Acetanilide Derivatives Research Articles

3‐(3,5‐Dimethyl‐1H‐Pyrazol‐1‐yl)‐3‐Oxopropanenitrile as Precursor for Some New Mono‐Heterocyclic and Bis‐Heterocyclic Compounds

3‐(3,5‐Dimethyl‐1 H ‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 1 was used as a cyanoacetylating agent for synthesis of the acetanilide derivative 3. Compound 3 was utilized as a key intermediate for the synthesis of some new mono‐chromene and di‐chromene derivatives 9 and 13, the dihydrazo derivatives 15, and the dithiazole derivatives 18 via the condensation with o‐hydroxybenzaldehyde derivatives, the coupling with aryl diazonium salts, or the reaction with phenyl isothiocyanate in presence of KOH followed by phenacyl bromide derivatives respectively.

Iodine(III)-Mediated para-Selective Direct Imidation of Anilides.

The direct, nucleophilic imidation of acetanilide derivatives has been performed under mild, iodine(III)-mediated or -catalyzed conditions, employing lithium triflimide as the nitrogen source. The reaction exhibits exclusive regioselectivity for the para position and shows a good tolerance for varied functional groups at both the ortho or meta positions. Preliminary mechanistic data suggest that the LiNTf2 reagent plays a key role in the reactivity.

Nootropic Activity of Some Quinazoline Amides

A series of quinazoline acetanilide derivatives were synthesized using direct alkylation of quinazoline-4(3H)-one by α-chlorocarboxylic acid anilides. The nootropic properties of 10 α-[4-oxoquinazolin-3(4H)-yl]carboxylic acid derivatives were studied. Pronounced nootropic activity was found for compounds III, IV, VI, and X, for which further detailed studies are planned.

Ноотропная активность амидов хиназолинового ряда

Ацетанилидные производные хиназолина синтезированы прямым алкилированием хиназолин-4(3H)-она анилидами α-хлоркарбоновых кислот. Изучены ноотропные свойства 10 производных α-[4-оксохиназолин-3(4H)-ил]карбоновых кислот. Установлено выраженное ноотропное действие у веществ III, IV, VI и X, далее планируется их углубленное изучение.

Charge density analysis of paracetamol, acetotoluidine and methacetin

Paracetamol (p-hydroxyacetanilide, Pbca), acetotoluidine (p-methylacetanilide, P21/c) and methacetin (p-methoxyacetanilide, Pbca) contain acetamide group included in molecular fragments, which play an important role in many drugs and proteins. As all of them are derivatives of acetanilide used in medicine, and due to the presence of the amide bond, their charge density analysis is important for better understanding amide infinite peptide chains. Thus, comparing the data obtained for paracetamol with acetotoluidine and with methacetin charge density data can provide deeper insight into NH···O bonding. Another point of interest is the possibility of methyl group rotation that remains to be ambiguous in these acetanilide molecule based compounds. In the present study we have attempted to elucidate these problems using precise X-ray diffraction at 100K with subsequent charge density topological analysis. All charge density refinements were based on the Hansen and Coppens multipolar atom model. The topologies of the inter- and intramolecular interactions are carefully analyzed for compounds. The atomic charges, bond orders, and the electrostatic energy in molecules are discussed. The topological characteristics in the critical point of the NH···O bond of paracetamol, acetotoluidine and methacetin are shown in the table below. In contrast to similarity in NH···O bonds for all studied compounds, intermolecular interactions between the double bonded oxygen atom and the hydrogen of dimer's methyl group are different. In acetotoluidine and methacetin the (3, –1) critical points with the same topological characteristics were detected between these atoms. In comparison to them, paracetamol with disordered methyl group [1, 2] has no such point. That can be related to the absence of the methyl group disorder in acetotoluidine and methacetin.

Acetanilide palladacycle: an efficient catalyst for room‐temperature Suzuki–Miyaura cross‐coupling reaction

The catalytic activity of three acetanilide palladacycles derived from easily accessible and commercially available acetanilide derivatives, viz. N‐phenylacetamide (L1), N‐(4‐chlorophenyl)acetamide (L2) and N‐(4‐methylphenyl)acetamide (L3) has been examined in Pd‐catalyzed Suzuki–Miyaura reaction of arylboronic acid with aryl bromides at room temperature. The complex 1L3 exhibited efficient activity in the Suzuki–Miyaura reaction (up to 99% isolated yield) under mild reaction conditions. Copyright © 2014 John Wiley & Sons, Ltd.

Efficient Synthesis of Novel Pyranoquinoline Derivatives from Simple Acetanilide Derivatives: Experimental and Theoretical Study of their Physicochemical Properties using DFT Calculations

A convenient reaction of 2-chloroquinoline-3-carbaldehyde derivatives and dimedone in the presence of KF-Al2O3 for the synthesis of useful pyranoquinolines is described. Reasonable yields (41-50%), easily available starting materials and less expensive efficient catalyst are the key features of the present method. A mechanism was proposed for the reaction course. Attribution of the chemical shifts was made with the help of the density functional theory (DFT) calculations. The computed nuclear magnetic resonance (NMR) chemical shifts are in good agreement with available experimental data. The nucleus-independent chemical shift (NICS) values were used as quantitative measures for the relative aromatic character in pyranoquinolines. The calculated NICS values obtained for the phenyl group of pyranoquinoline compounds are smaller than that of benzene.

Synthesis and Anxiosedative and Antidepressant Properties of α-[4-Oxoquinazolin-3(4H)-yl]carboxylic Acid Anilides

A series of new quinazoline acetanilide derivatives were synthesized by direct alkylation of quinazoline-4(3H)-one with α-chlorocarboxylic acid anilides. The anxiosedative and antidepressant properties of 10 original derivatives of α-[4-oxoquinazolin-3(4H)-yl]carboxylic acids were studied. It was established that N-(4-methoxyphenyl)-2-[4-oxo-3(4H)-quinazoline]acetamide and 3-[2-oxo-2-(4-phenyl-1-piperazinyl)-ethyl]quinazoline-4(3H)-one exhibited pronounced anxiolytic, antiphobic, and antidepressant activity and were promising candidates for further studies of their psychotropic properties.

Oxidative para-Triflation of Acetanilides

Direct triflation of acetanilide derivatives with silver triflate has been accomplished under mild iodine(III)-mediated oxidative conditions. The reaction shows excellent regioselectivity for the para position and tolerates a range of ortho and meta substituents on the aromatic ring. This method is also compatible with the preparation of arylnonaflates in synthetically useful yields.

The importance of the amide configuration in the gelation process and topochemical polymerization of phenylacetylene macrocycles

Two series of amide-containing phenylacetylene macrocycles (PAMs) were prepared and self-assembled through a gelation process in an organic solvent. Their gelation properties along with their molecular arrangements in the xerogel state, their morphological features and their reactivity toward the topochemical polymerization of the butadiyne units embedded within the structure were studied with respect to the amide configuration. The PAMs of series 1 with the nitrogen atom of the amide function directly attached to the phenyl groups of the PAMs (acetanilide derivatives) showed less organized molecular organization and less reactivity toward topochemical polymerization than the PAMs of series 2 with the inverted amide configuration (benzamide derivatives). The importance of the amide configuration in the gelation process was confirmed by theoretical calculations at the density functional theory level. Moreover, the computed architecture for molecules of series 1 was shown to be incompatible with topochemical reaction in agreement with experimental observation. The actual combination of experiments and calculations allows the design of larger covalently linked, rigid organic nanotubes.

ChemInform Abstract: Discovery of a Novel Acyl‐CoA: Cholesterol Acyltransferase Inhibitor: The Synthesis, Biological Evaluation, and Reduced Adrenal Toxicity of (4‐Phenylcoumarin)acetanilide Derivatives with a Carboxylic Acid Moiety.

AbstractThe introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity are accomplished on previously described (4‐phenylcoumarine)acetanilide derivatives like (I) or (V).

ChemInform Abstract: Discovery of a Potent and Orally Available Acyl‐CoA: Cholesterol Acyltransferase Inhibitor as an Antiatherosclerotic Agent: (4‐Phenylcoumarin)acetanilide Derivatives.

AbstractStructure‐activity relationship studies lead to the discovery of compound (I), which shows potent ACAT inhibitory activity (IC50 = 12 nM) and good pharmacokinetic profile in mice.

Relationships between poloxamer structure and the solubilization of some para-substituted acetanilides.

Saturation solubilities of several para-substituted acetanilides have been measured at 37 degrees C in aqueous solutions of structurally related polyoxyethylene-polyoxypropylene block copolymers-poloxamers L62, L63, L64, P65 and F68. These poloxamers differ only in the amount of ethylene oxide in the hydrophil. Solubilities increased with increasing poloxamer concentration. As the oxyethylene chain length of the poloxamer increased, then the solubilizing capacity per equivalent of oxyethylene decreased. The moles of acetanilide derivative solubilized per mole of poloxamer increased with poloxamer oxyethylene content in the case of the less hydrophobic acetanilides but was invariant in the more hydrophobic ones. The solubilizing capacities have been discussed in terms of the inter-relationships between the hydrophobic nature of the solubilizate and solubilizer and the site of solubilization on the poloxamer molecule.

Discovery of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: The Synthesis, Biological Evaluation, and Reduced Adrenal Toxicity of (4-Phenylcoumarin)acetanilide Derivatives with a Carboxylic Acid Moiety

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.

Discovery of a Potent and Orally Available Acyl-CoA: Cholesterol Acyltransferase Inhibitor as an Anti-atherosclerotic Agent: (4-Phenylcoumarin)acetanilide Derivatives

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).

ChemInform Abstract: The Synthesis of Spirocyclic (1,2,4)Triazolo(4,3-a)quinolines as Potential Ligands for the Benzodiazepine Receptor.

Two spirocyclic [1,2,4] triazolo [4,3-a] quinolines (1a and b) have been prepared as potential ligands for the benzodiazepine receptor. Both compounds were prepared using the strategy of doubly deprotonating an acetanilide derivative followed by reaction with α-tetralone. The resulting alcohols were converted to the corresponding spirocyclic 3,4-dihydroquinolin-2-one or -2-thione by treatment with neat HF. Triazole formation was effected by standard procedures. An alternate strategy starting with an intact triazole was unsuccessful but this route led to the first example of a lateral metallation of a 4-substituted 1,2,4-triazole

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity

Based on the structural similarity of viral fusion proteins within the family Paramyxoviridae, we tested recently described and newly synthesized acetanilide derivatives for their capacity to inhibit measles virus (MV)-, canine distemper virus (CDV)- and Nipah virus (NiV)-induced membrane fusion. We found that N-(3-cyanophenyl)-2-phenylacetamide (compound 1) has a high capacity to inhibit MV- and CDV-induced (IC(50) μM), but not NiV-induced, membrane fusion. This compound is of outstanding interest because it can be easily synthesized and its cytotoxicity is low [50 % cytotoxic concentration (CC(50)) ≥ 300 μM], leading to a CC(50)/IC(50) ratio of approximately 100. In addition, primary human peripheral blood lymphocytes and primary dog brain cell cultures (DBC) also tolerate high concentrations of compound 1. Infection of human PBMC with recombinant wild-type MV is inhibited by an IC(50) of approximately 20 μM. The cell-to-cell spread of recombinant wild-type CDV in persistently infected DBC can be nearly completely inhibited by compound 1 at 50 μM, indicating that the virus spread between brain cells is dependent on the activity of the viral fusion protein. Our findings demonstrate that this compound is a most applicable inhibitor of morbillivirus-induced membrane fusion in tissue culture experiments including highly sensitive primary cells.

ChemInform Abstract: Discovery of Novel Acetanilide Derivatives as Potent and Selective β3‐Adrenergic Receptor Agonists.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reactivity of acetanilides in the alkaline hydrolysis reaction: theory vs. experiment

The rate constants (at 25°C) for the alkaline hydrolysis of a series of seven acetanilide derivatives were determined experimentally. The series included the parent compound acetanilide and the following para-substituents: CH3, OCH3, NH2, CHO, COCH3 and NO2. The obtained kinetic data were then correlated with the following theoretically estimated reactivity indices: Mulliken and NBO atomic charges, the Parr electrophilicity index (ω), and the electrostatic potential at the carbon and nitrogen atoms of the reaction center (V C, V N). Very good correlation between the logarithm of the rate constant, ln k, and the ω values was established. Excellent correlations between V C and V N and ln k were found. The data obtained show that the model-independent electrostatic potential at the nuclei provides a reliable quantitative approach for describing the reactivity of organic compounds.

Vapor pressures and standard molar enthalpies, entropies and Gibbs energies of sublimation of three 4-substituted acetanilide derivatives

The vapor pressures of three 4-substituted acetanilide derivatives (namely, 4-ethoxyacetanilide, 4-hydroxyacetanilide and 4-bromoacetanilide) were measured above their liquids using the mass loss rates determined by thermogravimetry under both isothermal and nonisothermal diffusion-controlled conditions. The coefficient used to convert mass loss rates in vapor pressures showed a slight increase with increasing temperature. Therefore, the small deviations observed from the mean value enable the use of a single calibration value to be considered reasonable. From the temperature dependence of the vapor pressure estimated using a calibration constant for each technique the molar enthalpies of vaporization Δ l g H m ° ( T ) were determined, respectively, at the middle 〈 T〉 of the respective temperature intervals. The melting temperatures and the molar enthalpies of fusion of these compounds were measured by differential scanning calorimetry. Finally, the standard molar enthalpies of sublimation Δ cr g H m ° ( 298.15 K ) were obtained at the reference temperature of 298.15 K using the standard molar enthalpies of vaporization Δ l g H m ° ( T ) , the molar enthalpies of fusion, the heat capacity differences between gas and liquid and the heat capacity differences between gas and solid, Δ l g C p,m ° and Δ cr g C p,m ° , respectively, both estimated by applying a group additivity procedure. Therefore, the averages of the standard ( p° = 0.1 MPa) molar enthalpies, entropies and Gibbs energies of sublimation at 298.15 K, have been derived: Compound Δ cr g H m ° ( 298.15 K ) (kJ mol −1) Δ cr g S m ° ( 298.15 K ) (J mol −1 K −1) Δ cr g G m ° ( 298.15 K ) (kJ mol −1) 4-Ethoxyacetanilide 120 ± 3 232 ± 9 52 ± 5 4-Hydroxyacetanilide 138 ± 3 245 ± 9 65 ± 5 4-Bromoacetanilide 110 ± 4 204 ± 10 49 ± 6