electrons ring system imparts resonance stabilization, contributing to the triazoles’ chemical stability [24]. On account of these properties, the triazole ring has now been organically incorporated in most subject fields of chemistry, and the group is widely used in the synthesis of drugs, pesticides, and other materials as starting compounds to obtain new substances with the essential required properties [25].

Close

Figure 3.

Chemistry of both 1,2,3-Triazoles and 1,2,4-triazoles.

Export to PPT

2.1. Huisgen cycloaddition

The triazene group enabled the regioselective reaction and was subsequently substituted with various groups, including amide, halogen, and heterocycle groups. The study of cycloaddition utilizing 1-alkynyltriazene and benzyl azide under various conditions, and using various transition metal catalysts in the presence of [IrCl]₂ (2 mol%), gave a 98% yield, and this 1,4,5-trisubstituted pattern was confirmed by X-ray crystallography as well as spectroscopic methods [26]. A highly efficient procedure was reported to synthesize a purine-based triazol-9H- through a copper (I)-catalyzed reaction [27]. The copper-catalyzed cycloaddition is considered the protocol for the synthesis of triazole. Tri-, tetra-, hexa-, and initial reactants prepared octavalent sugar-linked triazole mimetics as azido-substituted pyran derivatives and different alkynes [28].

A new magnetically separable copper ferrite coated with silica@Cu complex as an entity was reported for the Huisgen 1,3-dipolar cycloaddition reaction of NaN₃, aryl or alkyl halides, and alkynes, yielding substituted triazoles. This was an economical, highly selective, and efficient process for the one-pot synthesis of substituted triazoles with excellent yield (94%), obtained within 20 minutes using (chloromethyl)benzene and ethynyl benzene [29]. Triazole-based moieties containing ester and thioether linkages from benzyl-2-azidoacetates and aryl(prop-2-yn-1-yl) sulfanes were synthesized using Cu(I) catalyzed cycloaddition. Benzyl-2-azidoacetates were synthesized in situ by reacting bromoacetate moieties with NaN₃ utilizing a catalytic amount of copper sulfate and sodium ascorbate in the presence of a dimethyl formamide (DMF): H₂O mixture to obtain the targeted products [30]. The copper-catalyzed cycloaddition reaction of different azides and acetylene yielded triazoles [31]. Triazole-thiazolidinone-carvone-based moieties were prepared using the Huisgen cycloaddition. The [3+2] cycloaddition reaction was conducted between substituted thiazolidin-4-one with aromatic NaN₃ in EtOH/water (1:5), with copper sulfate and ascorbate, and the reaction gave good yields (85–95%) [32]. Urea-based triazole moieties were prepared through a two-step cycloaddition reaction. Diazides were prepared by reaction dibromides with sodium azide in DMF at 70°C. These diazides underwent a copper-catalyzed reaction to get end products. The urea-linked alkynes were prepared by the reaction of isocyanate analogs with HC≡CCH₂NH₂ in the presence of triethylamine in CH₂Cl₂ [33]. Isoquinoline-based triazole compounds were prepared using a facile synthetic strategy. This bi-triazole framework utilizes benzaldehydes as the reactant materials to yield a compound for intramolecular ring closure. Then, 4-azido-1,2,3-triazoles were subjected to thermal Huisgen’s cycloaddition, yielding bis-triazole [34]. A series of indole derivatives of N-substituted 1,2,3-triazolylmethyl was synthesized by rationally introducing a pharmacophoric ring comprising triazole and indole moieties into one molecular frame by conventional and microwave irradiation methods. New compounds were prepared through carbazoles that undergo cycloaddition reaction with azides in the presence of CuSO₄.5H₂O. Carbazole reaction with propargyl bromide in NaH and DMF produced substituted tetrahydro-1H-carbazole in adequate amounts [35]. Triazoles were synthesized by Huisgen Cycloaddition, as shown in Figure 4.

Close

Figure 4.

Synthetic scheme of triazoles by huisgen cycloaddition [26-35].

Export to PPT

2.2. Copper-catalyzed azide-alkyne cycloaddition

Triazoles were prepared by copper-catalyzed cycloaddition of hydrazoic acid. In situ, the synthesis of hydrazoic acid was performed from sodium azide under acidic conditions. This reaction proceeded at room temperature in the presence of a MeOH-water mixture and catalyst (5 mol%), leading to the synthesis of 4-substituted-1,2,3-triazoles with high yield [36]. An efficient and accessible synthesis of azidotrifluoromethane and the longer perfluorocarbon-chain equivalents was achieved. This allows CF₃ and the perfluoroalkyl groups to be inserted into triazole ring systems directly. These azidoperfluoroalkanes express excellent reactivity copper-catalyzed cycloaddition reactions, to form the stable N-perfluoroalkyltriazoles [37]. The simplest approach to prepare fully substituted triazoles has recently been developed using an interrupted click reaction. This reaction was accessible from readily available alkynes with a multistep reaction synthesis. Toluene-based material was used to synthesize asymmetric triazole disulfide, which was prepared by in situ reaction of t-butyl thiochloride and potassium p-toluenesulfonothioate [38]. The sulfenylation reaction of benzyl thiosulfonates with organic azides was revealed. This metal-catalyzed reaction provided a diverse range of triazole-based heterocyclic compounds in good to high yield (51–94%) under mild conditions. Furthermore, using benzyl bromide, thiosulfonates, and NaN₃ for the delivery of fused-triazoles, this three-component reaction could also have achieved a 61–74% yield [39]. Various enamine-based triazole analogues were synthesized via the metal-catalyzed reaction of alkyne, azide, and azirine. 2H-Azirines are extremely strained three-membered N-heterocycles, which form reactive nitrile ylides and vinyl nitrenes under photolytic or thermal conditions. This reaction proceeds by inserting a vinyl nitrene into the C-Cu bond, providing an effective and economical method for the synthesis of enamine-based polysubstituted triazoles, which are subsequently converted to pyrazoles using a Rh catalyst [40]. Three 2-hydroxyphenyl benzothiazoles linked 1,2,3-triazoles were effectively synthesized under copper-catalyzed azide-alkyne cycloaddition (CuAAC) using 1,2,3-triazoles and 2-hydroxyphenyl benzothiazoles. The 2-(n-(bromoalkoxy) phenyl)benzo[d]thiazoles were synthesized from 2-hydroxy phenyl benzothiazole (HBT) by the alkylation on phenolic hydroxyl group of HBT with a variety of alkylating agents using anhydrous K₂CO₃ in acetone solvent. The resultant bromoalkoxy benzothiazoles were in situ transformed to azides upon reaction with NaN₃ during CuAAC reaction of p-substituted benzene with copper sulfate and Na-ascorbate in tetrahydrofuran (THF): H₂O, 8:2 v/v ratio. The required products (2-alkoxyphenyl benzothiazole-linked triazoles) were obtained with 87–94% yield [41].

The derivatives of triazoles were synthesized by treating different pyran-based carbonitriles with phenylacetylene using Cu(I) as a catalyst. The excellent yield was achieved in EtOH/water solvent because the copper-catalyzed reaction is highly selective to triazolic byproducts [42]. The preparation of a triazole conjugated with a 9H-carbazole derivative was demonstrated with an excellent yield and significantly reduced reaction time. The 1,2,3-triazole linker was produced under thermal conditions within 20 min and yielded more than 90% using copper as a catalyst [43]. A facile, efficient, and regioselective production of benzotriazole-triazole conjugates was proposed via a CuAAC reaction between aryl azides and a wide range of benzotriazole alkynes. This procedure avoided the usage of a reducing agent, thus giving an improved pathway to synthesize benzotriazole-linked triazole skeletons, and a maximum yield of 70% was achieved using a copper catalyst [44]. A new strategy was developed to synthesize triazoles through a Ugi-azide reaction that followed the CuAAC reaction, utilizing solvent-free conditions. This retrosynthetic strategy uses a propargylamine chemical having alkyne functionality for cycloaddition reaction [45]. The overall schemes for the synthesis of triazoles by CuAAC reaction have been exhibited in Figure 5.

Close

Figure 5.

Triazoles synthesis by copper-catalyzed azide-alkyne cycloaddition [36-45].

Export to PPT

2.3. Ruthenium-catalyzed azide-alkyne cycloaddition

A simple and regiospecific preparation of triazoles was catalyzed by ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) using microwave irradiation. Oleanolic acid–alkyne analogues and different azides yielded the series of 1,4- and 1,5-triazolyl derivatives in dimethyl formamide (DMF). The best conditions for this cycloaddition of alkyne and phenylazide were investigated using various concentrations of the catalyst Cp^∗RuCl(PPh₃)₂. A yield of 84% to 96% was achieved for the targeted compounds, exhibiting complete regiospecificity [46]. Stereo/regio-selective triazole oligomers and the C1-linked polymers were synthesized by RuAAC. Monofunctional precursors of t-BuAH formed a dimer after RuAAC polymerizations, which contained a disubstituted triazole moiety. Cp*RuCl(COD) and Cp*RuCl(PPh₃)₂ as Ru(II) catalysts were used to obtain polymers preferentially comprising 1,5-units [47]. Substituted amino-based triazoles were synthesized via Ru-catalyzed reactions, with the potential of varying side chains. The chiral alkyne and azide originated from the amino acid alanine. Utilizing both enantiomers, combined with propargylamine and methyl 2-azidoacetate, we synthesized eight different stereoisomers derived from triazole [48]. A novel method for in situ conversion of terminal alkynes to 1-cyanoalkynes under mild conditions using cyanogen was reported. Compared to terminal alkynes, 1-cyanoalkynes possess high reactivity to yield triazoles in Ru(II) catalyzed regiospecific cycloaddition. This azide–cyanoalkyne cycloaddition catalyzed by Ru exhibited a higher functional group tolerance [49]. A direct method was used to obtain thiocyanato-based triazoles from azide cycloaddition with higher regioselectivity. Several substituted triazolyl-based organosulfurs, such as 5-sulfinylcyanato-triazoles and 5-sulfur-triazoles, were produced from thiocyanate-based alkyne units. The cyanate is considered the leaving group, and sulfur serves as the starting material for useful triazolyl-organosulfur. A highly efficient solvent, THF, was used, and high yields were obtained [50]. Alkynes reaction with a secondary azide yielded triazole moieties utilizing the Cp^*RuCl(COD) catalyst. Both internal and terminal alkynes underwent highly regioselective cycloaddition under mild conditions, facilitating peptide release from resin and conversion to the resultant 1,2,3-triazoles [51]. RuAAC was considered for preparing a series of triazole diazabicyclooctane (DBOs) and their trisubstituted equivalents, yielding 44 to 94 % of the target compounds. The internal alkynes and cyanamides were subjected to Ru based reaction in azido-DBO and Cp*Ru(COD)Cl as a catalyst in dimethylformamide for 24 h at 70°C [52]. The synthesis of triazoles by RuAAC has been given in Figure 6.

Close

Figure 6.

Synthetic routes for synthesis of triazoles by RuAAC [46-52].

Export to PPT

2.4. Pinner triazole synthesis

Acetates-based triazoles were prepared by the Pinner reaction approach. α-Mono- and α,α-disubstituted ethylcyanoacetates were transformed into carboxyimidate salts, the key intermediates in the reaction. Further reaction with formylhydrazide yielded triazolylacetates, depending on the nucleophile nature and structure of the starting Pinner salt [53]. The triazole nucleus was synthesized and substituted with hydrazide, ester, and Schiff base systems. This synthetic strategy was started by reacting CH₃CN with EtOH in the presence of HCl to produce a product using the Pinner method, which was further reacted with ethyl carbazate to yield ethyl 2-(1-ethoxyethylidene)hydrazinecarboxylate at 0-5°C. The further reaction of this synthesized compound with ethyl 4-aminobenzoate by microwave irradiation was obtained [54]. The preparation of triazoles comprising linear and cyclic amines was achieved by thermally cyclizing hydrazides, which were synthesized through the reaction of carboxylic acid hydrazides and imido esters. The Pinner reaction and the reaction of nitriles with MeOH in the presence of sodium methoxide and imido esters were synthesized. The conversion of substituted triazoles to amino phenyl was done by reducing hydrazine hydrate with Raney nickel [55]. One-flask synthesis technique utilizing nitriles and N-arylhydrazonoyl chlorides for triazole moieties. This reaction was suitable for aliphatic and aromatic nitriles with N-arylhydrazonoyl chlorides having different functionalities on the benzyl group. A feasible dipolar cycloaddition reaction was presented to synthesize the desired triazole [56]. N-acylamidrazones were prepared using hydrazides and alkyliminoacetate hydrochloride, which were then reacted with chloroanhydride of the identical carboxylic acid. Diacylamidrazones were converted to carboxylates-based triazoles in a one-pot synthetic reaction [57].

The dicationic triazoles were prepared from the dinitriles by the copper-catalyzed cycloaddition, using the pinner approach. 3-Azidobenzonitrile and 4-azidobenzonitrile were synthesized by diazotizing/azidating commercially available aminobenzonitriles [58]. Imidates and hydrazides were utilized for the preparation of 3,5-dimethylene-1,2,4-triazoles. Several imidates were synthesized from nitriles, and the Pinner reaction, and hydrazides were synthesized from carboxylic acids, via esterification followed by a reaction with hydrazine. Once the imidates and hydrazides were thermally condensed to acylamidrazone intermediate at 50^oC, followed by increased heating to 105^oC to form the target triazole [59]. Triazole derivatives were synthesized from the reactions of triazol-5-ones with 2,6-dimethylmorpholine and formaldehyde. The obtained compounds were further reacted with 3-ethoxy-4-benzenesulfonyloxybenzaldehyde to give Schiff base targets [60]. Schiff base derivatives were efficiently prepared using the Pinner method, which involves reacting acetonitrile with EtOH and hydrochloric acid to obtain the starting compound. A benzoate-based triazole was reacted with a bromoacetic acid-based ethyl ester to obtain the required products [61]. The Schiff base triazoles were prepared by microwave irradiation reaction of ethyl p-bromophenylacetate etoxycarbonylhydrazone, with aldehydes [62]. Schemes for the synthesis of triazoles by the Pinner method have been exhibited in Figure 7.

Close

Figure 7.

Triazoles synthesis by Pinner method [53-62].

Export to PPT

2.5. Banert cascade reaction

The synthesis of 1H-triazoles from propargylic azides was done by the Banert cascade reaction. The Banert cascade protocol began with azide moieties using phenylacetylenes that underwent reaction with nBuLi and an aldehyde, yielding propargylic alcohols. Further derivatization with Et₃N, MsCl, and nucleophilic substitution with sodium azide produced propargylic azides [63]. The Banert cascade reaction produced triazole via click chemistry, and 1,4-dihydroxyalkyne derivatives were transformed into mesyl derivatives by converting the primary hydroxy group to the mesylate group. The targeted triazole derivatives were obtained from initial reactants using a catalyst-free approach [64]. Triazoles were synthesized by Banert cascade when propargylic azides were treated with AgF in CH₃CN, and regioselective products resulted from primary [3,3] rearrangement. Sigmatropic rearrangement was promoted by the slightly elevated temperature, and due to the highly basic nature of the fluoride anion in organic media [65]. A three-step process was employed to prepare a series of triazoles using the Banert cascade reaction as the primary step. Chlorosulfonamides prepared by treating 4-chlorobutyneamine with sulfonyl chlorides and potassium carbonate were transformed to the corresponding azidosulfonamides. The crude azides, with various sulphonamide groups in the presence of nucleophiles, went through the Banert cascade to form NH-triazole sulphonamides [66].

Triazoles were synthesized by inserting O- and S-nucleophiles and alkynes. This reaction was effectively accomplished in 2 h by utilizing CuI/Pd(PPh₃)₄ as a cocatalyst in dimethylsulfoxide at 60°C. Vinyl azides possessing a β-oxygen moiety offered as a low-molecular-weight motif in situ to combine a variety of functionalized N-vinyl-1,2,3-triazoles [67]. Vinyl azides and aryldiazonium salts go through a carboamination reaction to obtain a functionally wide range of triazoles in moderate to good yield. This was a cyclization method involving the new double-functionalization of vinyl azides with aryldiazonium salts to construct N2-substituted triazoles. This synthetic protocol offered the benefit of proceeding under an ambient atmosphere in addition to tolerating a variety of functional groups, resulting in the production of polyfunctional triazoles through readily accessible substrates [68]. The synthesized imines are converted into piperizine-based triazoles and azido enamines by cyclic addition reaction of the amine product with progargyl bromide [69]. Triazoles were prepared from propargyl substrates, with at least one additional functional group at C4 in the side chain. Short-lived allenyl azides were prepared by involving propargyl azides, which underwent [3,3]-sigmatropic rearrangement. Allenyl azides cyclized to produce triazafulvenes that might be trapped by adding O- or N-nucleophiles. The one-pot cascade incorporated allenyl azides, propargyl azides, and triazafulvenes to synthesize NH-1,2,3-triazoles [70]. Triazole synthesis without a catalyst and solvent with efficient microwave irradiation was accomplished from trimethylsilyl azide, Si/Ge-substituted aldehyde, and amines [71]. Silver-mediated conditions enabled the formation of C-C bonds alpha to NH-triazole product [72]. Triazoles and their derivatives synthesis schemes by the Banert Cascade method have been shown in Figure 8.

Close

Figure 8.

Triazoles and their derivatives Synthesis by Banert Cascade method [63-72].

Export to PPT

3.1. Antialzheimer

The coumarin-benzotriazole hybrid was synthesized to treat Alzheimer’s disease. The most potent hybrids were obtained from 1-benzotriazole and 4-hydroxycoumarin. The inhibition potential of compound 1 was also confirmed using a molecular modeling approach that demonstrated its activity in blocking both CAS and PAS of AChE. Compound 1 inhibited acetylcholinesterase (AChE) the most effectively (IC₅₀ = 0.059 M) [82]. The synthesis and assessment of pyridoxine-based triazoles against AChE inhibition were reported. Among all synthetic pharmacophores, compound 2 was found to be beneficial for AChE activity, with an IC50 of 1.56 ± 0.02 mM and 77.89% inhibition [83]. Quinazoline-triazole hybrids were introduced as a novel class of cholinesterase inhibitors for Alzheimer’s disease. According to biological assay results, the IC₅₀ range from 0.2-83.9 µM was demonstrated by all synthesized hybrids. The highest AChEI activity was observed, with compound 3 having an IC₅₀ value of 2.06 µM [84]. A highly capable synthetic pathway was designed for a series of chromenone carboxamide-based triazoles. The evaluation for cholinesterase inhibitory potential showed good inhibitory activity (IC₅₀ = 1.80 µM) for compound 4. However, it was highly selective towards acetylcholinesterase. The most promising candidate, 4, was also subjected to docking studies, which revealed better inhibition towards AChE [85]. Triazole-based thiosemicarbazone derivatives were efficiently prepared and screened in vitro for inhibition action against cholinesterase. Compound 5 emerged as the most active inhibitor with an IC₅₀ of 0.10 ± 0.050 µM for AChE and an IC₅₀ of 0.20 ± 0.050 µM for BuChE among all the synthesized compounds. The in vitro outcomes were also reinforced by molecular modeling studies [86]. Methylindolinone-based triazole derivatives were evaluated for cholinesterase inhibition. Modest to good activity was depicted against butyrylcholinesterase by all compounds, while the highest activity was observed by compound 6, having an IC50 value of 4.78 μM, which was more potent than donepezil. Based on molecular docking evaluation, compound 6 could exhibit interaction with the peripheral and binding sites of BuChE simultaneously [87]. Novel chromenone-based triazoles were prepared and evaluated for the anti-ChE activity. Compound 7 exhibited good anti-acetylcholinesterase activity. The IC₅₀ value determined for the most active candidate was 15.42 μM. Modeling and kinetic studies disclosed the dual binding potential of compound 7 to the catalytic active site and the peripheral anionic site of AChE [88]. A new class of triazole-based moieties was prepared and tested for Alzheimer’s disease. Among the synthetic derivatives, compound 8, possessing the O-CF₃ functional group on the benzyl ring, revealed the most effective 96.89% inhibition and an IC₅₀ of 8.065 ± 0.129 μM against Aβ₄₂ aggregation, compared with curcumin. The preferred binding regions and key interactions of compound 8 with Aβ₄₂ monomer were identified with molecular docking [89]. Tacrine-based triazole moieties were prepared via CuAAC reaction and were evaluated for inhibitory activity against cholinesterase as potent drug targets for Alzheimer’s disease. Compound 9 exhibited remarkable inhibition against BChE and AChE with IC₅₀ values of 3.61 μM and 4.89 μM, respectively [90]. Triazine derivatives containing triazole nuclei were assessed as therapeutic agents for AD. Compound 10 was demonstrated to be a promising inhibitor, with an IC₅₀ value of 8.55 ± 3.37 µM [91]. The Chemical Structures of triazoles derivatives as an Alzheimer inhibitor have been shown in Figure 9.

Close

Figure 9.

Structures of potent triazoles as a alzhiemer inhibitors.

Export to PPT

3.2. Antibacterial activity

Derivatization of dapsone resulted in the synthesis of disulfone-based compounds containing 1,2,3-triazoles, and antibacterial activity was examined against six pathogenic bacteria. The IC₅₀ values of potent compound 11 against P. aeruginosa, E. coli, K. pneumoniae, S. aureus, L. monocytogenes, and B. subtilis were determined as 11.11 µM, 22.42 µM, 16.54 µM, 25.31 µM, 31.38 µM, and 26.66 µM, respectively [92]. 1,2,4-triazole moieties (12 and 13) were synthesized by subjecting thiosemicarbazide derivatives to base-catalyzed cyclization. These derivatives were introduced in norfloxacin at the C-7 site through the Mannich reaction. When the antibacterial activity was evaluated, the results revealed that the synthesized hybrids exhibited enhanced antibacterial activity against both bacterial strains compared to norfloxacin. Compound 12 was considered to have the most substantial effect, with minimum inhibitory concentration (MIC) values of 0.25 μg/mL, ≤ 0.125 μg/mL, and 0.25 μg/mL against S. aureus, E. coli, and P. aeruginosa, respectively [93]. Various chalcone-based triazole hybrids were synthesized from dihydroacetic acid chalcone using a click reaction, and they were evaluated as antibacterial agents. According to primary research, the compounds exhibited bioactivities comparable to or even higher than those of reference drugs, highlighting the role of the triazole nucleus in antibacterial potential. Compound 14 was identified as the most active compound, with a MIC value of 0.0030 µM/mL against E. coli. Furthermore, the effective binding of this compound with the binding positions of DNA gyrase was indicated by molecular modelling studies [94].

The antibacterial activity of thiazolyl-triazole Schiff bases was determined against Gram-positive and Gram-negative bacteria. The results showed that compound 15 had a superior effect compared to ciprofloxacin. Compound 15 (3-nitro-phenyl) displayed a 20 mm diameter and an effective activity index against the bacterial strain [95]. Newly synthesized benzofuran-based triazole analogues were assessed for their inhibition action against bacterial strains. The screening results suggested that compound 16 is the most active among all synthetic pharmacophores, with a MIC value of 1.25 ± 0.60 µg/mL for B. subtilis, comparable to the effectiveness of penicillin (1 ± 1.50 µg/mL) [96]. A green synthetic protocol was conducted to prepare triazoles using Cu(I) nanomaterials supported by cellulose. In vitro, the antibacterial potential of some bacterial species was evaluated. Average to good inhibitory action was observed by these triazole derivatives. However, compound 17 showed good activity against bacterial strains, with MIC values of 0.0700 against B. subtilis, 0.0350 against E. coli, and 0.0350 against K. pneumoniae. In silico absorption, distribution, metabolism, and excretion (ADME) analysis also revealed good bioavailability of compound 17 [97]. Several triazole-thiazole derivatives were evaluated using a multi-step reaction protocol, and in vitro antimicrobial activity was analyzed. Most compounds exhibited encouraging inhibitory efficacy against the bacterial strains, with concentrations ranging from 2.8 to 15.7 µM. According to activity results, compound 18 exhibited promising activity against B. subtilis MTCC 121 and S. aureus MTCC 96 [98]. New acridone-based triazole derivatives were prepared by microwave irradiation and conventional methods. The results indicated that the compounds exhibited good inhibitory activity against certain strains. Moreover, compound 19 was the most effective inhibitor against both Gram-positive and Gram-negative organisms, but its potential was lower than that of chloramphenicol [99]. The anti-bacterial activity of newly synthesized substituted triazoles, using the click chemistry method, was investigated. According to the primary outcomes of antibacterial screening, the synthesized compounds demonstrated the greatest inhibitory potential compared to ciprofloxacin. Compound 20 was found to be the most effective active compound, with an MIC of 10 μg/mL, against various bacterial strains. A molecular docking study was performed to observe the possible interactions responsible for their anti-bacterial activity. The docking studies of compound 20 also reinforced its antibacterial potential, displaying a high inhibitory constant and binding energy [100]. The antibacterial effectiveness testing took place for various newly developed C-3 carboxylic group-containing ciprofloxacin-linked 1,2,3-triazole conjugates 21. Three different series of triazoles were synthesized using click chemistry and evaluated for their antibacterial activity against nine different pathogenic strains. These compounds exhibited exceptional antimicrobial potency against the various strains due to their low MIC values of 12.5 μg mL⁻¹. However, ciprofloxacin maintained higher MIC values ranging from 0.781–25 μg mL⁻¹ against different microbial strains [101]. 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione 22 derivatives with important antimicrobial properties. The antibacterial tests demonstrated that compounds produced MIC values between 16 to 25 µM when evaluated against ciprofloxacin MICs for their respective strains. The minimum inhibitory concentrations of most synthesized compounds demonstrated better results than standard vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus strains. A cytotoxicity test of compounds on SHSY-5Y cells conducted at up to 100 μg/mL concentrations revealed no detrimental impacts according to the research findings [102]. The effective triazole-based moieties as antibacterial agents have been shown in Figure 10.

Close

Figure 10.

Triazole-based moieties as antibacterial agents.

Export to PPT

3.3. Anticancer

Thiazolidinone analogs were synthesized by condensing corresponding triazole carbaldehydes with the thiazolidine-2,4-dione. Compounds were evaluated for their in vitro anticancer activity against cancer cell lines. Most of the synthetic pharmacophores exhibited good anticancer activity; however, compound 23 showed the highest activity (IC₅₀: 0.29 μM) against lung cancer cells. Compound 23 also displayed the maximum docking score (–5.539) according to docking results [103]. Novel naphthalene-substituted triazole spirodienones were discovered as agents for anticancer activity. Cytotoxic activity was conducted to explore the antineoplastic activity. Compound 24 possessed significant potential against MDA-MB-231 cells (IC₅₀ 0.05 μM) by arresting the cell cycle and was also found to suppress breast cancer 4T1 tumor growth [104]. Triazole-based moieties were tested for carcinogenic activity in four human cell lines, using Etoposide as a standard drug. IC₅₀ values were determined to be in the range of 0.01±0.003 to 23.7±3.72 μM. However, excellent activity was observed for compound 25 on all cell lines with IC₅₀ values of 0.390±0.630 μM, 0.010±0.003, 0.10±0.032 μM, and 0.510±0.088 μM against MCF, A54, Colo-205, and A2780, respectively [105]. Triazole-benzimidazole-chalcone hybrids were synthesized via click chemistry. The assessment of the anti-proliferative potential in prostate and breast cancer cell lines displayed that the compound 26 with chloro substituents at the chalcone ring of triazolebenzimidazole-chalcone skeleton improved the cytotoxic effects and exerted the highest effects in prostate cancer (PC3 cells), with an IC₅₀ value of 5.64 µM [106]. Triazole-containing hydrazide–hydrazones were derived from naproxen and studied for their anticancer activity against three prostate cancer cell lines. Compound 27 showed the best action with IC₅₀ values of 26.0 against PC3, 34.5 against DU-145, and 48.8 μM against LNCaP cancer cell lines. The screening results of compound 27, as determined by molecular modelling simulation, were also consistent with the experimental outcomes [107]. The design of triazole-based quinazoline analogues was achieved to evaluate their anticancer activity targeting epidermal receptors, and they exhibited good antiproliferative potential against cell lines (HCT116, HepG2, PC-3, and MCF-7). Compound 28 exhibited effective antiproliferative potential (IC₅₀ = 20.71 μM) against MCF-7 cell lines. Molecular Modeling outcomes also suggested that compound 28 interacted well with EGFR [108]. Indole Thiazolidinedione-Triazole molecules were prepared and studied for their anticancer potential against various cancer cell lines. m-acetylphenyl substituted compound 29 represented outstanding action against four cell lines linked with doxorubicin, with IC₅₀ values of 4.43±0.2 against HePG-2, 4.46±0.47 against HCT-116, 8.03±1.82 against PC-3, and 3.18±2.2 against MCF-7. The best active compound, 27, exhibited key receptor ligand interactions and had a docking score of 10.1 Kcal/mol [109]. Disubstituted triazole derivatives were examined for anticancer potential in the HeLa cancer cell line. Compound b showed considerable activity for the HeLa cell line with an IC₅₀ value of 11.7 μg/mL, with a stronger activity than cisplatin [110]. Indole derivatives linked with triazole were synthesized and studied for anticancer activity against cancer cell lines using the MTT assay. When IC₅₀ was determined, compound 31 showed potent anticancer activity: 72.8±1.04 μM and 53.17±1.02 μM against MCF-7 and HepG-2 cell lines, respectively. Molecular modeling studies also showed effective binding affinity values and interactions of compound 31 compared to doxorubicin [111]. The design and synthesis of pyridine-based triazole derivatives were performed and assessed for activity against cancer cell lines, with IC₅₀ values ranging from 2.35 to 120.46 μM for most of the synthesized compounds. Furthermore, compound 32 brings about the highest potential than cisplatin with IC₅₀ values of 2.35 μM and 10.89 μM against MCF-7 cells and the HeLa cell line, respectively. Molecular docking studies also observed the effective interactions and binding of compound 32 with receptors [112]. Synthetic 1,2,3 triazole and chiral Schiff base hybrid 33 were used against the cancer cell lines PC3 (prostate), A375 (skin), and MRC 5 (healthy) using the Almar Blue assay method to evaluate their anticancer activity. All synthesized derivatives demonstrated enhanced binding activities against androgen receptor modulators (PDB ID: 5t8e) and human MIA (PDB ID: 1i1j) relative to the standard anticancer drug (cisplatin). The compounds demonstrated weaker inhibitory action against PC3 cancer cells through IC₅₀ values extending from 40.46 to 75.05 μg/mL, but exhibited inferior performance than the reference standard cisplatin at 30.11 μg/mL. The anticancer activity of most compounds showed similar performance against A375 cancer cell lines with IC₅₀ values ranging from 21.86–40.37 μg/mL and matched the standard cisplatin with a 30.11 μg/mL IC₅₀ value. Studying the cytotoxicity effects of compounds 1-6 against MRC5 normal cells was an additional objective. All compounds demonstrated reduced toxicity against breast cancer cells through measurements of IC₅₀ values between 76.90–93.07 μg/mL, exceeding the standard cisplatin toxicity originating from its 60.34 μg/ML [113]. 1,2,3-triazole linked tetrahydrocurcumin 34 derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using the MTT assay. The anticancer activity of compound 4g showed a favorable IC₅₀ value at 1.09 ± 0.17 μM for human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines, while being compared to tetrahydrocurcumin and cisplatin controls [114]. Triazole derivatives that exhibit higher anticancer potential have been shown in Figure 11.

Close

Figure 11.

Triazoles structures as significant anticancer agents.

Export to PPT

3.4. Antidiabetic

A variety of novel thiazolidinone-based triazoles were synthesized by reaction of benzylidenethiazolidine-2,4-dione with triazole moieties. The new compounds were tested for in vitro antidiabetic activity, and their inhibitory potential was determined. The activity data showed a strong correlation with standard sorbinil. Compound 35 exhibited the highest activity among all synthesized pharmacophores (IC₅₀:1.42±0.21 µM). Furthermore, molecular docking findings showed that the compounds had greater binding affinities than sorbinil. The docking scores and interactions clearly defined the inhibitory intensity of the powerful drug [115]. 1, 2, 3-triazole-5-carboximidamide derivatives were effectively synthesized and evaluated for their ability to inhibit the DPP-4 enzyme. All the synthetic scaffolds had inhibitory efficacy. However, compound 36, with an IC₅₀ value of 14.75 nM, exhibited the desirable inhibitory potential of DPP-4. The best fitting of the suggested molecules at the proper distances in the DPP-4 catalytic region was also confirmed by the docking results [116]. Benzimidazole-based triazole moieties prepared by the click reaction, and their antidiabetic efficacy was evaluated. The IC₅₀ values for α-amylase and α-glucosidase inhibition, respectively, ranged from 0.0146 - 0.0916 µmoL/mL, suggesting a good-to-moderate inhibitory activity for both enzymes. α-glucosidase (IC₅₀ value: 0.0146 µmol/ml) and α-amylase (IC₅₀ value: 0.0534 µmol/ml) were both inhibited by compound 37. Furthermore, docking studies were done to determine the proper geometry of the most active drug [117]. The extent to which newly synthesized coumarin triazole hybrid compounds effectively inhibit α-amylase was considered. In the series of hybrids, compound 38 showed some positive results, with an α-amylase enzyme IC50 of 5.43 μM. Molecular docking also revealed that ligand 38 interacts with high efficiency, with a score of -3.42 (kcal/mol) [118]. The research was conducted to assess the ability of a series of newly synthesized xanthone-triazole derivatives to inhibit α-glucosidase and facilitate glucose transport in HepG2 cells. Regarding the inhibitory effects of the molecules, most of the compounds assessed in this study exhibited higher inhibitory effects, with an IC50 value of 2.06 μM calculated for compound 39. These computational predictions, like molecular docking and kinetics, were well justified by the experimental works [119]. 4,5-diphenyl-imidazol-1,2,3-triazole analogs were synthesized by click reaction and assayed against α-glucosidase. It had inhibition constant with IC₅₀ values that ranged from 85.6 ± 0.4 to 231.4 ± 1, and the results were higher than those of acarbose. Compound 40 exhibited the strongest inhibitory action (IC₅₀: 85.6 ± 0.4 µM) against α-glucosidase. Competitive inhibition was demonstrated by compound 40, according to kinetic studies. Additionally, the most potent compound interacts with four amino acids: THR307, HIS279, ARG312, and GLU304, as shown in molecular docking studies [120]. Piperazine and 1,2,3-triazole as scaffolds, novel benzimidazole hybrids were prepared by the click reaction with IC₅₀ values of 0.0144 and 0.0327 µmoL/mL. Compound 41 was shown to be the most powerful against α-glucosidase and α-amylase, showing some improvement contrast to acarbose. Docking analysis of α-glucosidase with 41 showed strong binding to the ARG439 and HIS348 residues. The results of in vitro biological study were validated by DFT and molecular electrostatic potential studies [121]. α-glucosidase was inhibited by newly synthesized quinoline-based triazole hybrids and showed an important in vitro inhibitory capability (IC₅₀ values ranging from 1.19 ± 0.05 to 20.01 ± 0.02 μM). Compound 42 had the highest level of efficacy as an α-glucosidase inhibitor, exhibiting competitive inhibition and an IC₅₀ of 1.19 ± 0.05 μM [122]. Cs-tri-carb triazole/carbazole chitosan biomaterial 43 was synthesized by treating chemically protected Cs-N3 with Carb-Prop while using Copper-mediated click chemistry. Cs-tri-carb biopolymer has inhibition properties against α-amylase and lipase activity. The granting of Cs-tri-carb to diabetic rats following their survival decreased both their intestinal α-amylase activity and blood glucose levels by 26 and 40% relative to diabetic rats without Cs-tri-carb treatment. Chitosan and its derivative (Cs-tri-carb) reduced intestinal lipase activities by 33% and 41% which resulted in blood lipid changes affecting total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) levels [123]. A simple method has been employed to obtain new aryl benzylidenethiazolidine-2,4-dione-based 1,2,3-triazoles 44 by uniting 1,2,3-triazole and benzylidenethiazolidine-2,4-dione pharmacophores. The test structures underwent in vitro diabetology research through aldose reductase enzyme inhibition, whereby their IC₅₀ levels were determined. Research outcomes matched those of Sorbinil as a standard drug with an IC₅₀ value of 3.45 ± 0.25 µM. The most active compounds against aldose reductase enzyme showed IC₅₀ values of 1.42 ± 0.21 µM - 1.98 ± 0.58 µM [124]. Triazoles and their equivalent structures as antidiabetics have been shown in Figure 12.

Close

Figure 12.

Effective triazole-based compounds as antidiabetic agents.

Export to PPT

3.5. Antiviral

1,2,4-Triazole Schiff base 4539 significantly inhibited tobacco mosaic virus in antiviral bioassays, with a percentage of 88.6%, which is higher than that of myricetin (50.9%) and ribavirin (73.3%). Compound 45 showed partial contact with TMV-CP, as exhibited by molecular docking studies [125]. 1,2,3-triazole and/or 1,2,4-triazole were tested against Omicron and SARS-CoV-2. Synthesized compounds 46 exhibited effective binding score values for the SARS-CoV-2 and Omicron spike proteins compared to reference drugs, as shown by molecular modeling studies and in vitro enzyme activity. The Omicron spike protein’s IC₅₀ value is 75.98 nM, whereas the SARS-CoV-2 spike protein’s is 74.51 Nm [126]. Quinolone-conjugated triazoles were synthesized, and antiviral activity was checked against SARS-CoV-2. Conjugate 47 showed strong antiviral inhibition (IC₅₀ = 0.060 mM) and a higher selectivity index than the reference [127]. Compounds having 1,2,3-triazole side chains attached to a phenylpyrazolone moiety and terminal lipophilic aryl portions with substituents were synthesized. In vitro testing against SARS-CoV-2 revealed that a 4-chlorophenyl pyrazolone derivative with carboxylic acid functionality 48 was the most effective, with an IC₅₀ value of 3.16 μM against the viral protease. Compound 48 had the highest drug-likeness and drug-score values [128]. A series of 1,4-disubstituted-1,2,3-triazole derivatives were evaluated against HSV-1 acute infection. Notable antiviral activity was observed by compound 49 with an EC₅₀ of 16 Mm [129]. Many triazole phenylalanine derivatives were examined against HIV-1CA inhibitors. Synthetic pharmacophores showed significant antiviral efficacy. The compound 50 (EC₅₀ = 3.13 µM) had particularly strong anti-HIV-1 activity. Additionally, MD simulations were performed on 50 and the results showed that binding to the CA was similar to that of PF-74 [130]. Two new triterpene derivatives, nitroaryl-1,2,3-triazole, were investigated as potential anti-respiratory syncytial virus (RSV) drugs. In vitro, tests of their anti-RSV efficacy were conducted, together with inosine monophosphate dehydrogenase (IMPDH) molecular modeling. The most effective compound, 51, exhibited an EC₅₀ value of 0.053 μM against respiratory syncytial virus [131]. The antiherpetic activity of two isosteric series of triazole analogues was examined concurrently as the compounds were synthesized. Acyclovir and molecule 52 are similar in structure, and the latter has high anti–HSV efficiency (IC₅₀ < 200 μM) against HSV-1. Furthermore, the docking simulation of compound 52 and in silico drug-likeness screening of compound 52 proved its anti-HSV-1 through thymidine kinase [132]. Hybrid compounds containing groups of 1H-1,2,3-triazole, naphthoquinone, and phthalimide were prepared and tested against the Zika virus (ZIKV). Compound 53 revealed better effectiveness against ZIKV with a selectivity index of 2.3 μM, and its IC₅₀ is 146.0 µM. Compound 53 also significantly bound to the ZIKV protein target, as indicated by docking analysis, XP Gscore, and binding free energy, and was further confirmed by molecular dynamics (MD) simulations [133]. Fused triazole derivatives and the antiviral activity of these compounds are described. Compounds against the human coronavirus 229E showed significant antiviral activity. Compound 54 displaced an 8.95 μM EC₅₀ value. Additionally, critical interactions between compound 54 and the virus’s 3-chymotrypsin-like protease were discovered using in silico research [134]. The antiviral chemical structures of triazole-based moieties have been shown in Figure 13.

Close

Figure 13.

Triazole structures as potent antiviral agents.

Export to PPT

3.6. Antiinflammatory

Triazole-based compounds were prepared, and their anti-inflammatory activity was investigated and reported [135]. Compound 55 showed the maximum efficacy (85.36% inhibition) in in vitro experiments, while in vivo investigations demonstrated 84.43% edema inhibition. Studies conducted in silico revealed that compound 55’s hinge region interaction with MET109 was comparable to that shown by standard SB 203580. [136]. The ability of 1,2,4-triazole compounds to reduce inflammation was investigated. The derivatives demonstrated anti-inflammatory properties by inhibiting the proliferation of lymphocytes, similar to the standard ibuprofen (IBU). Compound 56 had the most anti-inflammatory efficacy and lowered interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) by 84%, which in turn prevented lymphocyte proliferation and the generation of pro-inflammatory cytokines [137]. A series of 3-(substituted-4H-1,2,4-triazol-4-yl) was assessed as anti-inflammatory through an in vitro model with an effectiveness of 85.31%; compound 57 was selected for in vivo anti-inflammatory testing and was shown to be the most successful [138]. Ursolic acid was combined with triazole moieties to prepare three compounds, and research has been done on the anti-inflammatory qualities of all substances. The effective anti-inflammatory molecule’s ability to inhibit COX-1 and COX-2 was assessed through an in vitro model, and compound 58 exhibited IC₅₀ of 1.16 μM and a selectivity index (SI=64.66) comparable to celecoxib, effectively reducing COX-2. According to molecular modelling, compound 58 (-8.1 kcal/mol) binds to COX-2 with an efficiency similar to that of celecoxib [139]. After synthesizing 1, 2, and 3-triazole-linked indole-3-glyoxamide derivatives, the inhibitory effects of COX-1, COX-2, and 5-LOX were investigated through an in vitro assay. Compound 59 exhibited the best selectivity index (0.046) and demonstrated potent COX-2 inhibition (IC₅₀, 0.12 µM). Compound 59 inhibited 5-LOX similarly to norhihydroguaiaretic acid, with an IC₅₀ of 7.43 µM [140]. Researchers synthesized and evaluated the anti-inflammatory properties of 1,2,4-triazole and its hydrazone derivatives through in vitro and in vivo models. Compound 60 had remarkable anti-inflammatory properties, with an IC₅₀ of more than 40 µM and a percent inhibition of 64.44%. According to the docking study, derivative 60, the most active compound, exhibits binding energies of -10.5 kcal/mol and -11.2 kcal/mol for COX-1 and COX-2, respectively [141]. A range of triazoles modified with perimidines was synthesized, and their anti-inflammatory properties were evaluated. In contrast to ibuprofen, Compound 61 outperformed and was able to suppress inflammation, reducing pro-inflammatory cytokines (TNF-α and IL-6) by 49.26%. Furthermore, a mechanism similar to naproxen was discovered by docking investigations of compound 61 into the COX-2 binding site [142]. Two distinct series of 2’-hydroxychalcone-triazole hybrid molecules were synthesized, and their anti-inflammatory properties were assessed in vivo and in vitro. Most medications showed selective inhibition of COX-2. The COX-2 (IC₅₀ = 0.052 µM) and 15-LOX (IC₅₀ = 1.68 µM) enzymes were efficiently inhibited by compound 62. The experimental results were validated by a docking study conducted across the active areas of 15-LOX and COX-2 [143]. The anti-inflammatory properties of many pyridin-3/4-yl-thiazolo[3,2-b][1,2,4] triazole compounds were investigated. A few of the synthetic substances seemed to be useful as anti-inflammatory medications. Stronger anti-inflammatory effectiveness than diclofenac was shown by the thiazolo[3,2-b][1,2,4]triazole derivative 63 (inhibition percentage: 46.53% comparable to diclofenac) [144]. The anti-inflammatory effects of 1, 2, and 3 triazole compounds connected by 1, 3-thiazoline were designed, synthesized, and evaluated. According to the findings, compound 64 exhibited the greatest anti-inflammatory properties (inhibition (%): 78.91%), matching the effects of diclofenac [145]. New 1,2,4-triazole 65 derivatives were synthesized for their anti-inflammatory activity assessment. Three adequate steps led to the synthesis of 1,2,4-triazole compounds (SPG1-5) through hydrazide formation of ibuprofen, followed by cyclization to the 1,2,4-triazole nucleus, and finally Schiff’s base synthesis. An in vitro anti-inflammatory assay evaluated the compounds using albumin denaturation and protease action inhibition test protocols. The highest inhibition rate (62.44 ± 2.889%) of albumin occurred when using SPG4 at a concentration of 500 g/mL yet all substances exhibited a concentration-dependent inhibitory effect on albumin. SPG4 decreased protease activity by 46.63 ± 3.211% at 500 g/mL and this antiprotease effect increased with growing dosage concentrations [146]. The p38 MAP kinases participate as key elements in various inflammatory medical conditions. Fourteen compounds of 4-((2-cyclohexyl-4,5-diphenyl-1H-imidazol-1-yl) methyl)-1-phenyl 66 hybrids have been prepared by click reaction through linking 1,2,3 triazole molecules together. The spectral analysis confirmed the chemical composition of every final compound in this study. Final compounds demonstrated the best inhibitory activity against p38 mitogen-activated protein kinase (MAPK) with IC₅₀ values at 222.68±20.69 nM - 241.70±20.51 nM, respectively. Meanwhile, compounds 7d and 7e indicated relevant activity against the prototype drug adezmapimod (SB203580) with an IC₅₀ value of 257.13±23.94 nM [147]. Antiinflammatory activities exhibited by Triazoles moieties have been shown in Figure 14.

Close

Figure 14.

Antiinflammatory triazole-based moieties.

Export to PPT

3.7. Analgesics

Triazole derivatives were prepared using microwave technology, and their efficacy was studied in vivo. Compound 67 significantly reduced pain in all studies. [148]. Alkaloid lupinine’s quinolizine-based 1,2,3-triazole backbone was affected considerably in pain. Compounds 68 with a hydroxymethyl group at the triazole ring’s C-4 position exhibited a 58% reduction in the animals’ pain response, surpassing the analgesic effectiveness of lupinine and diclofenac sodium, the reference medication [149]. The analgesic efficacy of disubstituted triazole compounds of nor-codeine was tested in vitro along with in vivo studies, and the outcomes of the experiments were compared to docking studies. Synthetic pharmacophores showed encouraging findings; compound 69 had significant analgesic efficacy, with an ED50 of 8.68 mg/kg, greater than codeine. Furthermore, docking studies demonstrated a strong agreement with experimental findings. Compound 69 demonstrated the highest docking scores for S and R diastereomers, at −9.90 and −10.84 kcal/moL [150]. Soluble epoxide hydrolase (sEH) enzyme inhibition assays were performed in vitro and in vivo media, and compound 70 was declared more effective than sEH enzymes (sEH=1. 09 nM). In addition, the in vivo screening tests showed a higher anti-analgesic effect (55. 97–50.00%), proving their effective efficacy as compared to other derivatives [151]. This work was aimed at elucidating the analgesic properties of some newly synthesized triazolodiazepine derivatives. An investigation into the analgesic potential yielded promising results for the sample substances. Among all the compounds, compound 71, which contains chlorine, exhibited a relatively higher activity of 46% compared to other derivatives [152]. Compound 72 showed a very significant analgesic effect with a percent inhibition value of 89%, which was higher than in the case of standard medication acetylsalicylic acid. Additionally, molecular docking experiments have indicated that compound 72 exhibits a favorable binding affinity to the protein [153]. Benzylidene analogue of a sulfur-based heterocyclic compound was synthesized, while compound 73 had substantial analgesic potential, resulting in 80% inhibition [154]. The compound 4H-1,2,4-triazole-3-thiols was produced and tested using the writhing and tail-flick assays. Most compounds exhibited noteworthy pharmacological potential, and compound 74 had the highest level of analgesic potential [155]. New dipeptides 75 were synthesized by combining β-triazolalanines with (L)-α-amino acids while developing conditions that ensured the purity levels of both chemical structure and optical configuration in the final reaction products. Molecular docking revealed the intermolecular connections between dipeptides when binding to potential targets. Analysis of selected dipeptides through studies determined their character as analgesic substances through tail-flick testing, which revealed antinociceptive properties in certain compounds. The docking setup shows therapeutic structure fitments that bond to nAChRs in both active and allosteric positions. The docking scores identified Trp derivatives as well as Tyr derivatives as top candidates, yet the in vivo assessment revealed that the glycine derivative exhibited the strongest antinociceptive activity [156]. New 15 diaryl-1,2,4-triazolo[3,4-a]pyrimidine 76 hybrids served as dual COX-2/sEH in vitro inhibitors after their synthesis. The COX-2 inhibitor potency of compounds surpasses all others (IC₅₀ = 10.50 μM - 15.20 μM) alongside high selectivity versus COX-2 (value = 13 - 25), while celecoxib displays lower values (IC₅₀ = 42 μM, selectivity of 8). The in vitro testing of compounds analyzed their 5-LOX inhibitory properties. Compounds functioned as the most potent COX-2 selective inhibitors to inhibit 5-LOX activity better than the standard quercetin reference through IC₅₀ studies (2.90 and 3.05 μM, respectively). The IC₅₀ values of compounds against sEH stood at 2.20 nM - 3.20 nM [157]. The most active analgesic chemical Structures of triazoles have been exhibited in Figure 15.

Close

Figure 15.

Potent triazole-based compounds as analgesic agents.

Export to PPT