Phenylacetamide Derivatives Research Articles

6-Bromo-2,3-Dioxoindolin Phenylacetamide Derivatives: Synthesis, Potent CDC25B, PTP1B Inhibitors and Anticancer Activity

A series of 6-bromo-2,3-dioxoindolin phenylacetamide derivatives was synthesized and evaluated for inhibitory activity against CDC25B and PTP1B. Most of the synthesized compounds showed potential inhibitory activities for CDC25B and PTP1B with compound 12 being the most potent (IC50=3.87 µmol/L and 2.98 µmol/L, respectively). Compound 12 also exhibited higher cytotoxic activity against three cancer cell lines (HeLa, A549 and HCT116). In addition, compound 12 delayed the potent tumor inhibitory activity in a colo205 xenograft model in vivo. Keywords: 2, 3-Dioxoindolin phenylacetamide, CDC25B, PTP1B, MTT, Phosphatase inhibitors, Anticancer activity.

Insignificant in vitro falcipain-2 inhibitory activity of novel 2-(4-(substituted benzoyl) piperazine-1-yl)-N-phenylacetamide derivatives

Background: The cysteine protease, falcipain-2 (FP-2) is an important drug target for the management of infection by the human malaria parasite Plasmodium falciparum . The rapid emergence of resistance is the main problem with all antimalarial agents. Hence, the discovery of novel, effective drugs to counter the spread of malaria parasites that are resistant toward existing agents, especially drugs that can act on new targets, is urgently necessary. Materials and Methods: A novel series of 2-(4-(substituted benzoyl) piperazine-1-yl)- N -phenylacetamide derivatives was designed using the ligand-based approach, employing a three-point pharmacophore model. It consists of an aromatic group (monocyclic/bicyclic), which is attached to the hydrophobic moiety; commonly an aromatic residue through hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) atom(s) acting as the linker. The new chemical entities were synthesized from the key intermediate N -phenyl-2-(piperazine-1-yl) acetamide, by coupling it with various substituted acids in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 1 hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by 1 H NMR and by mass spectral data. Results: All the synthesized compounds were evaluated for their in vitro FP-2 inhibitory activity. Two compounds 5l and 5q showed very weak enzyme inhibition activities (3-5%) and the remaining 15 compounds showed no inhibition at 10 μm concentrations. However, unlike other reported FP-2 inhibitors, none of these molecules showed potent activity. Conclusion: This series of compounds did not have or had very less antimalarial activity.

RETENTION BEHAVIOR AND BIOLOGICAL ACTIVITY OF N-SUBSTITUTED-2-PHENYLACETAMIDE DERIVATES

Phenylacetamide derivatives are a group of compounds that exhibit a wide range of biological activities as analgetic, anticonvulsant, pesticide, cytostatic. It is well known that the biological activity and the field of activity of the substance are greatly dependent on its physical, chemical and structural properties. In this paper, we applied QSRR analysis (Quantitative Structure Retention Relationships), which is based on the prediction of biological properties of compounds based on their chromatographic retention behaviors. To that end, retention constants of investigated N-substituted-2-phenylacetamide were determined by reversed phase thin-layer chromatography, (HPTLC RP18 F 254s ) in the presence of different volume fractions of n -propanol and tetrahydrofuran. The resulting data were correlated with molecular descriptors determined in different ways in order to establish the mathematical model that describes the relationship between retention properties and biological activities of investigated phenylacetamides

Establishing dependences between different lipophilic parameters of new potentially biologically active N-substituted-2-phenylacetamide derivatives by applying multivariate methods.

Lipophilicity, a very important parameter in the potential biological activities of molecules, was investigated for newly synthesized N-substituted-2-phenylacetamide derivatives. The determination was carried out in two ways: first experimentally, by applying thin-layer chromatography (TLC) on reversed-phase TLC (RPTLC) RP18F254s in the presence of one protic (methanol) and one aprotic solvent (acetonitrile) and then mathematically, by using different software packages. The intercept of the linear dependence between volume fractions of the organic solvent and the retention parameters obtained by TLC is known as the retention chromatographic constant, R(M)(0), while the slope represents the m value. In order to establish the dependences between the partition coefficient, log P as the standard measure of lipophilicity and the alternative lipophilic parameters obtained experimentally by TLC, R(M)(0) and m values, linear regression analysis and multivariate methods, cluster analysis (CA) and principal component analysis (PCA), were used. All applied methods gave approximately similar results. Although there is a linear dependence between the two chromatographic parameters, the retention constant, R(M)(0), and the m values, only R(M)(0) shows suitable similarity with the standard measure of lipophilicity of the investigated N-substituted-2-phenylacetamide derivatives at the given conditions. The existence of this resemblance proves that the chromatographic retention constant, R(M)(0), obtained by RPTLC could be successfully used for the description of lipophilicity of investigated compounds. On the other hand, the results confirmed that the applied linear regression analysis and the multivariate analysis (CA and PCA) have the ability to compare lipophilic parameters of the investigated phenylacetamide derivatives obtained in different ways.

Synthesis and evaluation of 2-(5-(aryl)-1,3,4-oxadiazol-2-ylthio)-N-(3-(trifluoromethyl)phenyl)acetamides and N-(4-chloro-3-fluorophenyl)-2-(5-(aryl)-1,3,4-oxadiazol-2-ylthio)acetamides as antimicrobial agents

A series of 2-mercapto-5-phenyl-1,3,4-oxadiazole derivatives have been condensed with different phenyl acetamide derivatives possessing fluorine atom at meta position; resulting in the formation of 2-(5-aryl-1,3,4-oxadiazol-2-ylthio)-N-(3-(trifluoromethyl)phenyl)acetamide (5a–j) and N-(4-chloro-3-fluorophenyl)-2-(5-aryl-1,3,4-oxadiazol-2-ylthio)acetamide (5k–t) derivatives. The antimicrobial properties of the synthesized entities (5a–t) measured as their MIC (Minimum Inhibitory Concentration) values were evaluated by using the broth dilution method against Gram-positive bacteria (S. aureus and E. faecalis), Gram-negative bacteria (E. coli and P. aeruginosa) and fungi (C. albicans and A. niger). The results of antimicrobial activities (in μg/ml) revealed the fact that the compounds 5a and g bearing a maximum number of fluorine atoms showed the highest potency among the synthesized compounds against the broad panel of bacterial and fungal strains. The presence of fluorine atom at the meta position in the phenyl ring of final derivatives (5a–t) brought about an enhancement of their antimicrobial properties to a notable extent. Two novel series of oxadiazole bearing fluoro substituted acetamides were synthesized and characterized using different spectral techniques. In vitro antimicrobial test results and SAR study helped to conclude that electron-withdrawing substituent as well as presence of fluorine atoms play important role in increasing the antibacterial and antifungal potency of synthesized derivatives.

RETENTION BEHAVIOR AND BIOLOGICAL ACTIVITY OF N-SUBSTITUTED-2-PHENYLACETAMIDE DERIVATES

Phenylacetamide derivatives are a group of compounds that exhibit a wide range of biological activities as analgetic, anticonvulsant, pesticide, cytostatic. It is well known that the biological activity and the field of activity of the substance are greatly dependent on its physical, chemical and structural properties. In this paper, we applied QSRR analysis (Quantitative Structure Retention Relationships), which is based on the prediction of biological properties of compounds based on their chromatographic retention behaviors. To that end, retention constants of investigated N-substituted-2-phenylacetamide were determined by reversed phase thin-layer chromatography, (HPTLC RP18 F254s) in the presence of different volume fractions of n-propanol and tetrahydrofuran. The resulting data were correlated with molecular descriptors determined in different ways in order to establish the mathematical model that describes the relationship between retention properties and biological activities of investigated phenylacetamides.

Chemometric Approach in Studying of the Retention Behavior and Lipophilicity of Potentially Biologically ActiveN-Substituted-2-phenylacetamide Derivatives

The potential biological activity of a molecule largely depends on its lipophilicity. The lipophilicity of derivatives of N-substituted-2-phenylacetamide was investigated experimentally, by applying thin-layer chromatography on reversed phase (RP-TLC on RP 18 F254s) in the presence of ethanol and dioxane and by using relevant software packages. In order to establish dependence between lipophilicity obtained in different ways, linear regression analysis and multivariate methods were used. Approximately similar groupings of lipophilic parameters and tested compounds were registered in case of both chemometric methods. The obtained results confirm the fact that the applied linear regression analysis and multivariate analysis provide opportunities for comparing chromatographic retention data and lipophilic parameters of the investigated phenylacetamide derivatives. Results suggest that the lipophilicity of investigated molecules largely depends on the nature of the substituents linked to nitrogen atom and on the other hand that the chromatographic retention constants, RM0, determined by RP-TLC method, are similar to the standard measure of lipophilicity, log P, which makes this method appropriate for predicting lipophilicity.

Synthesis and Anticonvulsant and Antidepressant Activity of 2-(5-bromo-2,3-dioxoindolin)-N-substituted Phenylacetamide Derivatives

16 2-(5-bromo-2,3-dioxoindolin-1-yl)-N-substituted phenylacetamide derivatives were synthesized. The chemical structures of the compounds were proved by IR, 1H-NMR, 13C-NMR, Mass spectrometric data and microanalyses. The antidepressant activities of the compounds were investigated by Porsolt's behavioural despair (the forced swimming test) in mice. 2-(5-bromo-2,3-dioxoi-ndolin-1-yl)-N-(2-fluorophenyl)acetamide(4f), 2-(5-bromo-2,3-dioxoindolin-1-yl)-N-(3-chlorophenyl)acetamide(4j), 2-(5-bromo-2,3-dioxoindolin-1-yl)-N-(4-bromophenyl)acetamide(4m) reduced 54.9-44.6% duration of immobility times at 100 mg · kg-1 dose level. Anticonvulsant activities were determined by substances pentylenetetrazloe(metrazol)(anti-PTZ) test, and neurotoxicities were determined by the rotarod toxicity test in mice. 12 synthesized compounds were found protective against PTZ at 100 mg ∙ kg-1 dose level.

Hydroxylated phenylacetamides derived from bioactive benzoxazinoids are bioavailable in humans after habitual consumption of whole grain sourdough rye bread

Understanding relationships between dietary whole grain and health is hindered by incomplete knowledge of potentially bioactive metabolites derived from these foods. We aimed to discover compounds in urine correlated with changes in amounts of whole grain rye consumption. After a wash-out period, volunteers consumed 48-g whole grain rye foods per day for 4 wk and then doubled their intake for a further 4 wk. Samples of 24-h urines were analyzed by flow infusion electrospray MS followed by supervised multivariate data analysis. Urine samples from participants who reported high intakes of rye flakes, rye pasta, or total whole grain rye products could not be discriminated adequately from their wash-out samples. However, discrimination was seen in urine samples from participants who reported high whole grain sourdough rye bread consumption. Accurate mass analysis of explanatory signals followed by fragmentation identified conjugates of the benzoxazinoid lactam 2-hydroxy-1,4-benzoxazin-3-one and hydroxylated phenyl acetamide derivatives. Statistical validation showed sensitivities of 84-96% and specificities of 70-81% (p values < 0·05) for elevated concentrations of these signals after preferential whole grain sourdough rye bread consumption. Several potentially bioactive alkaloids have been identified in humans consuming fermented whole grain sourdough rye bread.

New Quinolinyl–1,3,4–Oxadiazoles: Synthesis, In Vitro Antibacterial, Antifungal and Antituberculosis Studies

In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N-aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4-oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2-chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 μg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates.

Multivariate analysis of chromatographic retention data and lipophilicity of phenylacetamide derivatives

One of the most important physicochemical parameters of a molecule that determines its bioactivity is its lipophilicity. Cluster analysis (CA), principal component analysis (PCA), and sum of ranking differences (SRD) were used to compare the lipophilic parameters of twenty phenylacetamide derivatives, obtained experimentally as chromatographic retention data in the presence of different solvents and calculated by different mathematical methods. All the applied methods of multivariate analysis gave approximately similar grouping of the studied lipophilic parameters. In the attempt to group the investigated compounds in respect of their lipophilicity, the obtained results appeared to be dependent on the applied chemometric method. The CA and PCA, grouped the compounds on the basis of the nature of the substituents R1 and R2, indicating that they determine to a great extent the lipophilicity of the investigated molecules. Unlike them, the SRD method could not be used to group the studied compounds on the basis of their lipophilic character.

2-(4-Fluorophenyl)-N-phenylacetamide Derivatives as Anticancer Agents: Synthesis and In-vitro Cytotoxicity Evaluation.

Cancer is a major global problem and is the second leading cause of mortality in the developed countries.Resistance to current chemotherapeutics and high incidence of adverse effects are the two principal reasons for developing new anticancer agents. Phenylacetamide derivatives can act as potential anticancer agents. Synthesis and screening of 2-(4-Fluorophenyl)- N-phenylacetamide derivatives in present study showed that these compounds act as potent anticancer agents especially against PC3(prostate carcinoma) cell line. Compounds 2a-2c with nitro moiety demonstrated a higher cytotoxic effect than compounds 2d-2f with methoxy moiety. All compounds in this series exhibited lower activity than imatinib as reference drug. Compounds 2b (IC50 = 52 μM) and 2c (IC50 = 80 μM) were the most active compounds against PC3 cell line in comparison with imatinib(IC50 = 40 μM). Compound 2c (IC50 = 100 μM) with p-nitro substituent was the most active compound compared to imatinib(IC50 = 98 μM) in MCF-7 cell line.

Transition Behavior of Hydrogen-Bonding-Mediated Block Copolymer Mixtures

We have investigated transition behavior for block copolymer (BCP) mixtures composed of a lamella-forming polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) and phenylacetamide derivatives, where the hydroxyl functionality at phenylacetamide unit is available only for 4-hydroxyphenylacetamide (HPA) and not for phenylacetamide (PA). Unlike a similar transition temperature for BCP mixtures with PA, measured by in situ small-angle X-ray scattering (SAXS) and depolarized light scattering (DPLS), an annealing temperature dependence for BCP mixtures with HPA indicates that only the complex by H-bonding mediation between the nitrogen units of P2VP block and hydroxyl group in the HPA enhances nonfavorable segmental interactions between two block components, leading to a significant increase in d-spacing for BCP mixtures with HPA. This result illustrates the importance of the availability for H-bonding mediation to control over transition behavior for BCP mixtures with the functional molecules.

QSAR and pharmacophore analysis on amides against drug-resistant S. aureus1

Considering the worth of developing new antibacterial agents against drug-resistant Stapylococcus aureus, the present study explores the structure-activity relationships analysis of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives using classical QSAR and 3D-common-feature pharmacophore hypothese approaches. QSAR analysis revealed that the compounds possessing a methylene group between the phenyl and the carboxyamido moiety played a role for decreasing the activity. On the other side, substituent effects on position R1 was found important for the activity and holding a substituent possessing a minimum width property on this position like as alkyl groups enhanced the activity. Moreover, substituting position R3 with a group enhancing the electron-donor capability of the phenolic ring system increased the potency. 3D-common-feature pharmacophore approach considered that the conformational properties of the compounds were important for the activity against drug-resistant S. aureus and compounds possessing a benzamide moiety rather than phenylacetamide structure increased the activity. Furthermore, holding NO2 and OH groups on the phenyl ring attached to the benzamide moiety was important for improving the potency against drug-resistant S. aureus. 1Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Synthesis and biological evaluation of new N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamides and phenylacetamides as antimicrobial agents

A new series of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives ( 1a– 1n, 2a– 2n) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and their drug-resistant isolate. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 500 and 1.95 μg/ml. Benzamide derivative 1d exhibited the greatest activity with MIC values of 1.95, 3.9, and 7.8 μg/ml against drug-resistant B. subtilis, B. subtilis, and S. aureus, respectively.

Synthesis and microbiological activity of some N-( o-hydroxyphenyl)benzamides and phenylacetamides as the possible metabolites of antimicrobial active benzoxazoles: part II

The synthesis of some N-( o-hydroxyphenyl)benzamides and benzacetamides ( 2a– 2p) in order to determine their in vitro antimicrobial activity against two Gram-positive bacteria, three Gram-negative bacteria and the fungus Candida albicans is described. The new compounds were compared with several control drugs. The derivative 2g, 4-amino- N-( o-hydroxyphenyl)benzamide, was found active at an MIC value of 25 μg/ml against the Gram-negative microorganism Klebsiella pneumoniae. Most of the compounds exhibited antibacterial activity at an MIC value of 25 μg/ml against Pseudomonas aureginosa. For the antifungal activity against C. albicans, compounds 2e, 2h and 2m were found more active than the other derivatives (MIC 12.5 μg/ml). The antimicrobial activity of some of these benzamide and phenylacetamide derivatives ( 2a, 2b, 2f, 2g, 2h and 2k), possible metabolites of benzoxazoles, was also compared with that of the cyclic analogues 3– 8. Compound 2f possesses two dilutions better antifungal activity than its cyclic analogue the benzoxazole derivative 5 against C. albicans, while having one dilution better antibacterial activity against Streptococcus faecalis and K. pneumoniae.

Ligand-induced conformational change in penicillin acylase

The enzyme penicillin acylase (penicillin amidohydrolase EC 3.5.1.11) catalyses the cleavage of the amide bond in the benzylpenicillin (penicillin G) side-chain to produce phenylacetic acid and 6-aminopenicillanic acid (6-APA). The enzyme is of great pharmaceutical importance, as the product 6-APA is the starting point for the synthesis of many semi-synthetic penicillin antibiotics. Studies have shown that the enzyme is specific for hydrolysis of phenylacetamide derivatives, but is more tolerant of features in the rest of the substrate. It is this property that has led to many other applications for the enzyme, and greater knowledge of the enzyme’s structure and specificity could facilitate engineering of the enzyme, enhancing its potential for chemical and industrial applications.An extensive study of the binding of a series of phenylacetic acid derivatives has been carried out. A measure of the relative degree of inhibition of the enzyme by each of the compounds has been obtained using a competitive inhibition assay, and the structures of a number of these complexes have been determined by X-ray crystallography. The structures reveal a clear rationale for the observed kinetic results, but show also that some of the ligands cause a conformational change within the binding pocket. This change can generally be understood in terms of the size and orientation of the ligand within the active site.The results reveal that ligand binding in penicillin acylase is facilitated by certain amino acid residues that can adopt two distinct, energetically favourable positions in order to accommodate a variety of compounds within the active site. The structures of these complexes provide evidence for conformational changes in the substrate-binding region that may act as a switch in the mechanism of autocatalytic processing of this enzyme.

Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective sigma1 receptor ligands.

A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.

HIV-1 specific phenylacetamide derivatives: A novel class of reverse transcriptase inhibitors with potent and selective antiviral activity in vitro: R. Pauwels 1, K. Andries 2, Z. Debyser 1, P. Van Daele 2, D. Schols 1, M.A.C. Janssen 2, J. Desmyter 1, E. De Clercq 1 and P.A.J. Janssen 21Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium and

HIV-1 specific phenylacetamide derivatives: A novel class of reverse transcriptase inhibitors with potent and selective antiviral activity in vitro: R. Pauwels 1, K. Andries 2, Z. Debyser 1, P. Van Daele 2, D. Schols 1, M.A.C. Janssen 2, J. Desmyter 1, E. De Clercq 1 and P.A.J. Janssen 21Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium and