Triazole Ring System Research Articles

1,5-Disubstituted-1,2,3-Triazoles as GABA analogues: Synthesis, QSAR and biological evaluation as Pseudomonas fluorescens GABA-AT inhibitors

We report the synthesis of a new series of γ-aminobutyric acid (GABA) analogues as possible GABA-AT inhibitors, where the nitrogen at the Ƴ-position is contained in a 1,5-disubstituted-1,2,3-triazole ring system. The triazole ring system was assembled by the Ru(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (RuACC) protocol. GABA-AT inhibition activity was predicted by means of a QSAR model that was constructed in this work. Different molecular descriptors families were employed for its construction, like steric type (Wap and PW5), solubility type (ΔPSA), and electronic type (ΔTriazole3). Additionally, a similarity analysis based on the electronic profile of 1,5-triazole and 1,4-triazole GABA analogues was done to support the QSAR predictions. Finally, the three best candidates were biologically tested as Pseudomonas fluorescens GABA-AT inhibitors showing an inhibition percent compared to FDA approved inhibitors.

An efficient total synthesis of a natural Penipanoid A

Natural products with heterocyclic core units are ample and widespread in nature, with many compounds exhibiting promising therapeutic properties. Penipanoid A (1) is a triazole based natural product isolated from the marine sediment derived fungus Penicillium Aneum SD-44 and exhibits the cytotoxicity and antimicrobial activity. Structurally, it features a 1,2,4-triazole motif. Herein, we report an efficient total synthesis of Penipanoid A (1) by a multi-component reaction involving formation of a triazole ring system as the key fragment starting from 4-methoxyphenyl acetic acid. Deprotection of the methoxy protected compound 2 provided the required natural product 1.

Design, synthesis, in vitro and in silico studies of some novel triazoles as anticancer agents for breast cancer

Against the increasing incidence of breast cancer in postmenopausal women in recent years, a few clinically approved inhibitors and their side-effect profiles indicate the need for the development of new aromatase inhibitors. In this study, carried out to develop a new aromatase inhibitor, the triazole ring system was preferred because of its known activity in the field. The triazole ring, which is in the structure of the most commonly used aromatase inhibitors such as anastrazole and letrazole, was synthesized from the thiourea residue. Inhibitor structures were elucidated using the 1H-NMR, 13C-NMR, 2D-NMR, and HRMS spectroscopic methods. A cytotoxicity (MTT) test was performed to determine the anticancer activity of the compounds on breast (MCF7) carcinoma cell type. In addition, to determine selectivity of their action, the final compounds were screened against a healthy NIH3T3 cell line (mouse embryonic fibroblast cells). In terms of the MTT assay, it was observed that the calculated IC50 values of compound 5e for the NIH3T3 cell line were found to be higher than for the MCF7 cell lines. Considering the viability results, it was found that the selected compound 5e showed a favorable safety profile and that it has anticancer activities. It was determined by in vitro studies that compound 5e showed inhibition potential on the aromatase enzyme with an IC50 = 0.028 μM value. The docking study of compound 5e revealed that there is a strong interaction between the active sites of the human aromatase enzyme and the analyzed compound.

A Facile Total Synthesis of Mubritinib

AbstractA five-step, practical, and concise total synthesis of mubritinib is described. The synthesis utilized Friedel–Crafts acylation, click reaction, reduction, and demethylation for the construction of the triazole ring system as key steps. Another important feature of this synthesis is the Bredereck oxazole synthesis. The main advantages of this process are the improved yield and decreased number of reaction steps, which paves the way for the industrial-scale synthesis of mubritinib.

Synthesis and Evaluation of Schiff Bases of 4-Amino-5-(chlorine substituted phenyl)-4H-1,2,4-triazole-3-thione as Antimicrobial Agents

Triazole ring system has attracted a continuously growing interest of synthetic organic chemists and those dealing with the medicinal compounds due to its versatile potential to interact with biological systems. Schiff bases are also considered as one of the most biologically active compounds. The aim of the present study was to synthesize new Schiff bases bearing triazole nucleus and to assess their antimicrobial activities. Four new Schiff base derivatives of 1,2,4-triazole-3-thione were synthesized by combining two different pharmacophores viz. triazole nucleus and Schiff base moiety and were characterized by spectral techniques (UV, FT-IR, and NMR). The Schiff bases were evaluated for antibacterial (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) and antifungal (Candida albicans) activities. The synthesized compounds exhibited good to moderate activities against different strains of bacteria and fungi tested.

DFT, molecular docking and experimental FT-IR, laser-Raman, NMR and UV investigations on a potential anticancer agent containing triazole ring system

The experimental FT-IR, Ra, NMR, and UV spectral data along with the theoretical quantum chemical calculations for 5-methyl-1-(4-methylphenyl)-Nʹ-[1-(thiophen-2-yl)ethylidene]-1H-1,2,3-triazole-4-carbohydrazide were investigated in detail. For the theoretical computations, the DFT/B3LYP functional and 6–311++G(d,p) basis set was used in the ground state and the assignments of harmonic vibrational wavenumbers were carried out using potential energy distribution (PED) based on the use of the VEDA4 software. Additionally, the analyses of the Hirshfeld surface, frontier molecular orbital (HOMO-LUMO), UV based on the IEFPCM solvent model, MEP and NLO were performed for the optimized structure. Finally, the molecular docking between the molecule and protein-PDB:2KCE was investigated using the AutoDock Vina program. The compound was found to be a good potential anticancer due to its binding energy and affinity for protein active sites.

1,4‐Disubstituted‐1,2,3‐triazole GABA Analogues: Synthesis, In Vitro Evaluation, Quantum QSAR and Molecular Docking against Pseudomonas fluorescens GABA‐AT

AbstractWe report the synthesis of a new series of γ‐aminobutyric acid (GABA) analogues where the nitrogen at the ɣ‐position is contained in a 1,4‐disubstituted‐1,2,3‐triazole ring system. The triazole ring system was assembled by the Cu(I)‐catalyzed alkyne‐azide 1,3‐dipolar cycloaddition (CuACC) protocol. We have identified two active compounds with 43 and 59 % inhibition respectively. A descriptive quantum QSAR study was carried out to correlate this activity with the structural changes in the GABA scaffold. The inhibitory activity of the compounds is related to the electronic properties of the triazole ring and substituents. The interaction with P. fluorescens GABA‐aminotransferase (GABA‐AT) was evaluated by molecular docking, using a homology model of the biological target. One compound showed the best interaction energy, the thiophene‐ substituted triazole 26 c, with a value that correlates well with the experimental inhibition results. The triazole ring is determinant for a proper orientation for interaction with the GABA‐AT enzyme. In addition, the molecular docking revealed the importance of a hydrophobic pocket near the PLP prosthetic group and how this pocket can be used to improve the inhibitory activity of GABA analogues. Human GABA‐AT molecular docking studies of these analogues showed their great potential as competitive inhibitors of this enzyme.

Application of triazoles as bioisosteres and linkers in the development of microtubule targeting agents.

The triazole ring system has emerged as an exciting prospect in the optimization studies of promising lead molecules in the quest for new drugs for clinical usage. Several marketed drugs possess these versatile moieties that are used in a wide range of medical indications. This stems from the unique intrinsic properties of triazoles, which impart stability to the basic pharmacophoric unit with an added advantage of being a bioisostere of different chemical functionalities. In the last decade, the use of triazoles as bioisosteres and linkers in the development of microtubule targeting agents has been extensively investigated. The present review highlights the advances in this promising area of drug discovery and development.

2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-1-naphthaldehyde

In the title compound, C21H17N3O2, the triazole ring system is inclined at dihedral angles of 4.14 (18) and 69.24 (11)° with the naphthalene ring system and phenyl ring, respectively. In the crystal, molecules are linked by C—H...O hydrogen bonds into double columns propagating along the b-axis direction.

Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation.

Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects.Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition.In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.

Integrating regression and classification-based QSARs with molecular docking analyses to explore the structure-antiaromatase activity relationships of letrozole-based analogs

Aromatase is a multienzyme complex responsible for the biosynthesis of estrogen and its level has been found higher in breast cancer. Although the designing strategy of aromatase inhibitors (AIs) has continued for more than four decades, it may still be in demand to design highly effective and less toxic AIs. In this study, several chemometric approaches have been used to explore the important structural features of a series of letrozole-based analogs for their promising aromatase inhibitory activity. All techniques are statistically validated individually and in turn, validated with each other along with the structure–activity relationship (SAR) observations. The imidazole ring has been found to interact with the heme iron, whereas the triazole ring system has not shown any interaction. Moreover, imidazole function is better than 1,2,3-triazole, whereas 1,2,3-triazole is better than the 1,2,5-triazole ring system. Additionally, a bulky aryl substitution in the azole ring along with the orientation of the azole nitrogens and the cyanophenyl function has an essential role in the inhibition of aromatase. Furthermore, a cyano group substituted at the phenyl moiety interacts with Arg115, Met374, and Ser478 at the enzyme active site to form hydrogen bonding interactions. These observations are useful for designing potential AIs in the future.

Azidoperfluoroalkanes: Synthesis and Application in Copper(I)-Catalyzed Azide-Alkyne Cycloaddition.

We report an efficient and scalable synthesis of azidotrifluoromethane (CF3 N3 ) and longer perfluorocarbon-chain analogues (RF N3 ; RF =C2 F5 , n C3 F7 , n C8 F17 ), which enables the direct insertion of CF3 and perfluoroalkyl groups into triazole ring systems. The azidoperfluoroalkanes show good reactivity with terminal alkynes in copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), giving access to rare and stable N-perfluoroalkyl triazoles. Azidoperfluoroalkanes are thermally stable and the efficiency of their preparation should be attractive for discovery programs.

Azidoperfluoroalkanes: Synthesis and Application in Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition

AbstractWe report an efficient and scalable synthesis of azidotrifluoromethane (CF3N3) and longer perfluorocarbon‐chain analogues (RFN3; RF=C2F5, nC3F7, nC8F17), which enables the direct insertion of CF3 and perfluoroalkyl groups into triazole ring systems. The azidoperfluoroalkanes show good reactivity with terminal alkynes in copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC), giving access to rare and stable N‐perfluoroalkyl triazoles. Azidoperfluoroalkanes are thermally stable and the efficiency of their preparation should be attractive for discovery programs.

4-[(4-Hydroxymethyl-2H-1,2,3-triazol-2-yl)methyl]-6,8-dimethyl-2H-chromen-2-one

In the title compound, C15H15N3O3, the dihedral angle between the triazole ring and coumarin ring system [r.m.s. deviation = 0.040 Å] is 77.40 (6)°. The O atom of the hydroxymethyl group deviates from the triazole ring plane by 1.345 (1) Å. In the crystal, inversion dimers linked by pairs of O—H...O hydrogen bonds generate R 2 2(22) loops; C—H...O and C—H...N interactions link the dimers into a three-dimensional network.

Novel Armed Pyrazolobenzothiazine Derivatives: Synthesis, X-Ray Crystal Structure and POM analyses of Biological Activity Against Drug Resistant Clinical Isolate of Staphylococcus aureus

Novel structural hybrids of pyrazolobenzothiazine and triazole ring systems have been prepared to observe a synergistic effect of the two ring systems. The methodology involves condensation of pyrazolobenzothiazine rings with methyl chloroacetate, followed by hydrazide formation. The hydrazides were converted to triazoles through the formation of intermediate potassium salts of dithiocarbazate. The final compounds as well as intermediates were screened for their antibacterial activity against a multidrug resistant strain of Staphylococcus aureus. It was interesting to observe that dithiocarbazates (7a, 7b) and target triazoles (8a, 8b) exhibited antibacterial activity.

Fluorous 1,2,3-Triazol-4-ylmethyl Amines and Amine Derivatives for Novel Surfactant Applications

A series of fluorous surfactants with additional functionality were generated through the attachment of substituents at the amino nitrogen atom of the surfactant moiety. Examples of molecules containing one and two triazole ring systems were synthesized through N-alkylation and N-acylation strategies.

ChemInform Abstract: Microwave Assisted Synthesis of Triazolobenzoxazepine and Triazolobenzoxazocine Heterocycles.

Abstract Intramolecular click chemistry was utilized to effect synthesis of the benzofused, triazole ring systems. The trimethylsilyl group was found to impede the reaction progress, and therefore, conditions employing in situ removal of the TMS group coupled with microwave irradiation give the penultimate targets with good conversion.

Microwave assisted synthesis of triazolobenzoxazepine and triazolobenzoxazocine heterocycles

Intramolecular click chemistry was utilized to effect synthesis of the benzofused, triazole ring systems. The trimethylsilyl group was found to impede the reaction progress, and therefore, conditions employing in situ removal of the TMS group coupled with microwave irradiation give the penultimate targets with good conversion.

Synthesis of new 4-(2,5-dimethylpyrrol-1-yl)/4-pyrrol-1-yl benzoic acid hydrazide analogs and some derived oxadiazole, triazole and pyrrole ring systems: a novel class of potential antibacterial, antifungal and antitubercular agents

A series of 4-(2,5-dimethylpyrrol-1-yl)/4-pyrrol-1-yl benzoic acid hydrazide analogs, some derived 1,3,4-oxadiazoles, 5-substituted-4-amino-1,2,4-triazolin-3-thione and 2,5-dimethyl pyrroles have been synthesized in good yields and structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass spectral and elemental analysis. These compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activities against Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. Twelve of these compounds displayed good antimicrobial activity, with a minimum inhibitory concentration (MIC) values 1–4 μg mL−1. Several compounds 4, 8d, 9, 12c–d and 12f–h exhibited good in vitro antitubercular activity with MIC values 1–2 μg mL−1. Further, some title compounds were also assessed for their cytotoxic activity (IC50) against mammalian Vero cell lines and A549 (lung adenocarcinoma) cell lines using MTT assay method. The results reveal that these compounds exhibit antitubercular activity at non-cytotoxic concentrations. Synthesis, spectral studies and antibacterial, antifungal and antitubercular activities of a novel series of pyrrole derivatives are described