Trisubstituted Imidazoles Research Articles

Green synthesis and characterization of trisubstituted imidazole derivatives by an ecofriendly and efficient heterogenous nanocatalyst based on magnetite nanoparticles coated modified nanocellulose

In the present work, a nanocellulose based magnetic nanocomposite [(pH-PDA-DANC)@Fe3O4NPs] was synthesized by an ecofriendly and a simple protocol and characterized by means of different techniques such as Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Thermal Gravimetric Analysis (TGA), Scanning Electron Microscopy (SEM) equipped with an Energy Dispersive X-ray (EDX) probe and the Value Stream Mapping (VSM). The theoretical study of [(pH-PDA-DANC)@Fe3O4NPs] was investigated using Density Functional Theory (DFT) at the DFT-D3/ B3LYP/LanL2DZ level of theory to explore the nature of the interactions between the (pH-PDA-DANC) ligand and magnetite nanoparticles. The results indicate that the Fe3O4 nanoparticles form covalent bonds with the N-ring of the ligand. Then, it was used as a catalyst in the green and efficient procedure for one-pot multicomponent syntheses of imidazole derivatives by the condensation of benzil or 9.10-phenanthrenequinone, benzaldehyde derivatives and ammonium acetate. The catalytic reaction provided the synthesis of above imidazole derivatives with high reaction efficiency (80 %-98.1 %) in a short reaction time (3 h) and in presence of a minimum amount of ethanol. The identification and structure of imidazole derivatives was determined analyzing the 1H NMR (Nuclear Magnetic Resonance) and FTIR spectra. This procedure has several advantages compared to the conventional method such as the high yields, short reaction times, easy separation of the nanocatayst from the reaction mixture by using a magnet, and the reusability of the catalyst.

Solvent free green synthesis of tri-substituted imidazoles catalyzed by multi-doped ZnO-GCN nanocomposites

Applying the method of grinding, a series of 2,4,5-tri-substituted imidazole derivatives have been synthesised in highly satisfactory yields without the need for a solvent. In which grinding a mixture of benzoin or benzil and verities of the aldehydes in the existence of ammonium acetate, as a nitrogen source is successfully synthesized by using the efficient multi-doped ZnO- graphitic carbon nitride (g-C3N4) nanocomposite catalyst (Bi (4 %), Cr(1 %)-doped ZnO-GCN). In this protocol, comparative studies of the single-pot synthesis of 2,4,5-trisubstituted imidazole compounds are performed by using conventional and mechanochemical grinding methods with and without Bi-Cr-doped ZnO-GCN nanocomposite catalyst. All synthesised compoundswere characterised by their melting points, 1HNMR, and 13CMR spectra. In these studies, we found that grinding methodology with Bi-Cr-doped ZnO-GCN nanocomposite catalyst enhanced the reaction efficiencies with a short reaction time, excellent products, a cleaner reaction, and an easy workup. Additionally, the reaction follows green chemistry guidelines because it just requires the grinding of the substrates and catalyst in the absence of a solvent. Furthermore, the final product is simply purified by recrystallization as well as whenever needed using the column chromatography process.

Synthesis of Sulfur-Containing Trisubstituted Imidazoles by One-Pot, Multicomponent Reaction via Electron Donor-Acceptor Complex Photoactivation.

Rapid and efficient construction of multifunctionalized skeletons through a one-pot multicompound domino reaction has been recognized as a simple and practical strategy. Herein, a visible-light-enabled three-component reaction of isothiocyanates, isocyanides, and thianthrenium salt-functionalized arenes is presented, which affords a facile approach to sulfur-containing trisubstituted imidazoles in good yields with a broad substrate scope and excellent functional group tolerance. The byproduct thianthrene is recovered in quantity, thereby ultimately reducing the production of chemical waste. The developed methodology has potential value for the discovery and development of thioimidazole-based drugs.

Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors.

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 μM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression.

Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

One pot multicomponent synthesis of highly functionalized tri-substituted imidazole derivatives using TiO2-rGO nanocomposite as a recyclable catalyst

One pot multicomponent synthesis of highly functionalized tri-substituted imidazole derivatives using TiO2-rGO nanocomposite as a recyclable catalyst

Eco-friendly synthesis of various tri-substituted imidazole derivatives by using a novel functionalized NCP@SiO3PrNHPrSiO3TiO2 under solvent-free conditions

In this research, a novel NCP@SiO3PrNHPrSiO3TiO2 nano catalyst has been designed, synthesized and fully characterized using various analytical techniques such as; XRD, FT-IR, SEM, EDS, BET and TG analyses. The catalytic activity of NCP@SiO3PrNHPrSiO3TiO2 was also employed for the synthesis of tri-substituted imidazoles via three-component condensation reactions of aldehydes, benzyl and NH4OAc under solvent-free conditions. This synthesis features environmentally benign, short reaction time, efficiency, and feasibility of large-scale synthesis compared to classical reactions.

Fe(III), Ni(II), and Cu(II)-moxifloxacin-tri-substituted imidazole mixed ligand complexes: Synthesis, structural, DFT, biological, and protein-binding analysis

Herein, three new mixed-ligand complexes were synthesized through the reaction of Fe(III), Ni(II) and Cu(II) with moxifloxacin (MOX) in the presence of tri-substituted imidazole (TSI) to investigate their antibacterial, antifungal, and antioxidant potential. Elemental analysis, molar conductivity, electronic spectra, infrared spectroscopy, mass spectrometry, magnetic studies, thermal gravimetric investigations have been utilized for insuring the chelation process and structural elucidation. Results revealed that MOX and TSI interact with the metal ions via the (carbonyl oxygen and the carboxylic oxygen) and (hydroxyl oxygen and imidazole-ring nitrogen) atoms for MOX, and TSI, respectively. Octahedral geometries have been proposed for the Fe(III), Ni(II) complexes, while a distorted tetrahedral geometry was proposed for the Cu(II) complex. The proposed structures had been optimized via Density functional theory (DFT) calculations. Moreover, the frontier molecular orbitals (FMOs), in terms of HOMO and LUMO, and the molecular electrostatic potential (MEP) were obtained. Furthermore, the energy gap, chemical hardness, softness, chemical potential, electrophilicity index were evaluated. The antimicrobial potential was in vitro investigated against some common pathogenic bacterial and fungal strains; moreover, the antioxidant activity was evaluated using DPPH method. Results revealed that the three synthesized complexes had high antimicrobial activity against all tested phytopathogens and a significant antioxidant potential, compared to the free ligands. Furthermore, the in vitro potential was validated utilizing molecular docking investigation against four target receptors: 5JQ9, 6CLV, 3CKU, and 5IJT. The molecular docking results showed that Fe(III), Ni(II), and Cu(II) complexes had the highest activity towards the 5JQ9, (6CLV and the 3cku), and 5IJT receptors, respectively.

Substituent-Controllable Cascade Regioselective Annulation of β-Enaminones with N-Sulfonyl Triazoles for Modular Access to Imidazoles and Pyrroles.

A controllable synthesis of trisubstituted imidazoles and pyrroles has been developed through rhodium(II)-catalyzed regioselective annulation of N-sulfonyl-1,2,3-trizaoles with β-enaminones. The imidazole ring was formed through a 1,1-insertion of the N-H bond to α-imino rhodium carbene, followed by a subsequent intramolecular 1,4-conjugate addition. This occurred when the α-carbon atom of the amino group was bearing a methyl group. Additionally, the pyrrole ring was constructed by utilizing a phenyl substituent and undergoing intramolecular nucleophilic addition. The mild conditions, good tolerance towards functional groups, gram-scale synthesis capability, and ability to undergo valuable transformations of the products qualify this unique protocol as an efficient tool for the synthesis of N-heterocycles.

Influence of halogen atoms and hydrogen bonds in the crystal structure of 1,2,4-trisubstituted imidazoles having haloaryl groups

A new family of trisubstituted imidazoles having the privileged 1-haloarylethanol group at position 1 was synthesized by a microwave-assisted reduction reaction of N-aroyilmethyl-imidazoles. Structures of halogenated precursors (4-FPh, 4-ClPh, 4-BrPh) and the reduction product 4-bromophenyl substituted were studied via single X-ray crystallography (SXRC) and computational calculations. The halogen atoms’ effect on the crystal structure was analyzed using electrostatic potentials mapped over Hirshfeld surfaces, allowing us to confirm that fluorine atoms do not form σ-holes; instead, these atoms have negative electrostatic potentials all over the atomic position favoring the formation of short CH‧‧‧F hydrogen bonds that are similar in length to classic hydrogen bonds. However, such σ-hole effects in chlorine and bromine atoms induce the formation of CCl‧‧‧π and C-Br‧‧‧O interactions in the absence of strong hydrogen bonding. This remark is confirmed in 4c, where the hydroxyl group forms strong OH‧‧‧N hydrogen bonds avoiding the bromine atoms to form other interactions apart from the typical CH‧‧‧Br contacts despite their potential behavior to induce other interactions via σ-holes.

Molecular Docking, Microwave-Assisted Synthesis, Characterization and Pharmacological Evaluation of 2,4,5-trisubstituted Imidazole’s

Introduction: Nitrogen containing heterocycles such as azoles have gained popularity in me-dicinal chemistry research due to their versatile pharmacological activities. Imidazole’s are one such class of adaptable compounds. The aim of the study was to explore pharmacological activities of 2,4,5-trisubstituted imidazole’s and also to develop a novel method of synthesis using microwave chemistry. Methods: In the present study, the in-silico studies of 2,4,5-trisubstituted imidazole’s was carried out to predict their anti-leishmanial as well as COX-2 inhibitory activity. Although, the results are not satisfacto-ry for the anti-leishmanial activity, the molecules showed comparable docking scores with standard celecoxib for the COX-2 inhibitory activity. Later, the microwave-assisted green synthesis of tri-substituted imidazole’s was attempted using green catalyst and solvent, molecular iodine and ethanol respectively. The synthesised derivatives (TG-1-4) were purified and characterised. Results: The derivatives were subjected to in-vitro COX-2 inhibitory assay, which showed good results. The molecules under study showed exemplary results against COX-2 PDB in molecular docking studies. A novel microwave-irradiation method was developed for the synthesis and also the in-vivo studies car-ried out for testing COX-2 inhibition was fruitful. Conclusion: In conclusion, the selected derivatives can be further studied in-vivo to develop new COX-2 inhibitors.

Trisubstituted Imidazole and N-Propargyl Imidazole Analogues: Synthesis, Characterization, In Silico Studies and Enzyme Inhibitory Properties

Trisubstituted Imidazole and N-Propargyl Imidazole Analogues: Synthesis, Characterization, In Silico Studies and Enzyme Inhibitory Properties

An effective and eco‐friendly sonochemical multicomponent synthesis of trisubstituted imidazoles via modified silica‐coated cobalt ferrite nanoparticles by tungstic acid

This research is providing a method for the synthesis of 2,4,5‐trisubstituted imidazole derivatives based on pursuing the green chemistry principles. Therefore, a one‐pot multicomponent cyclocondensation reaction through aldehyde interaction with ammonium acetate and 1,2‐diketone was carried out in EtOH:H2O solvent under ultrasound irradiation. This protocol was utilized as an eco‐effective synthetic route by applying CoFe2O4@SiO2@(‐CH2)3OWO3H nanocomposite as a nanocatalyst. The stabilized tungstic acid on 3‐chloropropyl anchored to SiO2‐coated CoFe2O4 magnetic nanoparticles was designed, prepared, and applied as a recyclable heterogeneous acid catalyst to attain high product yields and short reaction times. The structure of nanocatalyst was confirmed by using Fourier transform infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), field emission scanning electron microscopy (FE‐SEM), energy dispersive spectroscopy (EDS), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA), and Brunauer–Emmett–Teller (BET) techniques, and the obtained organic derivatives were examined through melting point, FT‐IR, and 1H NMR analyses.

One-pot synthesis, spectral characterization, biological evaluation, molecular docking studies and in silico ADME/Tox profiling of new 2,4,5 triaryl imidazole derivatives as anti tubercular agents

BackgroundTuberculosis still looms large on the global epidemiological radar and warrants continuous effort in the direction of developing new anti TB drugs to battle evolving resistance mechanisms of the causative agent Mycobacterium tuberculosis. MethodsIn the present paper, synthesis of n has been attempted. All the synthesized compounds were characterized by 1H-NMR, 13C-NMR, IR and Mass spectroscopy. Anti TB profile of the synthesized compounds were tested by MABA assay employing M.tb H37Rv strain. ResultsTwo compounds namely N-(2-acetoxy)-N-methyl-4-(4,5-diphenyl-1H-imidazole-2-yl) benzenamine and 2-(N-(4-(4,5-bis(4-methoxyphenyl)-1H-imidazole-2-yl)phenyl)-N-methylamino) ethanol exhibited impressive anti TB inhibitory potential with an MIC of 3.125 μg/mL. To visualize the binding interactions of the active compounds molecular docking studies were carried out on putative target M. tuberculosis Glutamine synthetase (MtGS) in complex with a trisubstituted imidazole. To ascertain their drug likeliness and safety profile in silico ADME/T prediction was performed on all the synthesized compounds. ConclusionThree compounds 1a, 2g and 2c exhibited good inhibitory potency against M.tb H37Rv and all the synthesized compounds also show promising antifungal activity.

An efficient and eco-compatible multicomponent synthesis of 2,4,5-trisubstituted imidazole derivatives using modified-silica-coated cobalt ferrite nanoparticles with tungstic acid.

The aim of this study has been to offer a method for the synthesis of 2,4,5-trisubstituted imidazole derivatives based on green chemistry principles. Therefore, a one-pot multicomponent cyclocondensation reaction through aldehyde interaction with ammonium acetate and 1,2-diketone under solvent-free conditions was utilized as an eco-effective synthetic route using CoFe2O4@SiO2@(-CH2)3OWO3H NPs as the catalyst. The stabilized tungstic acid on 3-chloropropyl-anchored SiO2-coated CoFe2O4 magnetic nanoparticles was designed, prepared, and applied as a recyclable heterogeneous acid catalyst to attain high product yield in a short reaction time. The nanocatalyst structure was confirmed using FT-IR, Raman, XRD, FE-SEM, EDX, VSM, and TGA techniques, and the organic product structures were examined by melting point, FT-IR and 1H NMR analyses.

Preparation and Characterization of NiCoFe2O4 Nanoparticles as an Effective Catalyst for the Synthesis of Trisubstituted Imidazole Derivatives Under Solvent-free Conditions.

In this study, NiCoFe2O4 nanoparticles were prepared and used as a reactive catalyst for the synthesis of trisubstituted imidazoles. The multicomponent reactions of aromatic aldehydes, benzil and ammonium acetate were carried out under solvent-free and conventional heating conditions. In this reaction, some imidazole derivatives with high purity, short reaction times and high yields were obtained. The prepared nanocatalyst was characterized by FT-IR, XRD, EDX, VSM and SEM techniques. Moreover, the organic products were identified by melting point, FT-IR and 1H NMR analyzes.

EAN (Ethyl Ammonium Nitrate): A Novel Catalyst for Synthesis of 2,4,5- Trisubstituted Imidazole and their Antibacterial Activity

EAN (Ethyl Ammonium Nitrate): A Novel Catalyst for Synthesis of 2,4,5- Trisubstituted Imidazole and their Antibacterial Activity

Conventional vs. Microwave-assisted Synthesis: A Comparative Study on The Synthesis of Tri-substituted imidazoles

Background: The organic and peptide synthesis, various nanotechnology, and biochemistry processes are being carried out using microwave irradiation. The use of microwaves for synthesis has increased in the past two decades. The microwave offers several advantages such as ease of handling, lesser reaction times, quality of the product, and eco-friendly, which is green. The conventional method of synthesis, on the other hand, requires a longer time, is difficult to handle and maintenance of temperature is also difficult. The use of microwave-assisted reactions over conventional methods is advantageous in medicinal chemistry research as they will be less time-consuming and crucial in drug discovery and development. On the other side, they might not work in bulk synthesis due to their limited capacity for loading the reaction mixture. Objective: The present work aims to compare reaction time, temperature and percentage of yield of the microwave-assisted synthesis method against the conventional method. Method: A novel, simple, and green method was developed for the synthesis of tri-substituted imidazoles by microwave irradiation. Both derivatives from conventional and microwave-assisted synthesis were characterized by IR spectroscopy, Mass spectrometry, and 1H-NMR spectroscopy. The same derivatives were also synthesized by the conventional method for comparison. Result: A comparison of both methods was made by comparing the reaction time and the percentage yield. It was found that microwave-assisted reactions produced greater yield in the minimal time, though at different reaction temperatures. Conclusion: It can be concluded from the present comparison study that the use of the microwave for synthesis provides numerous advantages; thus, newer molecules are developed quickly anthat are developed quickly. To further proceed in this direction and to produce evidences, synthesis of more derivatives may be required. The only disadvantage is that it cannot be used for bulk synthesis of the compounds.

Synthesis of Trisubstituted Imidazoles by Sulfonated Magnetic Cellulose-Nanoparticles

Key words imidazoles - nanoparticles - acid catalysis - diketones - aldehydes

Multicomponent Assembly of Trisubstituted Imidazoles and Their Photochemical Cyclization into Fused Polyheterocyclic Scaffolds

A straightforward route to a large and diverse library of trisubstituted imidazoles was established via a three-component reaction of 2-oxoaldehydes, 1,3-dicarbonyl compounds, and acyclic nitrogen bis-nucleophiles. The obtained products were subsequently explored in a photochemical cyclization yielding a variety of imidazole-fused polycyclic compounds.