Phenacyl Halides Research Articles

Synthesis and evaluation of anticancer activity of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives

An efficient method for the synthesis of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives has been developed. New ketones were obtained by N-alkylation of TBBi or 2-Me-TBBi with various phenacyl halides and then reduced to the corresponding alcohols. All compounds were obtained with satisfactory yields in the range of 40–91 %. The synthesized compounds appeared a weak CK2 and PIM-1 inhibitors but exhibit an interesting cytotoxic activity against cancer cell lines, i.e. MCF-7, PC-3, CCRF-CEM, K-562. 1-Phenyl-2-(4,5,6,7-tetrabromo-1H-benzimidzol-1-yl)ethanone 3aA exhibits the highest cytotoxic activity with IC50 value of 5.30 µM for MCF-7 and 6.80 µM for CCRF-CEM. Moreover, this compound shows the highest selectivity against both MCF-7 and CCRF-CEM with SI selectivity coefficients (against MRC-5 and Vero cells) equal 5.45 and 4.30 for MCF-7 and 4.25 and 3.35 for CCRF-CEM, respectively. Furthermore, it was shown that compound 3aA exhibits very good pro-apoptotic properties, through induction of the mitochondrial apoptotic pathway in CCRF-CEM cells. These results correlate with data showing the effect of 3aA on intracellular level of CK2α protein and CK2-mediated phosphorylation of Ser529 in NF-κBp65. Study of the effect of compound 3aA on mRNA levels of CK2α and CK2α’ showed no significant differences in gene expression levels in control CCRF-CEM and cells treated with 3aA, indicating 3aA action at the protein level.

Nicotinonitriles as potential inhibitors of α-glucosidase, tyrosinase, and urease enzymes: Synthesis, characterization, in vitro, and in silico studies

In an effort to develop novel enzyme inhibitors with potent activity and high selectivity, a series of nicotinonitrile derivatives was synthesized. Cyano pyridone intermediates undergo nucleophilic substitution reactions with variously substituted phenacyl halides to yield the nicotinonitriles 1–20. All nicotinonitriles exhibited moderate to excellent in vitro enzyme inhibitory activities against α-glucosidase, tyrosinase, and urease. Compound 1 (IC50 = 27.09 ± 0.12 µM) selectively displayed more significant activity than the standard acarbose (IC50 = 40.00 ± 0.70 µM). Compound 1 also showed good urease inhibition (IC50 = 33.04 ± 0.70 µM); however, it exhibited activity less than the standard acetohydroxamic acid (IC50 = 27.00 ± 0.50 µM).Furthermore, the most effective compound of the series against tyrosinase compared to the standard kojic acid (IC50 = 16.9 ± 1.30 µM) was 16 with an IC50 value of 10.55 ± 0.08 µM. In contrast, this compound showed no activity against α-glucosidase and urease. DFT calculations were carried out to analyze electronic transitions and energy levels (HOMO and LUMO) in nicotinonitrile derivatives, offering insights into their chemical reactivity and stability. Molecular docking studies and molecular electrostatic potential (MEP) revealed the interactions of the active compounds with the amino acid residues at the active sites of the enzymes, thereby shedding light on the mechanism of enzyme inhibition. Therefore, compound 1 can be further studied as a promising α-glucosidase and urease inhibitor, while compound 16 is an effective tyrosinase inhibitor.

Boronic acid functionalized silica‐coated Fe3O4 as a novel magnetically separable catalyst for the synthesis of hydrazinyl thiazoles

A novel silica‐coated magnetite supported boronic acid functionalized nanocatalyst (Fe3O4@SiO2‐Pr‐N=CH‐C6H4B[OH]2) was synthesized using a simple synthetic protocol. The catalyst was fully characterized by using Fourier transform‐infrared (FT‐IR), X‐ray diffraction (XRD), energy dispersive X‐ray (EDX), thermogravimetric analysis‐differential thermal analysis (TGA‐DTA), field emission scanning electron microscopy (FE‐SEM), transmission electron microscopy (TEM) and vibrating sample magnetometry (VSM) techniques. The structural investigations revealed that the catalyst is nano‐sized (average crystallite size 13 nm), spherical, thermally stable, and magnetic in nature having a magnetic saturation of 51.26 emu/g. The catalytic activity of Fe3O4@SiO2‐Pr‐N=CH‐C6H4B(OH)2 was explored in the synthesis of hydrazinyl thiazoles via one‐pot, three‐component reaction of phenacyl halide, thiosemicarbazide and aryl aldehyde in EtOH:H2O (50:50, v/v) at room temperature and it gave above 90% yields of hydrazinyl thiazoles. The catalyst being magnetically separable can be reused six times with the retention of catalytic activity. The present approach offers the advantages of operational simplicity, shorter reaction time, ambient reaction condition, facile separation of catalyst, and higher yields of the products.

光化学的活性化を駆動力としたヨウ素を利用する新規分子変換反応の開発

Effective use of the light that surrounds us is the hottest research topic in all fields, including the energy field. Light is the means by which reactions occur, and can be thought of as a “type of reagent.” Since light has no shape or weight, it is a clean substance that does not leave any residue, and can be one of the most important methods for investigating processes that reduce environmental impact. Against this background, the authors have been conducting research aiming at the development of novel molecular transformation reactions driven by photochemical activation of representative elements. In this study, we focused on iodine, which is easy to handle, has low toxicity, and is highly responsive to visible light. That is to say, iodine and carbon-iodine bonds readily respond to light energy as small as visible light and undergo bond cleavage to generate radical species. By applying this phenomenon to fine organic synthesis reactions, the authors have succeeded in developing a methodology for easily synthesizing compounds such as phenacyl halides, cyclopropanes, and lactones, which have high industrial value, from light energy and inexpensive raw materials.

Regioselective syntheses of 2-oxopyridine carbonitrile derivatives and evaluation for antihyperglycemic and antioxidant potential

A library of 2-oxopyridine carbonitriles 1–34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, 1H NMR, and 13C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC50 = 3.00 ± 0.11–43.35 ± 0.67 μM and α-amylase inhibition potential in the range of IC50 = 9.20 ± 0.14–65.56 ± 1.05 μM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC50 value of 3.00 ± 0.11 μM, while the most active compound against α-amylase was 6, with an IC50 value = 9.20 ± 0.14 μM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.

Microwave‐Assisted Nanocatalysed Synthesis of Phenacyl Halides as Future Anti‐Platelet Agents

AbstractAn efficient, environmentally benign and novel method for the synthesis of phenacyl halides as antiplatelet agents has been reported in the presence of nanocatalyst (TiO2) by using N‐halosuccinimides (NXS, X=Cl, Br) as a source of halogen and tert‐Butyl Hydrogen Peroxide (TBHP) under microwave irradiation. Compound 2a showed best in vitro antiplatelet activity with 540 and 480 sec as clotting time in prothrombin time (PT) and activated partial thromboplastin time (APTT) assay respectively. Rest compounds showed good to moderate activity. Structures of all synthesized compounds were elucidated by IR, NMR and Mass spectrometry.

Pyridine—Azepine Structural Modification of 3,4-Dihydro-nor-isoharmine

Structural modification of 3,4-dihydro-nor-isoharmine through expansion of the dihydropyridine ring to dihydroazepine was accomplished in two stages including pyridine-azepine recyclization of the quaternized substrate by the action of phenacyl halides and their heterocyclic analogs. The recyclization process can be accompanied by 1,2-migration of the acyl group to give mixtures of 4-acyl-9-methoxy-3-methyl-1,2-dihydroazepino[4,5-b]indoles and their 5-acyl-substituted isomers. Factor influencing the recyclization direction and product ratio were analyzed.

Design, synthesis, in-silico and in-vitro evaluation of di-cationic pyridinium ionic liquids as potential anticancer scaffolds

An array of dicationic pyridinium ionic liquids (DILs) based hydrazone linkage were designed and synthesized via the quaternization of the appropriate bispyridine hydrazone with different phenacyl halides and led to the formation of halogenated DILs, which undergo metathesis reaction to give the specific task dicationic pyridinium liquids carrying fluorinated counter anions (PF6−, BF4−, CF3COO−). The newly synthesized DILs were well characterized using whole spectroscopic data. The Anticancer evaluation of DILs against breast and colon cancer cell lines revealed that compound 22 appears to be the most active compound in the series with IC50 in the two-digit micromolar range. The in-vitro anticancer results were further supported by in-silico molecular docking studies revealing the highest potency of compound 22. The docking analysis demonstrated good docking score and binding affinities of the synthesized compounds on the target protein PI3Kinase.

Synthesis and the activity assessment of adamantylcontaining thiazolium inhibitors of butyrylcholinesterase

Cholinesterase inhibitors can be used for treatment of neuropsychiatric symptoms and functional impairments in neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases. Aim. To synthesize and assess the inhibitory activity of adamantyl-containing 5-substituted N-benzyl and N-phenacylthiazolium salts against butyrylcholinesterase and acetylcholinesterase. Results and discussion. The synthesis of 3-aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts included preparation of 5-acyloxyethyl thiazole derivatives by the reaction of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole with the corresponding adamantoyl- or adamantylacetyl chlorides. The derivatives of 5-acyloxyethyl thiazole were quaternized in the reaction with benzyl or phenacyl halides. The studies in vitro have shown that the compounds synthesized inhibit butyrylcholinesterase with IC50 values in the micromolar range. Some of them exhibited selectivity over acetylcholinesterase. The molecular docking was performed for understanding the mechanisms of the enzyme-inhibitor complex formation. Experimental part. The synthesis of the intermediate and target compounds was carried out by the classical methods. The structures of compounds were proven by NMR 1H-spectroscopy and elemental analysis. The methods of enzymatic kinetics were used for determination of the inhibitory effects of the compounds synthesized. Calculations by molecular docking were carried out using Autodock 4.2 program. Conclusions. 3-Aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts with adamantylcontaining substituents in position 5 can selectively inhibit butyrylcholinesterase compared to their effect on acetylcholinesterase.

Reaction of 5-O-succinoylavermectin B1 with alkylating agents

A reaction of 5-O-succinoylavermectin B1 with alkylating agents, namely phenacyl halides, bromoacetanilides, and benzyl bromides, was studied. Esters of 5-O-succinoylavermectin B1 were obtained for the first time, which are of interest as potential antiparasitic agents.

Synthesis, structure–activity relationship and antinociceptive activities of some 2-(2′-pyridyl) benzimidazole derivatives

In the present study, a new series of 2-(2′-pyridyl) benzimidazole derivatives 1–11 were resynthesized and evaluated for analgesic activity. The 2-(2′-pyridyl) benzimidazole was quaternized at its nitrogen atom in the ring with various substituted and unsubstituted phenacyl halides. As a result, eleven novel derivatives were synthesized. The structures of these new synthetic derivatives of 2-(2′-pyridyl) benzimidazole were confirmed by using different spectroscopic techniques i.e., UV/Visible, IR, 1HNMR and Mass spectroscopy. Percentage of carbon, hydrogen and nitrogen was also determined by elemental analysis. All the synthetic compounds showed significant analgesic activity with dose-dependent manner.

Synthesis of some new thiazolo[3,2-a]pyrimidine derivatives and screening of their in vitro antibacterial and antitubercular activities

The novel 5H-thiazolo[3,2-a]pyrimidin-5-ones were synthesized by thiophene ring closure. The first step is the synthesis of S-alkylated derivatives by the reaction of 6-substituted-2-thiouracils with the appropriate substituted phenacyl halides. Upon treatment of S-alkylated derivatives at different temperatures, intramolecular cyclization to 3-(substituted phenyl)-5H-thiazolo[3,2-a]pyrimidin-5-ones or sulfonation of cyclized products to the corresponding sulfonic acid derivatives occurred. Further, acylation of the 7-NH2 group of 5H-thiazolo[3,2-a]pyrimidin-5-ones afforded amide derivatives, and reduction of the NO2 group of 5H-thiazolo[3,2-a]pyrimidin-5-ones gave amino derivatives. All the new compounds were confirmed by 1H NMR, 13C NMR, IR and HRMS spectra, and their antibacterial and antitubercular activities were screened. Some compounds showed significant antibacterial and antitubercular activities.

ChemInform Abstract: Synthesis and Reactivity of 2‐Pyrrolidino‐, 2‐N‐Methylpiperazino‐, 2‐Piperidino‐, and 2‐Morpholino‐1,3,4‐thiadiazines.

AbstractA variety of the title thiadiazine derivatives (III) are synthesized by cyclocondensation of phenacyl halides with thiosemicarbazides (I).

Synthesis and Antifungal activity of Phenacyl Azoles

A new N-(4-methoxyphenacyl)imidazole and three new substituted N-(phenacyl)triazoles were prepared by reaction of the heterocycle with a phenacyl halide. The former ketone and one example of the latter were reduced to the corresponding alcohols. All six compounds were screened in vitro for antifungal activity against two pathogenic fungal strains, Candida albicans (fluconazole-resistant) and Aspergillus fumigatus. The results revealed that most of the compounds showed activity against both strains at 100 μg mL-1and 80 μg mL-1, some comparable with control compound fluconazole. The alcohols were less active than the corresponding ketones.

ChemInform Abstract: γ‐Halo‐enones: A Method for Their Synthesis from Arylacyl Halides and Their Application to the Preparation of Five‐Membered Ring Heterocycles.

A simple method has been developed for synthesis of γ-halo-enones. The approach employs a sequence involving initial indium-mediated allenylation reactions of phenacyl halides with propargyl bromide. This process is followed by acid-promoted rearrangement reactions of the formed homoallenic halohydrins. The new method can be incorporated into routes for the efficient synthesis of various five-membered heterocyclic compounds.

Synthesis and Reactivity of 2‐Pyrrolidino‐, 2‐N‐Methylpiperazino‐, 2‐Piperidino‐, and 2‐Morpholino‐1,3,4‐thiadiazines

A variety of 2‐pyrrolidino‐, 2‐N‐methylpiperazino‐, 2‐piperidino‐, and 2‐morpholino‐1,3,4‐thiadiazines were prepared by cyclocondensation of phenacyl halides with thiosemicarbazides. Heating of the products resulted in desulfurization and formation of pyrazoles. The rate of this process strongly depends on the substitution pattern of the 1,3,4‐thiadiazines.

γ-Halo-enones: A Method for their Synthesis from Arylacyl Halides and Their Application to the Preparation of Five-Membered Ring Heterocycles

A simple method has been developed for synthesis of γ-halo-enones. The approach employs a sequence involving initial indium-mediated allenylation reactions of phenacyl halides with propargyl bromide. This process is followed by acid-promoted rearrangement reactions of the formed homoallenic halohydrins. The new method can be incorporated into routes for the efficient synthesis of various five-membered heterocyclic compounds.

Copper‐Catalyzed Coupling of Oxime Acetates with Sodium Sulfinates: An Efficient Synthesis of Sulfone Derivatives

AbstractSulfone derivatives are important synthetic intermediates. However, the general method for their preparation is through traditional coupling reaction: the alkylation of sodium sulfinates with phenacyl halides. Based on our previous work on sodium sulfinates and oxime acetates, we herein report a novel method for sulfone derivatives by oxidative coupling with sodium sulfinates and oxime acetates using copper as catalyst. The sulfonylvinylamine products could be formed in excellent yields. Upon hydrolysis by silica gel in CH2Cl2, β‐ketosulfones could also be efficiently constructed. Various sulfonylvinylamines and β‐ketosulfones were obtained in good to excellent yields under the optimized reaction conditions. Mechanistic studies indicated that this transformation involved copper‐catalyzed NO bond cleavage, activation of a vinyl sp2 CH bond, and CS bond formation. The oxime acetates act as both a substrate and an oxidant, thus the reaction needs no additional oxidants or additives.

Copper‐Catalyzed Coupling of Oxime Acetates with Sodium Sulfinates: An Efficient Synthesis of Sulfone Derivatives

Sulfone derivatives are important synthetic intermediates. However, the general method for their preparation is through traditional coupling reaction: the alkylation of sodium sulfinates with phenacyl halides. Based on our previous work on sodium sulfinates and oxime acetates, we herein report a novel method for sulfone derivatives by oxidative coupling with sodium sulfinates and oxime acetates using copper as catalyst. The sulfonylvinylamine products could be formed in excellent yields. Upon hydrolysis by silica gel in CH2 Cl2 , β-ketosulfones could also be efficiently constructed. Various sulfonylvinylamines and β-ketosulfones were obtained in good to excellent yields under the optimized reaction conditions. Mechanistic studies indicated that this transformation involved copper-catalyzed N-O bond cleavage, activation of a vinyl sp(2) C-H bond, and C-S bond formation. The oxime acetates act as both a substrate and an oxidant, thus the reaction needs no additional oxidants or additives.

A concise formation of N-substituted 3,4-diarylpyrroles – synthesis and cytotoxic activity

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.