Benzotriazole Chemistry Research Articles

Microwave-Assisted Synthesis of Tri-Substituted 1,3,5-Triazines from Metformin Using Benzotriazole Chemistry

A simple, metal-free, cost-effective, and eco-friendly protocol for the preparation of trisubstituted 1,3,5 triazine from metformin using benzotriazole chemistry is reported. Short reaction time, large-scale synthesis, easy and quick isolation of the product, and excellent yield are the main advantages of this procedure. Furthermore, the use of benzotriazole chemistry results in a product free from metal traces. Our optimized reaction condition and methodology overcome the challenges of using a metal catalyst, such as a longer reaction time, lower yields, and expensive starting materials.

Copper adatoms mediated adsorption of benzotriazole on a gold substrate

The adsorption of organic molecules on metal surfaces is often mediated by metal adatoms, however their effect on the geometry of the resulting supramolecular structure can be difficult to determine. Herein, the role played by reactive copper atoms in the adsorption chemistry of benzotriazole (BTAH), an organic corrosion inhibitor for copper well-known for forming adatom mediated supramolecular structures, on an inert substrate, Au(111), has been investigated in an ultra-high vacuum environment using a combination of complementary surface sensitive techniques and density functional theory calculations. Pseudo-ordered and hydrogen bonded flat-lying assemblies convert into ordered -[CuBTA]n- flat-lying organometallic species of well-defined stoichiometry upon addition of copper atoms from the gas phase onto an Au(111) surface, which has been pre-dosed with BTAH. The formation and characterisation of these organometallic species are discussed in the light of the experimental results and computational modelling. The combination of complementary experimental and computational methods is crucial in order to obtain a thorough characterisation of such a complex system. The final supramolecular structure shows previously unseen BTA phases, which are favoured by the adsorption distribution of copper adatoms on Au(111), and are stable up to 500 K.

Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates.

The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R2 = 0.926, 0.935; R2cvOO = 0.898, 0.915; R2cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates.

Ultrafast and selective labeling of endogenous proteins using affinity-based benzotriazole chemistry.

Chemical modification of proteins is enormously useful for characterizing protein function in complex biological systems and for drug development. Selective labeling of native or endogenous proteins is challenging owing to the existence of distinct functional groups in proteins and in living systems. Chemistry for rapid and selective labeling of proteins remains in high demand. Here we have developed novel affinity labeling probes using benzotriazole (BTA) chemistry. We showed that affinity-based BTA probes selectively and covalently label a lysine residue in the vicinity of the ligand binding site of a target protein with a reaction half-time of 28 s. The reaction rate constant is comparable to the fastest biorthogonal chemistry. This approach was used to selectively label different cytosolic and membrane proteins in vitro and in live cells. BTA chemistry could be widely useful for labeling of native/endogenous proteins, target identification and development of covalent inhibitors.

New Pyrazine Conjugates: Synthesis, Computational Studies, and Antiviral Properties against SARS-CoV-2.

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). We have developed a set of pyrazine‐based small molecules. A series of pyrazine conjugates was synthesized by microwave‐assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR‐CoV‐2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine‐triazole conjugates (5 d–g) and (S)‐N‐(1‐(benzo[d]thiazol‐2‐yl)‐2‐phenylethyl)pyrazine‐2‐carboxamide 12 i show significant potency against SARS‐CoV‐2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir).

Cover Picture: Renaissance of Ring‐Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle (Chem. Rec. 7/2020)

Cover Picture: Renaissance of Ring‐Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle (Chem. Rec. 7/2020)

An Efficient Greener Approach for N-Acylation of Amines in Water Using Benzotriazole Chemistry.

A straightforward, mild and cost-efficient synthesis of various arylamides in water was accomplished using versatile benzotriazole chemistry. Acylation of various amines was achieved in water at room temperature as well as under microwave irradiation. The developed protocol unfolds the synthesis of amino acid aryl amides, drug conjugates and benzimidazoles. The environmentally friendly synthesis, short reaction time, simple workup, high yields, mild conditions and free of racemization are the key advantages of this protocol.

Renaissance of Ring-Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle.

1,2,3-Benzotriazoles could undergo ring cleavage to form ortho-amino arenediazonium or α-diazo-imine species via a Dimroth-type equilibrium. Historically, the synthetic potential of this unique reactivity had remained underdeveloped. Recently, some new strategies have been developed to effect the ring-opening chemistry of benzotriazoles in more practical manners. A wide range of conceptually novel and synthetically useful reactions have been developed, which enable the access to diverse valuable heterocycles and ortho-amino arene derivatives. As one of the players in this field, our group has also contributed a series of intriguing transition-metal-catalyzed denitrogenative functionalizations of benzotriazoles. In this account, we aim to provide an overview of the ring-opening chemistry of benzotriazoles, with a focus on relevant works published in the past decade. In order to show a whole picture of the research field, some pioneering works in its developing history will also be discussed briefly.

Fluoroquinolone-3-carboxamide Amino Acid Conjugates: Synthesis, Antibacterial Properties And Molecular Modeling Studies.

Bacterial infections are considered as one of the major global health threats, so it is very essential to design and develop new antibacterial agents to overcome the drawbacks of existing antibacterial agents. The aim of this work is to synthesize a series of new fluoroquinolone-3-carboxamide amino acid conjugates by molecular hybridization. We utilized benzotriazole chemistry to synthesize the desired hybrid conjugates. All the conjugates were synthesized in good yields, characterized, evaluated for their antibacterial activity. The compounds were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Synthesized conjugates were tested for activity against medically relevant pathogens; Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27856) Staphylococcus aureus (ATCC 25923) and Enterococcus faecalis (ATCC 19433). The observed antibacterial experimental data indicates the selectivity of our synthesized conjugates against E.Coli. The protecting group on amino acids decreases the antibacterial activity. The synthesized conjugates are non-toxic to the normal cell lines. The experimental data were supported by computational studies.

One-pot synthesis of bi- and tricyclic heterocyclic compounds using benzotriazole chemistry

Microwave-mediated one-step synthesis of several bi- and tricyclic heterocycles via the intermolecular cyclization of N-acylbisbenzotriazoles with ortho-phenylenediamine in good yield is reported.

Synthesis and molecular modeling of antimicrobial active fluoroquinolone–pyrazine conjugates with amino acid linkers

Novel fluoroquinolone–pyrazine conjugates 7a–h with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antimicrobial bioassay showed that the synthesized bis-conjugates have antimicrobial properties comparable to the parent drugs. Compound 7h showed superior antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes (MIC=74.6μM and 149.3μM, respectively). This matched well with the estimated values obtained from 3D-pharmacophore and 2D-QSAR studies (MIC=67μM and 92.9μM, respectively).

Novel antibacterial active quinolone-fluoroquinolone conjugates and 2D-QSAR studies.

Novel, quinolone-fluoroquinolone conjugates 10a-f, 11a-f, 13a-f and 14a-f with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antibacterial bioassay showed the synthesized bis-conjugates exhibit anti-bacterial properties comparable with the parent drugs.

Synthesis and QSAR study of novel anti-inflammatory active mesalazine-metronidazole conjugates.

Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties.

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies.

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

Microwave assisted synthesis and QSAR study of novel NSAID acetaminophen conjugates with amino acid linkers

Novel, non-steroidal anti-inflammatory drug (NSAID), acetaminophen conjugates 6a–l with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates (6d, 6e, 6h, and 6k) exhibit more potent anti-inflammatory activity than their parent drugs, (b) the potent bis-conjugates show no visible stomach lesions in contrast to parent drugs which are highly ulcerogenic, and (c) that the potent bio-active compounds have no mortality rates or toxic symptoms at 5 fold the applied anti-inflammatory dosage. A statistically significant QSAR model describing the anti-inflammatory properties of 6a–l (N = 15, n = 3, R(2) = 0.891, R(2)cvOO = 0.770, R(2)cvMO = 0.796, F = 29.904, s(2) = 0.011) was obtained employing CODESSA-Pro that validated the observed bio-activity.

ChemInform Abstract: The Chemistry of Benzotriazole. Preparation, Characterization and Reactions of Novel Vicinal Dibenzotriazol-l-yl Derivatives of Benzotriazole and Glyoxal.

ChemInform Abstract: The Chemistry of Benzotriazole. Preparation, Characterization and Reactions of Novel Vicinal Dibenzotriazol-l-yl Derivatives of Benzotriazole and Glyoxal.

Combined Studies on the Surface Coordination Chemistry of Benzotriazole at the Copper Electrode by Direct Electrochemical Synthesis and Surface‐Enhanced Raman Spectroscopy

AbstractThe surface coordination chemistry of benzotriazole (BTAH) on a Cu electrode was investigated by electrochemical synthesis of surface complexes and in situ electrochemical surface‐enhanced Raman spectroscopy (SERS) in nonaqueous solution. Two different surface complexes were prepared in solution with or without triphenylphosphane (PPh3). A new mixed‐valence Cu–N cluster compound containing BTAH was synthesized by direct electrochemical oxidation of Cuin nonaqueous solutions with PPh3. The final product, Cu5Cl(BTA)5(PPh3)4 was crystallized and characterized by microanalysis and Raman spectroscopy together with X‐ray crystallographic determinations. The complex crystallized in a monoclinic space group (P21/n) with lattice parameters a = 16.739(2) Å, b = 18.919(2) Å, c = 31.042(4) Å, β = 103.194(3)°, V = 9571.0(19) Å3, R1 = 0.0704, wR2 = 0.1643. The results showed that the complex was a pentanuclear compound. The central CuII atom is coordinated to four equatorial and one axial BTA– ligands to form a distorted tetragonal pyramidal coordination polyhedron, whereas each surrounding CuI ion is in a distorted tetrahedral environment. The in situ SERS studies revealed that the BTA– ion was coordinated to a Cu surface through its two N atoms of the triazole ring to form a surface polymer complex of [Cu(BTA)]n, which suppressed the dissolution and oxidation of Cu effectively. The introduction of PPh3 blocked the surface coordination of BTAH with the electrode, and a complex of BTA– and PPh3 with Cu was formed in the bulk solution.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Direct Synthesis of Esters and Amides from Unprotected Hydroxyaromatic and -aliphatic Carboxylic Acids

A facile method for the activation of hydroxy-substituted carboxylic acids using benzotriazole chemistry without prior protection of the hydroxy substituents is presented. The N-acylbenzotriazole intermediates 2a-g, 6a-d, and 9a-c have been used for high-yielding synthesis of both aliphatic (3a-l) and aromatic (7a-h, 10a-f) hydroxy carboxamides. High yields of aromatic hydroxy esters 12a-h and 13a-i were obtained using either neat alcohols in neutral microwave conditions or nucleophilic alkoxides and the intermediate N-(arylacyl)benzotriazoles. Moderate yields were obtained in the case of aliphatic hydroxy esters 11a,b and thiolesters 11e-g from the intermediates 2a-c.

Solid-supported benzotriazoles. 2. Synthetic auxiliaries and traceless linkers for the combinatorial synthesis of unsymmetrical ureas.

Resin-bound benzotriazole chemistry applied to the solid-phase synthesis of arrays of unsymmetrical aryl ureas is described here. The chemistry assessment process, the monomer rehearsal, the preparation of a discrete library by automated parallel synthesis, the parallel purification protocol employing solid-phase scavenging, and the complete analytical characterization of the library components are also presented.

N-Benzotriazol-1-yl-methyl-1,2,3,4-tetrahydro-b-carboline

Katritzky's well-established chemistry of benzotriazole [1] was applied to the synthesis of 1,2,3,4- tetrahydro-b-carboline, which have been traditionally prepared by Pictet-Spengler condensation2, Fischer cyclisation and other methods3.[...]