Plausible PEPPSI catalysts for direct C-H functionalization of five-membered heterocyclic bioactive motifs: synthesis, spectral, X-ray crystallographic characterizations and catalytic activity.

In this study, a series of benzimidazolium salts were synthesized as asymmetric N-heterocyclic carbene (NHC) precursors. Nine novel palladium complexes with the general formula [PdX2(NHC)(pyridine)] were synthesized using benzimidazolium salts in the PEPPSI (Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation) theme. All synthesized Pd(ii) complexes are stable. The synthesized compounds were thoroughly characterized by respective spectroscopic techniques, such as 1HNMR, 13C NMR, FTIR spectroscopy, X-ray crystallography and elemental analysis. The geometric structure of the palladium N-heterocyclic carbene has been optimized in the framework of density functional theory (DFT) using the B3LYP-D3 dispersion functional with LANL2DZ as a basis set. The on/off mechanism of pyridine assisted Pd-NHC complexes made them the best C-H functionalized catalysts for regioselective C-5 arylated products. Five membered heterocyclic compounds such as 2-acetyl furan, furfuryl acetate 2-acetylthiophene and N-methylpyrrole-2-carboxaldehyde were treated with numerous aryl bromides and arylchlorides under optimal catalytic reaction conditions. Interestingly, all the prepared catalysts possessed essential structural features that facilitated the formation of desired coupling products in quantitative yield with excellent selectivity. The arylation reaction of bromoacetophenone was highly catalytically active with only 1 mol% catalyst loading at 150 °C for 2 hours. To check the efficiency of the synthesized complexes, three different five member heterocyclic substrates (2-acetylfuran, 2-acetylthiophen, 2-propylthaizole) were tested with a number of aryl bromides bearing both electron-donating and electron-withdrawing groups on para position. The data in Tables 2-4. Indicated that electron-donating groups on the para position of aryl halide decreased the catalytic conversion while electron-withdrawing groups increased the catalytic conversion this was due to the high nucleophilicity of the electron-donating substituents.

Synthesis, antimicrobial activity and molecular docking study of benzyl functionalized benzimidazole silver(I) complexes.

In this study, a series of N-functionalized benzimidazole silver(I) complexes were prepared and characterized by FT-IR, 1H, 13C{1H} NMR spectroscopy, and elemental analysis. Synthesized N-benzylbenzimidazole silver(I) complexes were evaluated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. The results indicated that N-alkylbenzimidazole silver(I) complexes exhibited good antimicrobial activity compared to N-alkylbenzimidazole derivatives. Especially, complex 2e presented perfect antimicrobial activity than the other complexes. The characterized molecules were optimized by DFT-based calculation methods and the optimized molecules were analyzed in detail by molecular docking methods against bacterial DNA-gyrase and CYP51. The amino acid residues detected for both target molecules are consistent with expectations, and the calculated binding affinities and inhibition constants are promising for further studies. A series of N-alkylbenzimidazole silver(I) complexes were synthesized and fully characterized by means of 1H NMR, 13C NMR, and FT-IR spectroscopies. Synthesized N-alkylbenzimidazole silver(I) complexes were investigated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. All complexes showed better activity according to Ampicilin against Pseudomonas aeruginosa. The molecules which were firstly optimized by DFT-based calculation methods were also analyzed by molecular docking methods against DNA gyrase of E. Coli and CYP51. 338 × 190 mm (96 × 96 DPI).

Design, synthesis, antimicrobial activity and molecular docking study of cationic bis-benzimidazole-silver(I) complexes.

Two series of bis(1-alkylbenzimidazole)silver(I) nitrate and bis(1-alkyl-5,6-dimethylbenzimidazole)silver(I) nitrate complexes, in which the alkyl substituent is either an allyl, a 2-methylallyl, an isopropyl or a 3-methyloxetan-3-yl-methyl chain, were synthesized and fully characterized. The eight N-coordinated silver(I) complexes were screened for both antimicrobial activities against Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii) and Gram-positive (Staphylococcus aureus, Staphylococcus aureus MRSA, and Enterococcus faecalis) bacteria and antifungal activities against Candida albicans and Candida glabrata strains. Moderate minimal inhibitory concentrations (MIC) of 0.087 µmol/mL were found when the Gram-negative and Gram-positive bacteria were treated with the silver complexes. Nevertheless, MIC values of 0.011 µmol/mL, twice lower than for the well-known fluconazole, against the two fungi were measured. In addition, molecular docking was carried out with the structure of Escherichia coli DNA gyrase and CYP51 from the pathogen Candida glabrata with the eight organometallic complexes, and molecular reactivity descriptors were calculated with the density functional theory-based calculation methods.

Synthesis, Characterization, Antimicrobial Properties, and Antioxidant Activities of Silver-N-Heterocyclic Carbene Complexes.

The emergence of antimicrobial resistance has become a major handicap in the fight against bacterial infections, prompting researchers to develop new, more effective, and multimodal alternatives. Silver and its complexes have long been used as antimicrobial agents in medicine because of their lack of resistance to silver, their low potency at low concentrations, and their low toxicity compared to most commonly used antibiotics. N-Heterocyclic carbenes (NHCs) are widely used for coordination of transition metals, mainly in catalytic chemistry. In this study, several N-alkylated benzimidazolium salts 2a-j were synthesized. Then, the N-heterocyclic carbene (NHC) precursor was treated with Ag2O to give silver (I) NHC complexes (3a-j) at room temperature in dichloromethane for 48 h. Ten new silver-NHC complexes were fully characterized by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), elemental analysis, and LC-MSMS (for complexes) techniques. The antibacterial and antioxidant activities of salt 2 and its silver complex 3 were evaluated. All of these complexes were more effective against bacterial strains than comparable ligands. With MIC values ranging from 6.25 to 100 g/ml, the Ag-NHC complex effectively showed strong antibacterial activity. Antioxidant activity was also tested using conventional techniques, such as 2, 2-diphenyl-1-picrylhydrazine (DPPH) and hydrogen peroxide scavenging assays. In DPPH and ABTS experiments, compounds 3a, 3b, 3c, 3e, 3g, and 3i showed significant clearance.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Enzymatic Inhibitory Agents with Antioxidant, Antimicrobial, Antiparasitical and Antiproliferative Activity.

A series of [RuCl2(p-cymene)(NHC)] complexes were obtained by reacting [RuCl2(p-cymene)]2 with in situ generated Ag-N-heterocyclic carbene (NHC) complexes. The structure of the obtained complexes was determined by the appropriate spectroscopy and elemental analysis. In addition, we evaluated the biological activities of these compounds as antienzymatic, antioxidant, antibacterial, anticancer, and antiparasitic agents. The results revealed that complexes 3b and 3d were the most potent inhibitors against AchE with IC50 values of 2.52 and 5.06 µM mL-1. Additionally, 3d proved very good antimicrobial activity against all examined microorganisms with IZ (inhibition zone) over 25 mm and MIC (minimum inhibitory concentration) < 4 µM. Additionally, the ligand 2a and its corresponding ruthenium (II) complex 3a had good cytotoxic activity against both cancer cells HCT-116 and HepG-2, with IC50 values of (7.76 and 11.76) and (4.12 and 9.21) µM mL-1, respectively. Evaluation of the antiparasitic activity of these complexes against Leishmania major promastigotes and Toxoplasma gondii showed that ruthenium complexes were more potent than the free ligand, with an IC50 values less than 1.5 µM mL-1. However, 3d was found the best one with SI (selectivity index) values greater than 5 so it seems to be the best candidate for antileishmanial drug discovery program, and much future research are recommended for mode of action and in vivo evaluation. In general, Ru-NHC complexes are the most effective against L. major promastigotes.

Vinyl functionalized 5,6-dimethylbenzimidazolium salts: Synthesis and biological activities.

A series of vinyl functionalized 5,6-dimethylbenzimidazolium salts are synthesized. All compounds were fully characterized by elemental analyses, MS, 1 H-NMR, 13 C-NMR, and IR spectroscopy techniques. Enzyme inhibition is a very active area of research in drug design and development. In this study, the synthesized novel benzimidazolium salts were evaluated toward the human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. They demonstrated highly potent inhibition ability against hCA I with Ki values of 484.8 ± 62.6-1389.7 ± 243.2 nM, hCA II with Ki values of 298.9 ± 55.7-926.1 ± 330.0 nM, α-glycosidase with Ki values of 170.3 ± 27-760.1 ± 269 µM, AChE with Ki values of 27.1 ± 3-77.6 ± 1.7 nM, and BChE with Ki values of 21.0 ± 5-61.3 ± 15 nM. As a result, novel vinyl functionalized 5,6-dimethylbenzimidazolium salts (1a-g) exhibited effective inhibition profiles toward studied metabolic enzymes. Therefore, we believe that these results may contribute to the development of new drugs particularly to treat some global disorders including glaucoma, Alzheimer's disease, and diabetes.

Benzimidazol-2-ylidene ruthenium complexes for C-N bond formation through alcohol dehydrogenation.

A low temperature hydrogen borrowing approach to generate secondary amines using benzimidazole-based N-heterocyclic carbene (BNHC) ruthenium complexes is reported. A series of the piano-stool complexes of the type [(η6-p-cymene)(BNHC)RuCl2] (1a-g) were synthesized via one-pot reaction of the NHC salt precursor, Ag2O, and [RuCl2(p-cymene)]2 and characterized using conventional spectroscopic techniques. The geometry of two precursors, [(η6-p-cymene)(Me4BnMe2BNHCCH2OxMe)RuCl2] (1f) and [(η6-p-cymene)(Me5BnMe2BNHCCH2OxMe)RuCl2] (1g), was studied by single crystal X-ray diffraction. These catalysts were found to dehydrogenate alcohols efficiently at temperatures as low as 50 °C to allow Schiff-base condensation and subsequent imine hydrogenation to afford secondary amines. Notably, this ruthenium-based procedure enables the N-alkylation of aromatic and heteroaromatic primary amines with a wide range of primary alcohols in excellent yields of up to 98%. The present methodology is green and water is liberated as the sole byproduct.

Synthesis, characterization, antimicrobial and antibiofilm activity, and molecular docking analysis of NHC precursors and their Ag-NHC complexes.

Microorganisms attach to surfaces and interfaces and form biofilms which create a sheltered area for host cell response. Therefore, biofilms provide troubles in fields such as medicine, food, and pharmaceuticals. Inhibition of formation of biofilms through hindering of quorum sensing could be a method for the production of new generation antibiotics. In this study, four new benzimidazole type NHC precursors (1-allyl-3-benzyl-5,6-dimethylbenzimidazolium chloride, 1-allyl-3-(2,4,6-trimethylbenzyl)-5,6-dimethylbenzimidazolium chloride, 1-allyl-3-(2,3,5,6-tetramethylbenzyl)-5,6-dimethylbenzimidazolium chloride, and 1-allyl-3-(2,3,4,5,6-pentamethylbenzyl)-5,6-dimethylbenzimidazolium chloride and Ag-NHC complexes of these molecules were synthesized and characterized by elemental analysis, FT-IR spectroscopy, 1H, and 13C{1H} NMR spectroscopy, LC-MS, and single crystal crystallography. Antimicrobial and biofilm formation inhibition activities of the molecules were evaluated. In addition, the activities of the molecules were examined in detail by molecular docking analysis. According to the results obtained, higher activity was achieved with the complex molecules when compared with the benzimidazole derivative ligands.

Silver-N-heterocyclic carbene complexes-catalyzed multicomponent reactions: Synthesis, spectroscopic characterization, density functional theory calculations, and antibacterial study.

Nowadays, silver-N-heterocyclic carbene (silver-NHCs) complexes are widely used in medicinal chemistry due to their low toxic nature toward humans. Due to the success of silver-NHCs in medicinal applications, interest in these compounds is rapidly increasing. Therefore, the interaction of N,N-disubstituted benzimidazolium salts with Ag2 O in dichloromethane to prepare novel Ag(I)-NHCs complexes was carried out at room temperature for 120 h in the absence of light. The obtained complexes were identified and characterized by 1 H and 13 C nuclear magnetic resonance, Fourier-transform infrared, UV-Vis, and elemental analysis techniques. Then, the silver complexes were applied for three-component coupling reactions of aldehydes, amines, and alkynes. The effect of changing the alkyl substituent on the NHCs ligand on the catalytic performance was investigated. In addition, it has been found that the complexes are antimicrobially active and show higher activity than the free ligand. The silver-carbene complexes showed antimicrobial activity against specified microorganisms with MIC values between 0.24 and 62.5 µg/ml. These results showed that the silver-NHC complexes exhibit an effective antimicrobial activity against bacterial and fungal strains. A density functional theory calculation study was performed to identify the stability of the obtained complexes. All geometries were optimized employing an effective core potential basis, such as LANL2DZ for the Ag atom and 6-311+G(d,p) for all the other atoms in the gas phase. Electrostatic potential surfaces and LUMO-HOMO energy were computed. Transition energies and excited-state structures were obtained from the time-dependent density functional theory calculations.

Ruthenium(η6,η¹-arene-CH2-NHC) Catalysts for Direct Arylation of 2-Phenylpyridine with (Hetero)Aryl Chlorides in Water.

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N-CH2-arene group. The benzimidazolium halides were readily converted into ruthenium(II)-NHC complexes with the general formula [RuCl2(η6,η¹-arene-CH2-NHC)]. The structures of all new compounds were characterized by ¹H NMR (Nuclear Magnetic Resonance), 13C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C-Ru bond and two Ru-Cl bonds. The catalytic activity of [RuCl2(η6,η¹-arene-CH2-NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient.

N-Heterocyclic carbene-palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides.

New Pd-NHC complexes have been synthesized and employed for palladium-catalyzed direct arylation of pyrrole derivatives by using electron-deficient aryl chlorides as coupling partners. The desired coupling products were obtained in moderate to good yields by using 1 mol % of these air-stable palladium complexes. This is an advantage compared to the procedures employing air-sensitive phosphines, which have been previously shown to promote the coupling of aryl chlorides with heteroarenes.

Preparation of a series of Ru(II) complexes with N-heterocyclic carbene ligands for the catalytic transfer hydrogenation of aromatic ketones.

The reaction of [RuCl(2)(p-cymene](2) with Ag-N-heterocyclic carbene (NHC) complexes yields a series of [(p-cymene)Ru(NHC)] complexes (2a-f). All synthesised compounds were characterized by elemental analysis, NMR spectroscopy and the molecular structure of 2a was determined by X-ray crystallography. All complexes have been tested as catalysts for the transfer hydrogenation of aromatic ketones, showing excellent activity in this reaction.

Comparison of reproductive toxicity caused by cisplatin and novel platinum-N-heterocyclic carbene complex in male rats.

Cisplatin and other platinum complexes are important chemotherapeutic agents and useful in the treatment for several cancers such as prostate, ovarian and testis. However, severe side effects including reproductive toxicity of cisplatin and other platinum complex cause limitations in their clinical usage. In this context, we aimed to compare the damage in testis caused by cisplatin and a novel platinum-N-heterocyclic carbene complex (Pt-NHC). To this end, 35 Sprague-Dawley rats were divided randomly into five equal groups (n = 7 in each group). Cisplatin and Pt-NHC were intraperitoneally administered as a single dose of 5 mg/kg or 10 mg/kg, and the rats were then killed 10 days after this treatment. The testicular tissues and serum samples were taken from all rats for the determination of reproductive toxicity. The results showed that cisplatin and Pt-NHC caused toxicity on the reproductive system via increased oxidative and histological damage, decreased serum testosterone levels and negatively altered sperm characteristics in a dose-dependent manner (p < 0.05). At the same dose levels, cisplatin generally caused lower toxicity on the reproductive system compared with Pt-NHC. In conclusion, these results suggest that Pt-NHC has more toxic effects on the male reproductive system than cisplatin, and in terms of clinical usage, Pt-NHC may be unsafe compared with cisplatin.

Novel platinum-N-heterocyclic carbene complex is more cardiotoxic than cis-platin in rats.

Cis-platin and other platinum complexes are important chemotherapeutic agents useful in the treatment of several cancers. However, therapeutic usage of cis-platin and other platinum complex are limited by their undesirable side effects including cardiotoxicity. In this context, we aimed to compare the damage caused in heart by cis-platin and novel platinum-N-heterocyclic carbene (Pt-NHC) complex. For this purpose, 35 Sprague-Dawley rats were divided randomly into five equal groups (n = 7 for each group). Cis-platin and novel Pt-NHC complex were intraperitoneally administered at a single dose of 5 mg/kg and 10 mg/kg and then sacrificed 10 days after this treatment. The heart tissues were taken from all rats for determination of oxidative and myocardial damage. Cis-platin and novel Pt-NHC complex caused oxidative and histological damage in the heart tissue in a dose-dependent manner (p < 0.05). On the other hand, at the same dose levels, cis-platin caused lower oxidative and histological damage in heart tissue compared to novel Pt-NHC complex. These results suggest that novel Pt-NHC complex is more cardiotoxic than cis-platin.

Synthesis and antimicrobial activity of novel Ag-N-hetero-cyclic carbene complexes.

A series of imidazolidinium ligand precursors are metallated with Ag2O to give silver(I) N-heterocyclic carbene complexes. All compounds were fully characterized by elemental analyses, 1H-NMR, 13C-NMR and IR spectroscopy techniques. All compounds studied in this work were screened for their in vitro antimicrobial activities against the standard strains: Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and the fungi Candida albicans and Candida tropicalis. The new imidazolidin-2-ylidene silver complexes have been found to display effective antimicrobial activity against a series of bacteria and fungi.

Palladium-catalyzed heck coupling reaction of aryl bromides in aqueous media using tetrahydropyrimidinium salts as carbene ligands.

An efficient and stereoselective catalytic system for the Heck cross coupling reaction using novel 1,3-dialkyl-3,4,5,6-tetrahydropyrimidinium salts (1, LHX) and Pd(OAc)2 loading has been reported. The palladium complexes derived from the salts 1a-f prepared in situ exhibit good catalytic activity in the Heck coupling reaction of aryl bromides under mild conditions.

1,3-Bis(2-thienylmeth-yl)-4,5-dihydro-imidazolium trichlorido(η-p-cymene)ruthenate(II).

The asymmetric unit of the title compound, (C(13)H(15)N(2)S(2))[RuCl(3)(C(10)H(14))], contains a 1,3-(2-thienylmeth-yl)-4,5-dihydro-imidazolium cation and a trichlorido(η(6)-p-cymene)ruthenate(II) anion. The thio-phene rings of the cation are disordered by an 180° rotation about the thio-phene-CH(2) bonds with occupancies of 0.847 (5)/0.153 (5) and 0.700 (5)/0.300 (5), respectively. The Ru atom exhibits a distorted octa-hedral coordination with the benzene ring of the p-cymene ligand formally occupying three sites and three Cl atoms occupying the other three sites. The short C-N bond lengths in the imidazoline ring indicate partial electron delocalization within the N-C-N fragment. Cation and anions are connected through five inter-molecular C-H⋯Cl hydrogen bonds and one C-H⋯π hydrogen bond, forming a three-dimensional hydrogen-bonded network.

Synthesis, characterization and catalytic activity of novel N-heterocyclic carbene-palladium complexes.

The reaction of Pd(OAc)2 with 1-(benzhydryl)-3-(alkyl)benzimidazolium salts 1a-d yields trans-bis[1-(benzhydryl)-3-(alkyl)benzimidazolin-2-ylidene]dibromopalladium(II) complexes (2a-d) which were characterized by elemental analysis, NMR spectroscopy and the molecular structures of 2b, and 2d were determined by X-ray crystallography. The catalytic activity of PdBr2bis(benzimidazolin-2-ylidene) complexes 2a-d was evaluated in the direct arylation reaction of benzothiazole with bromobenzene derivatives.

1,3-Bis(thio-phen-2-ylmeth-yl)-3,4,5,6-tetra-hydro-pyrimidinium trichlorido(η-p-cymene)ruthenate(II).

The asymmetric unit of the title compound, (C(14)H(17)N(2)S(2))[Ru(C(10)H(14))Cl(3)], contains a 1,3-bis-(thio-phen-2-ylmeth-yl)-3,4,5,6-tetra-hydro-pyrimidinium cation and a trichlorido(η(6)-p-cymene)ruthenate(II) anion. The Ru atom exhibits a distorted octa-hedral coordination with the benzene ring of the p-cymene ligand formally occupying three sites and three chloride atoms occupying the other three sites. The N-C bond lengths of the N-C-N unit of the pyrimidinium cation are shorter than the average single C-N bond length of 1.48 Å, thus showing double-bond character, indicating a partial electron delocalization within the N-C-N fragment. The pyrimidine ring has an envelope conformation. Four inter-molecular C-H⋯Cl hydrogen bonds generate a three-dimensional hydrogen-bonded framework.