Synthesis and antimicrobial activity of novel 1,4,5-triphenyl-1<Emphasis Type="Italic">H</Emphasis>-imidazol-[1,2,3]-triazole derivatives

Novel 1-phenyl-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole derivatives were synthesized by click chemistry reaction and screened for antimicrobial activity against grampositive and gram-negative bacterial and fungal species. All the compounds were characterized by ¹H and ¹³C NMR, IR, and mass spectral data. The results of antibacterial study indicated that 1-(4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, 1-(4-(4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone, 1-(2,6-dichloro-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, and 1-(2-methoxy-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole showed appreciable antibacterial activity while 1-(4-fluorophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy) methyl)-1H-1,2,3-triazole, 1-(2,6-dichloro-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, and 1-(4-methoxyphenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole emerged as the most potential antifungal agents.     

Homo-C-nucleoside analogs III. Studies on the base-catalyzed dehydrative cyclization of 4-(d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole

Treatment of 4-(d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole with one molar equivalent of 2,4,6-triisopropylbenzenesulfonyl chloride (TIBSCl) in pyridine solution afforded the homo-C-nucleoside analog; 4-(2,5-anhydro-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole in 54% yield and 4-(α-d-arabinopyranosyl)-2-phenyl-2H1,2,3-triazole analog in 3% yield. The 4-(5-O-triisopropylbenzenesulfonyl)-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was isolated as an intermediate and identified as its tetra-O-acetyl derivative. The 4-(5-chloro-5-deoxy-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was isolated as a byproduct. The structure and anomeric configuration of the products were determined by acylation, NMR spectroscopy, and mass spectrometry.     

Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids

Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogues was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analogue 5 bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivatives, depending on the nature of heterocycle. Replacement of the amide group of the first generation analogues by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.     

Discovery of 1,2,3-triazole-based fibroblast growth factor receptor modulators

To avoid production of a phospholipidosis-inducing metabolite, we replaced the amide structure of SUN13837 (1) with a 1,2,3-triazole. The resulting 1,2,3-triazole analog of 1 (compound 2) displayed greater neuroprotective activity than 1. Structural modification of 2 yielded compound 10, which showed improved neuroprotective activity and negligible mechanism-based inactivation against CYP3A4. In addition, installation of a methyl group at the 5-position of 1,2,3-triazole of 10 significantly boosted the neuroprotective activity. These 1,2,3-triazole derivatives displayed reduced phospholipidosis risk, sufficient systemic exposure, and high central nervous system penetration, and therefore may be potentially useful agents for the treatment of neurodegenerative diseases.     

Design,Synthesis, Antioxidant and Antibacterial Activities of Novel 2-((1-Benzyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-Triazol-4-yl)methyl)-5-(2<Emphasis Type="Italic">H</Emphasis>Chromen- 3-yl)-2H-Tetrazoles

1,4-Disubstituted 1,2,3-triazole derivatives of 2H-chromene-3-tetrazoles synthesized regioselectively by copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click reaction were characterized by ¹HNMR, ¹³C NMR, IR, and mass spectral data. These derivatives were screened for in vitro antioxidant activity using DPPH radical, H₂O₂ scavenging, and iron chelating activity methods and also evaluated for in vitro antibacterial activities against E. coli and S. aureus bacterial strains. The MIC and IC₅₀ values for all these compounds were found to match the docking scores and relevant binding energies with the receptor active sites. These results allows one to consider the compounds as leads for a new generation of antioxidant and antibacterial agents.     

Synthesis of 1H-1,2,3-triazole derivatives as new α-glucosidase inhibitors and their molecular docking studies

Inhibition of α-glucosidase is an effective strategy for controlling the post-prandial hyperglycemia in diabetic patients. For the identification of new inhibitors of this enzyme, a series of new (R)-1-(2-(4-bromo-2-methoxyphenoxy) propyl)-4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazole derivatives were synthesized (8a–d and 10a–e). The structures were confirmed by NMR, mass spectrometry and, in case of compound 8a, by single crystal X-ray crystallography. The α-glucosidase inhibitory activities were investigated in vitro. Most derivatives exhibited significant inhibitory activity against α-glucosidase enzyme. Their structure-activity relationship and molecular docking studies were performed to elucidate the active pharmacophore against this enzyme. Compound 10b was the most active analogue with IC₅₀ value of 14.2 µM, while compound 6 was found to be the least active having 218.1 µM. A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in 1H-1,2,3-triazole derivatives is responsible for this activity and can be used as anti-diabetic drugs. The molecular docking studies of all active compounds were performed, in order to understand the mode of binding interaction and the energy of this class of compounds.     

4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40–83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.     

Studies on Epimeric D-xylo-and D-lyxo-Tetritol-yl-2-phenyl-2H-1,2,3-triazoles. Synthesis and Anomeric Configuration of 4-(α- and β-D-Threofuranosyl)-2-phenyl-2H-1,2,3-triazole C-Nucleoside Analogs

Abstract

Treatment of 4-(D-xylo-tetritol-1-y1)-2-phenyl-2H-1,2,3-triazole (1) with one mole equivalent of tosyl chloride in pyridine solution, afforded the C-nucleoside analog; 4-(β-D-threofuranosyl)-2-phenyl-2H-1,2,3-triazole (2) in 55% yield, as well as the byproduct 4-(4-chloro-4-deoxy-D-xylo-tetritol-1-y1)-2-pheny1-2 H-1,2,3-triazole (4). Treatment of the epimeric 4-(D-lyxo-tetritol-1-y1)-2-pheny1-2H-1,2,3-triazole (6) with tosyl chloride in pyridine solution afforded the anomeric C-nucleoside analog; 4-(δ-D-threofuranosy1)-2-pheny1-2H-1,2,3-triazole (7) in 29% yield, as well as the byproduct 4-(4-chloro-4-deoxy-D-lyxo-tetritol-1-y1)-2-pheny1-2 H-1,2,3-triazole (9). Similar treatment of 1 and 6 with trifluoromethanesulfonyl chloride in pyridine solution afforded 2 and 7, respectively. The structure and anomeric configuration of these compounds were determined by acetylation, NMR, NOE, and circular dichroism spectroscopy, as well as mass spectrometry.     

Synthesis of novel (R)-4-fluorophenyl-1H-1,2,3-triazoles: A new class of α-glucosidase inhibitors

Diabetes is a non-communicable disease, which occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicates an increase in the trend of people diagnosed with Type 2 diabetes mellitus (T2DM). α-Glucosidase inhibitors are known to reduce the impact of carbohydrates on blood glucose level and prevent the digestion of carbohydrates. α-glucosidase inhibitors hold great potential for the treatment of T2DM. In search of better α-glucosidase inhibitors, a series of novel (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives were synthesized (6 and 8a-n) and evaluated for their α-glucosidase inhibitory activity in vitro. All new compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR, ESI-MS, and where applicable by single crystal X-ray diffraction (8 m). A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives has remarkable contribution in the overall activity. Molecular docking studies were carried out to investigate the binding mode of compounds within the active site of the α-glucosidase enzyme. Docking results are in complete agreement with the experimental finding. This study unravelled a new class of triazole derivatives with α-glucosidase inhibitory activity.     

1,2,3-Triazole fused with pyridine/pyrimidine as new template for antimicrobial agents: Regioselective synthesis and identification of potent N-heteroarenes

The 1,2,3-triazole ring fused with pyridine/pyrimidine was explored as new template for the identification of potential antimicrobial agents. The regioselective synthesis of these pre-designed N-heteroarenes was achieved via exploring the application of Buchwald’s strategy (i.e. C–N bond formation/reduction/diazotization/cyclization sequence) to the N-heteroarene system. Two of them showed promising antibacterial (comparable to streptomycin) and several showed potent antifungal (comparable to mancozeb) activities.     

Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression

The C/EBP-homologous protein (CHOP) acts as a mediator of endoplasmic reticulum (ER) stress-induced pancreatic insulin-producing β cell death, a key element in the pathogenesis of diabetes. Chemicals that inhibit the expression of CHOP might therefore protect β cells from ER stress-induced apoptosis and prevent or ameliorate diabetes. Here, we used high-throughput screening to identify a series of 1,2,3-triazole amide derivatives that inhibit ER stress-induced CHOP-luciferase reporter activity. Our SAR studies indicate that compounds with an N,1-diphenyl-5-methyl-1H-1,2,3-triazole-4-carboxamide backbone potently protect β cell against ER stress. Several representative compounds inhibit ER stress-induced up-regulation of CHOP mRNA and protein, without affecting the basal level of CHOP expression. We further show that a 1,2,3-triazole derivative 4e protects β cell function and survival against ER stress in a CHOP-dependent fashion, as it is inactive in CHOP-deficient β cells. Finally, we show that 4e significantly lowers blood glucose levels and increases concomitant β cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of small molecule inhibitors of CHOP expression that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes.     

Studies ON Epimeric-D-asabino-and-D-ribo-tetritol-1-yl-2-phenyl-2 H-1,2,3-triazoles. Synthesis and Anomeric Configuration of 4-(α-and β-D-Erythrofuranosyl)-2-phenyl-2 H-1,2,3-Triazole C-Nucleoside Analogs

Abstract

Treatment of 4-(D-arabino-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole (1) with one mole equivalent of tosyl chloride in pyridine solution, afforded the C-nucleoside analogs, 4-(α-D-erythrofuranosyl)-2-phenyl-2 H-1,2,3-triazole (2) in 25% yield, as well as the byproduct 4-(4-chloro-4-deoxy-D-arabino-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole(3). Treatment of the epimeric 4-(D-ribo-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole(8) with tosyl chloride in pyridine solution afforded the anomeric C-nucleoside analogs, 4-(β-D-erythrofuranosyl)-2-phenyl-2 H-1,2,3-triazole (9) in 23% yield. Similar treatment of 8 with trifluoromethanesulfonyl chloride in pyridine solution afforded 9. The structure and anomeric configuration of these compounds were determined by acylation, NMR, NOE, circular dichroism spectroscopy and mass spectrometry.     

Design and synthesis of 1H-1,2,3-triazoles derived from econazole as antitubercular agents

Econazole has been known to be active against Mycobacterium tuberculosis. We have designed and synthesized 1H-1,2,3-triazoles derived from econazole as antitubercular agents. The majority of triazole derivatives have been prepared by microwave-assisted click chemistry. It turned out that all of the prepared triazoles had no antifungal activities. However, most of the hydroxy-triazoles (6a and 10) apparently turned out to have antitubercular activities. Overall, hydroxy-triazoles 10 were more active than their corresponding ether-triazoles 11. While the MIC value of hydroxy-triazole 10d was as good as econazole (16 μg/mL), the MIC value of 10a was two-fold more active than econazole, suggesting that this 1H-1,2,3-triazole scaffold (3) could be further optimized to develop Mtb specific agents.     

Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity

A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with diverse substituted alkyl/perfluoroalkyl/aryl/aryl amide azides under Sharpless conditions. All the synthesized compounds 3 and 4 were screened for cytotoxic activity against four human cancer cell lines such as U937, THP-1, HL60 and B16-F10. Compounds 3e, 4g, 4i and 4j which showed promising activity have been identified.     

1,2,3-Triazole analogs of combretastatin A-4 as potential microtubule-binding agents

A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.     

Synthesis,anti-plasmodial and cytotoxic evaluation of 1H-1,2,3-triazole/acyl hydrazide integrated tetrahydro-β-carboline-4-aminoquinoline conjugates

A series of 1H-1,2,3-triazole/acylhydrazide-tethered tetrahydro-β-carboline-4-aminoquinoline conjugates was synthesized with an aim to study their anti-plasmodial structure-activity relationship. The presence of 1H-1,2,3-triazole-core along with a flexible alkyl chain length on aminoquinoline core has favourable influence on the anti-plasmodial activity against Chloroquine-resistant W2 strain of P. falciparum while the introduction of hydrazine core not only diminished the activities but also resulted in increased cytotoxicity against mammalian Vero cells.     

Design, synthesis, and preliminary biological evaluation of a novel triazole analogue of ceramide

The amide bond of ceramide was replaced by the non-hydrolyzable 1,2,3-triazole functionality. Click chemistry was employed for synthesis of the designed analogues. Our preliminary biological evaluation indicated that the amide moiety of ceramide is amenable to bioisosteric substitution with the triazole moiety. Some of the analogues were more potent than C2-ceramide as cytotoxic agents, and the observed cytotoxicity was possibly mediated through the induction of apoptosis.     

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using ‘click’ chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the ‘linker’ property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.     

Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents

Rapid and efficient synthesis of a phenyl-1H-1,2,3-triazole library enabled cost-effective biological testing of a range of novel non-steroidal anti-inflammatory drugs with potential for improved drug efficacy and toxicity profiles. Anti-inflammatory activities of the phenyl-1H-1,2,3-triazole analogs synthesized in this report were assessed using the xylene-induced ear edema model in mice. At least four analogs, 2a, 2b, 2c, and 4a, showed more potent effects than the reference anti-inflammatory drug diclofenac at the same dose of 25 mg/kg. To explore relationships between the structural properties of phenyl-1H-1,2,3-triazole analogs and their anti-inflammatory activities in xylene-induced ear edema, comparative molecular field analysis was performed, and pharmacophores showing good anti-inflammatory activities were identified based on an analysis of contour maps obtained from comparative molecular field analysis. The anti-inflammatory effect on the molecular level was tested by the expression of tumor necrosis factor-alpha induced COX-2 using Western blots. Because the addition of the analog 2c caused the expression change of TNF-α induced COX-2, the molecular binding mode between 2c and COX-2 was elucidated using in silico docking.     

Expanding the scope of ‘Click’ derived 1,2,3-triazole ligands: New palladium and platinum complexes

Using the ‘Click Protocol’ the new ligands 1-(cyclohexyl)-4-(2-pyridyl)-1,2,3-triazole (1), 1-(2-trifluoromethyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (2), 1-(4-hexyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (3), 1-(2-mercaptomethyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (4) and 1-(4-N,N-dimethylamino phenyl)-4-(2-pyridyl)-1,2,3-triazole (5) were prepared by reacting 2-ethynylpyridine with the corresponding azides. In the next step the ligands were reacted with suitable palladium and platinum precursors to yield the cis-dichloro-palladium complexes 1a-4a and platinum complexes 1b-4b. Investigation of the molecular structure of the free ligands 1 and 5 reveals the formation of infinite chains in the 3D structure which are governed by hydrogen bonds between the triazole units. Likewise the 3D structure of 1a shows infinite chains which are held together by multiple remarkably short C-H?Cl-Pd contacts. Electrochemical investigation of the free ligands by cyclic voltammetry showed irreversible reduction processes at highly negative potential. Upon metal complexation huge anodic shifts of the reduction potential were observed. To further characterize the electronic properties of all the compounds UV-Vis spectra were also analyzed.