Triazole-based Compounds Research Articles

Exploration of triazole derivatives, SAR profiles, and clinical pipeline against Mycobacterium tuberculosis.

Tuberculosis is a highly infectious disease and it is a global threat in particular affecting people from developing countries. It is thought that nearly one-third of the global population lives with this causative bacterium in its dominant form. The spread of HIV and the development of resistance to both multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) aggravates the spread of the disease and needs novel drugs which combat this disease effectively. Triazole-containing anti-tubercular drugs are promising and need further tuning to develop as a potent scaffold for tuberculosis. In this review, we highlight the structural activity relationships of triazole-containing drugs and detailed understanding for the researchers in the field of medicinal chemistry to further explore these triazole-based compounds as well as synthesize new compounds for antitubercular activity against drug-sensitive and resistant strains.

Miniaturized click chemistry and direct screening facilitate the discovery of triazole piperazine SARS-CoV-2 Mpro inhibitors with improved metabolic stability.

The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design and develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on the efficient discovery of potent non-covalent non-peptide-derived Mpro inhibitors using miniaturized click chemistry and direct screening. Based on the privileged piperazine scaffold, 68 triazole-containing derivatives were assembled and screened. Notably, representative compound C1N46 (IC50 = 1.87 μM, EC50 = 6.99 μM, CC50 > 100 μM) displayed potent inhibition activity against Mpro and showed promising anti-SARS-CoV-2 properties in vitro. Additionally, C1N46 exhibited improved liver microsome stability compared to lead compound GC-14. Docking studies predicted a multi-site binding mode of the triazole-based compounds. In conclusion, our studies validate the efficacy and feasibility of click chemistry in rapidly discovering antiviral agents.

Identification of potential bi-triazole based antimalarial compounds and their effects against asexual stages of Plasmodium isolates

Malaria is a parasitic infection that can become severe and lead to a patient’s death, besides having records of resistance to treatment and only a few options to treat it, generating the need for more research on new antimalarial compounds. The present study aimed at evaluating the antiplasmodial activity of two synthetic compounds, through in vitro assays, and ex vivo assays. The in vitro studies demonstrated that the synthetic molecules presented inhibitory concentrations for 50% of the parasite population (IC50) of 4.4 and 6.3 µM against sensitive and resistant strains, respectively. Compound 3RJ was observed to act in the first 8h against young trophozoites. Regarding the ex vivo study, 3RJ didn’t behave similarly to the reference drug, but remained effective against the circulating strains of P. falciparum in the state of Rondônia, Brazil. The results observed demonstrate that these triazole-based compounds are promising candidates in the development of antimalarial drugs.

Review on Design and Development of Pyridyl Triazole Derivatives

Triazole-based compounds, which combine pyridine and triazole rings, are studied in the paper. Design and development of pyridyl triazole derivatives, along with their synthesis and biological activities. The study emphasizes how important these derivatives are to Pharmacology and agro chemistry. For coordination chemistry to advance, heterocyclic legends especially five-membered triazoles are essential. Because of their wide range of biological activities, triazoles Named for their three nitrogen atoms are significant. Pyridyl Triazoles are being researched for a number of therapeutic applications, and the addition of Pyridine improves these compounds therapeutic qualities.

Direct access of 4-acyl-1,2,3-triazoles from acetophenones: A synthetic shortcut for novel p.Phe508del-CFTR traffic correctors

Direct access of 4-acyl-1,2,3-triazoles from acetophenones: A synthetic shortcut for novel p.Phe508del-CFTR traffic correctors

Exploration of nonlinear optical properties of 4-methyl-4H-1,2,4-triazol-3-yl)thio)-N-phenylpropanamide based derivatives: experimental and DFT approach

Triazoles, nitrogen-containing heterocycles, have gained attention for their applications in medicinal chemistry, drug discovery, agrochemicals, and material sciences. In the current study, we synthesized novel derivatives of N-substituted 2-((5-(3-bromophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)thio)-N-phenylpropanamide and conducted a comprehensive investigation using density functional theory (DFT). These novel structural hybrids of 1,2,4-triazole were synthesized through the multi-step chemical modifications of 3-bromobenzoic acid (1). Initially, compound 1 was converted into its methyl-3-bromobenzoate (2) which was then transformed into 3-bromobenzohydrazide (3). The final step involved the cyclization of compound 3, producing its 1,2,4-triazole derivative (4). This intermediate was then coupled with different electrophiles, resulting in the formation of the final derivatives (7a–7c). Additionally, the characterization of these triazole-based compounds (7a, 7b, and 7c) were carried out using techniques such as IR, HNMR, and UV–visible spectroscopy to understand their structural and spectroscopic properties. The DFT study utilized M06/6-311G(d,p) functional to investigate geometrical parameters, HOMO–LUMO energies, natural bond orbital analyses, transition density matrix (TDM), density of states, and nonlinear optical (NLO) properties. The FMO analysis revealed that compound 7c exhibited the lowest band gap value (4.618 eV). Notably, compound 7c exhibited significant linear polarizability (4.195 > × 10–23) and first and second hyperpolarizabilities (6.317 > × 10–30, 4.314 × 10–35), signifying its potential for nonlinear optical applications. These NLO characteristics imply that each of our compounds, especially 7c, plays a crucial part in fabricating materials showing promising NLO properties for optoelectronic applications.

In-silico and in-vitro identification of triazole based compounds as potential EGFR inhibitors targeting lung cancer

ABSTRACT The use of FDA-approved drugs for the therapy of lung cancer through drug repurposing is a noteworthy approach. We retrieved all the FDA-approved triazole-based drugs from Drugbank and conducted docking-based virtual screening of the triazole-based FDA-approved drugs against the EGFR target. Deferasirox demonstrated hydrogen bonding interactions with residues Thr 830, Asp 831, Lys 721 and Met 769 of the EGFR-TKD receptor (PDB ID: 1M17) and Posaconazole showed hydrogen bonding with residues Met 769 and Glu 734 of the similar EGFR receptor along with the binding energies of −9.60, −9.50, kcal/mol respectively. The dock score for reference molecule found to be −6.70 (kcal/mol). Best two ligands (Deferasirox and Posaconazole) were selected on the basis of dock score from the virtual screening results for in vitro NRU assay using A549 cells to determine their cytotoxicity and cell viability. During the in vitro NRU experiment, Deferasirox and Posaconazole demonstrated IC50 values of 114.9 and 910.2 µM, respectively. MD simulations were performed to investigate the dynamic behaviour and stability, and interactions were compared to the standard inhibitor for the EGFR target. DFT studies were carried out to determine their molecular properties, including their electronic structure, bond lengths and bond energies. The results of the in silico and in vitro studies were analysed to assess the potential of Deferasirox and Posaconazole for use as anticancer agents in the mitigation of lung cancer symptoms. This study focused on repurposing FDA-approved triazole-based compounds to identify their potential as effective lung cancer treatments with anticancer properties.

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

The main aim of the current project was to investigate the effect of the linker size in 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives, known as a group of antiepileptic drug candidates, on their affinity towards voltage-gated sodium channels (VGSCs). The rationale of the study was based both on the SAR observations and docking simulations of the interactions between the designed ligands and the binding site of human VGSC. HYDE docking scores, which describe hydrogen bonding, desolvation, and hydrophobic effects, obtained for 5-[(3-chlorophenyl)ethyl]-4-butyl/hexyl-1,2,4-triazole-3-thiones, justified their beneficial sodium channel blocking activity. The results of docking simulations were verified using a radioligand binding assay with [3H]batrachotoxin. Unexpectedly, although the investigated triazole-based compounds acted as VGSC ligands, their affinities were lower than those of the respective analogs containing shorter alkyl linkers. Since numerous sodium channel blockers are recognized as antiepileptic agents, the obtained 1,2,4-triazole derivatives were examined for antiepileptic potential using an experimental model of tonic–clonic seizures in mice. Median effective doses (ED50) of the compounds examined in MES test reached 96.6 ± 14.8 mg/kg, while their median toxic doses (TD50), obtained in the rotarod test, were even as high as 710.5 ± 47.4 mg/kg.

HSV-1 Glycoprotein D and Its Surface Receptors: Evaluation of Protein-Protein Interaction and Targeting by Triazole-Based Compounds through In Silico Approaches.

Protein-protein interactions (PPI) represent attractive targets for drug design. Thus, aiming at a deeper insight into the HSV-1 envelope glycoprotein D (gD), protein-protein docking and dynamic simulations of gD-HVEM and gD-Nectin-1 complexes were performed. The most stable complexes and the pivotal key residues useful for gD to anchor human receptors were identified and used as starting points for a structure-based virtual screening on a library of both synthetic and designed 1,2,3-triazole-based compounds. Their binding properties versus gD interface with HVEM and Nectin-1 along with their structure-activity relationships (SARs) were evaluated. Four [1,2,3]triazolo[4,5-b]pyridines were identified as potential HSV-1 gD inhibitors, for their good theoretical affinity towards all conformations of HSV-1 gD. Overall, this study suggests promising basis for the design of new antiviral agents targeting gD as a valuable strategy to prevent viral attachment and penetration into the host cell.

Insight into non-nucleoside triazole-based systems as viral polymerases inhibitors

Viruses have been recognized as the etiological agents responsible for many pathological conditions ranging from asymptomatic infections to serious diseases, even leading to death. For this reason, many efforts have been made to identify selective viral targets with the aim of developing efficient therapeutic strategies, devoid of drug-resistance issues. Considering their crucial role in the viral life cycle, polymerases are very attractive targets. Among the classes of compounds explored as viral polymerases inhibitors, here we present an overview of non-nucleoside triazole-based compounds identified in the last fifteen years. Furthermore, the structure-activity relationships (SAR) of the different chemical entities are described in order to highlight the key chemical features required for the development of effective antiviral agents.

Azole-Based Compounds That Are Active against Candida Biofilm: In Vitro, In Vivo and In Silico Studies.

Fungal pathogens, including Candida spp., Aspergillus spp. and dermatophytes, cause more than a billion human infections every year. A large library of imidazole- and triazole-based compounds were in vitro screened for their antifungal activity against C. albicans, C. glabrata, C. krusei, A. fumigatus and dermatophytes, such as Microsporum gypseum, Trichophyton rubrum and Trichophyton mentagrophytes. The imidazole carbamate 12 emerged as the most active compound, showing a valuable antifungal activity against C. glabrata (MIC 1–16 μg/mL) and C. krusei (MIC 4–24 μg/mL). No activity against A. fumigatus or the dermatophytes was observed among all the tested compounds. The compound 12 inhibited the formation of C. albicans, C. glabrata and C. krusei biofilms and reduced the mature Candida biofilm. In the Galleria mellonella larvae, 12 showed a significant reduction in the Candida infection, together with a lack of toxicity at the concentration used to activate its antifungal activity. Moreover, the in silico prediction of the putative targets revealed that the concurrent presence of the imidazole core, the carbamate and the p-chlorophenyl is important for providing a strong affinity for lanosterol 14α-demethylase (CgCYP51a1) and the fungal carbonic anhydrase (CgNce103), the S-enantiomer being more productive in these interactions.

P-187 - Ga-68-labelling of quinuclidine triazole-based compound

P-187 - Ga-68-labelling of quinuclidine triazole-based compound

Novel 2-aryl-4-aryloxyquinoline-based fungistatics for Mucor circinelloides. Biological evaluation of activity, QSAR and docking study

Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazole-based compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the Csp2-O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment.

In Silico Identification and Validation of Organic Triazole Based Ligands as Potential Inhibitory Drug Compounds of SARS-CoV-2 Main Protease.

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

Unravelling the potency of triazole analogues for inhibiting α-synuclein fibrillogenesis and in vitro disaggregation.

A series of triazole-based compounds was synthesized using a click chemistry approach and evaluated for the inhibition of α-synuclein (α-syn) fibrillogenesis and its disaggregation. Compounds Tr3, Tr7, Tr12, Tr15, and Tr16 exhibited good effect in inhibiting α-syn fibrillogenesis confirmed by Thioflavin-T assay and fluorescence microscopy and α-syn disaggregation confirmed by fluorescence microscopy. Molecular docking was used to understand the plausible mechanism of the test compounds for inhibiting the α-syn fibrillogenesis and to verify the in vitro results. Compounds Tr3, Tr7, Tr12, Tr15 and Tr16 showed good binding interactions with the essential amino acid residues of α-syn. The compounds which were found to be good inhibitors or disaggregators had no toxic effects on the SH-SY5Y cell line. These compounds have the potential to be developed as therapeutic interventions against synucleinopathies including Parkinson's disease and Lewy body dementia.

Corrosion inhibition of mild steel in acidic medium by simple azole-based aromatic compounds

Many organic corrosion inhibitors are complex and may include complicated chemical structures, mixture of different species, or require numerous and tedious preparation steps. In this study, we demonstrate inhibition by triazole- and imidazole-based compounds, which are synthesized in a one-step method and possess austere chemical structures. The inhibition effect was studied on the corrosion of mild steel in 1.0 M HCl solution at 40 °C by electrochemical impedance spectroscopy (EIS), potentiodynamic polarization, and weight loss. Results from electrochemical measurements showed that the aromatic compounds were effective in inhibiting corrosion in acidic medium, such that the inhibition efficiency increased with increasing inhibitor concentration. The triazole-based compound had the best inhibitive performance (efficiency >90%), followed by the imidazole-based (~85%), at a concentration of 850 μM. These results were supported by analyses obtained from scanning electron and atomic force microscopy, which showed improved mild steel topology and decrease in surface roughness by up to a factor of five, and x-ray diffraction, which revealed the extent of oxide layer formation. In addition, the adsorption of a protective inhibitor layer on the metal surface was confirmed by Raman spectroscopy, while the underlying mode and mechanism were postulated based on a Langmuir adsorption isotherm and computational studies, which showed good correlation between the inhibitive ability and the electron donating and accepting capability of the compounds.

1,4-Disubstituted 1H-1,2,3-Triazoles for Renal Diseases: Studies of Viability, Anti-Inflammatory, and Antioxidant Activities.

Inflammation is a hallmark of many metabolic diseases. We previously showed that ferrocene-appended 1H-1,2,3-triazole hybrids inhibit nitric oxide (NO) production in in vitro models of lipopolysaccharide-induced inflammation in the BV-2 cell. In the present study, we explored the viability, anti-inflammatory, and antioxidant potential of ferrocene-1H-1,2,3-triazole hybrids using biochemical assays in rat mesangial cells (RMCs). We found that, among all the ferrocene-1H-1,2,3-triazole hybrids, X2–X4 exhibited an antioxidant effect on mitochondrial free radicals. Among all the studied compounds, X4 demonstrated the best anti-inflammatory effect on RMCs. These results were supplemented by in silico studies including molecular docking with human cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) enzymes as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Besides, two new crystal structures of the compounds have also been reported. In addition, combining the results from the inducible nitric oxide synthase (iNOS), cPLA2, COX-2, and matrix metalloproteinase-9 (MMP-9) enzymatic activity analysis and NO production also confirmed this argument. Overall, the results of this study will be a valuable addition to the growing body of work on biological activities of triazole-based compounds.

Synthesis, characterization and gravimetric studies of novel triazole-based compound

Abstract4-Amino-3-(2-bromo-5-methoxyphenyl)-1H-1,2,4-triazole-5(4H)-thione (ATH) was synthesized and characterized by nuclear magnetic resonance and Fourier-transform infrared as spectroscopical techniques and elemental analysis. ATH was studied for corrosion inhibition of mild steel in corrosive environment by means of weight loss technique, scanning electron microscopy and the adsorption isotherm. ATH demonstrates a superior inhibition efficiency against corrosion of mild steel. Adsorption data fit well to a Langmuir isotherm model.

Blue-phosphorescent bis-cyclometalated iridium complexes with aryl isocyanide ancillary ligands

Abstract The design of organometallic complexes with efficient blue phosphorescence remains a challenge in the field of optoelectronics. This paper describes a series of eight cationic, isocyanide-ligated bis-cyclometalated iridium complexes of the general formula [Ir(C^Y)2(CNAr)2](PF6), where C^Y is a triazole-based C^N cyclometalating ligand or an NHC-based C^C: cyclometalating ligand, and CNAr is an aryl isocyanide. The triazole- and NHC-derived cyclometalating ligands, in combination with the π-acidic isocyanide ancillary ligands, result in large HOMO–LUMO gaps and engender these compounds with photoluminescence in the blue region of the spectrum. The complexes are synthesized by a general synthetic procedure and isolated in moderate to good isolated yields, with a combination of NMR spectroscopy, mass spectrometry, and X-ray crystallography (for six of the eight compounds) establishing the identity and bulk purity of each compound. The redox properties of the compounds are studied by cyclic voltammetry, which provide evidence for the large HOMO–LUMO gaps that are critical for the blue photoluminescence. The triazole-based compounds are weakly luminescent in fluid solution at room temperature, and all complexes luminesce at 77 K in frozen solvent glass or at room temperature when immobilized in a transparent poly(methyl methacrylate) (PMMA) film. CIE coordinates for the photoluminescence spectra indicate pure blue emission for all compounds, with CIEy ≤ 0.15 for all but one compound.

Multifunctional Mono-Triazole Derivatives Inhibit Aβ42 Aggregation and Cu2+-Mediated Aβ42 Aggregation and Protect Against Aβ42-Induced Cytotoxicity.

Amyloid beta (Aβ) peptide aggregation is considered as one of the key hallmarks of Alzheimer's disease (AD). Moreover, Aβ peptide aggregation increases considerably in the presence of metal ions and triggers the generation of reactive oxygen species (ROS), which ultimately leads to oxidative stress and neuronal damage. Based on the 'multitarget-directed ligands' (MTDLs) strategy, we designed, synthesized, and evaluated a novel series of triazole-based compounds for AD treatment via experimental and computational methods. Among the designed MTDLs [4(a-x)], the triazole derivative 4v exhibited the most potent inhibition of self-induced Aβ42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 μM and also disassembled the preformed Aβ42 aggregates significantly. In addition, compound 4v showed excellent metal chelating ability and maintained copper in the redox-dormant state to prevent the generation of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled the Cu2+-induced Aβ42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v did not show cytotoxicity and was able to inhibit the toxicity induced by Aβ42 aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of 4v with Aβ42 monomer and Aβ42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.