Phenylacetamide Derivatives Research Articles

Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.

Metal-free Borylation of α-Naphthamides and Phenylacetic Acid Drug.

Site-selective C-H borylation is an important strategy for constructing molecular diversity in arenes and heteroarenes. Although transition-metal-catalyzed borylation is well explored, developing metal-free strategies remains scarce. Herein, we developed a straightforward approach for BBr3-mediated selective C-H borylation of naphthamide and phenyl acetamide derivatives under metal-free conditions. This methodology appears to be economical and cost-effective. Successful borylation of drug molecules such as ibuprofen and indoprofen demonstrates the versatility and utility of this metal-free borylation. An exclusive monoselectivity was observed without a trace of diboration. Despite the possibility of forming a 5-membered boronated intermediate at the ortho-position, the selectively 6-membered intermediate paved the way for the formation of the peri-product, which was further supported by detailed computational investigation.

DENSITY FUNCTIONAL THEORY, DOCKING, SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME 2-(2-ARYL AMINO) PHENYL ACETAMIDE DERIVATIVES

A series of new 2-(2-aryl amino) phenyl acetamide derivatives were synthesized and their chemical structures were identified using spectroscopic techniques (UV-VIS, FTIR, 1HNMR, and MS). Computational studies have been carried out for prediction reactivity and density function theory (DFT) calculations for the acetamide derivatives, as well as the spatial electron distribution of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were computed. The docking study against prostaglandin synthetase-2 (COX-II coenzyme) was computed, and four compounds (D, F, H, and L) gave high scores (Kcal/mol). Some of these synthetic compounds were evaluated for their biological activities in vitro (antimicrobial, antioxidant, anticancer, and anti-inflammatory). Finally, the compounds B, D, F, and K have a good correlation between theoretical and experimental studies as cyclooxygenase inhibitors and weak to moderate antimicrobial, antioxidant, and cancer activities

Copper supported modified magnetic carrageenan as a bio-based catalyst for the synthesis of novel scaffolds bearing the 1,2,3-triazole unit through the click reaction.

The ongoing work delineates the design of a novel library of 1,2,3-triazole-attached phenylacetamides through molecular hybridization of propargyl and phenylacetamide derivatives. Copper-supported modified magnetic carrageenan serves as a green heterogeneous catalyst, ensuring high yield, efficient reaction times, high atom economy, utilization of an environmentally friendly catalyst from a natural source, and a straightforward workup procedure. The successful synthesis of the catalyst is confirmed and evaluated using various analytical techniques, while the synthetic compounds are characterized through 1H NMR and 13C NMR.

ADME, Synthesis and Antimycobacterial Activity of 1,2,4-Triazol-3-thiol Linked Phenylacetamide Derivatives

Background:: Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is one of the most contagious and fatal human pathogens which necessitates the development of modified existing drugs or derivatives with action against novel targets. Aims and Objectives:: In the present work, we have explored a few, 2-(5-(substituted)-4H-1,2,4-triazole-2-ylthio)-N-(substituted) phenyl acetamide (5A-5E) derivatives as anti-TB. Materials and Methods:: On the basis of SAR were synthesized and screened against Mycobacterium tuberculosis H37Rv using MABA assay. Their ADME properties were also checked. Results:: ADME analysis showed results comparable with standard drug (rifampicin). Derivative 5D turned out to be the most active amongst all the derivatives with MIC of 0.8μg/ml, comparable to standard drugs like rifampicin(0.8μg/ml) and streptomycin(0.8μg/ml). Conclusion:: All five compounds have shown excellent inhibitory activity (1.6μg/ml) against the Mycobacterium tuberculosis H37Rv strain. Compound 5D shows a promising activity (0.8μg/ml) as compared to standard drugs and also it has shown the highest docking score. Literature search has revealed the presence of 1,2,4-triazole derivatives linked to aromatic link and possessing amide linkage and the presence of Sulphur atom in the most active derivatives, which supports our designed compounds. Based on these findings, further derivatives would be synthesized and explored for their role in tuberculosis.

N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives: Design, synthesis and biological evaluation against MCF7 breast cancer cell line

This work describes the straightforward and efficient one-pot synthesis of a new library of N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives (19–27). Using the MTT assay, these compounds were evaluated for their in vitro anticancer activity against the MCF7 human breast cancer cell line, and the results were compared to the standard doxorubicin. The majority of compounds exhibited an inhibitory effect against the cancer cell line, with compounds 19, 22, and 26 exhibiting exceptional cytotoxicity against MCF7 cells. Using flow cytometry, the most potent compound 19 on the induction of apoptosis in the breast cancer cell line was determined. Compound 19 induced G1-phase cell cycle arrest followed by apoptotic cell death. In silico analyses of potent compounds 19, 22, and 26 were conducted to investigate their interactions with Human DNA topoisomerase II. The energy calculations were found to be in excellent agreement with the calculated IC50 values. In addition, drug similarity parameter values for the three active compounds were determined using in silico ADME prediction studies. Considering all of these results, it appears that these N-(benzazol-2-yl)-2-substituted phenylacetamide derivatives may be effective anticancer agents. This work may possibly generate new concepts for the enhancement of inhibitors of human DNA topoisomerase II for breast cancer treatment.

Design, synthesis, α‐glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole‐carbohydrazide‐phenoxy‐N‐phenylacetamide derivatives

A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were designed, synthesized, and screened for their α-glucosidase inhibitory abilities and cytotoxic effects. The results obtained in the α-glucosidase inhibition assay indicated that most of the synthesized derivatives displayed good to moderate inhibitory abilities (Ki values ranging from 14.65 ± 2.54 to 37.466 ± 6.46 μM) when compared with the standard drug acarbose (Ki = 42.38 ± 5.73 μM). Among them, 2-mehoxy-phenoxy derivatives 7l and 7h with 4-nitro and 4-chloro substituents on the phenyl ring of the N-phenylacetamide moiety, respectively, displayed the most inhibition effects. The inhibitory mechanism of these compounds was investigated by molecular docking studies. The in vitro cytotoxicity assay showed that only one compound, 2-methoxy-phenoxy derivative 7k with a 4-bromo substituent on the phenyl ring of the N-phenylacetamide moiety, exhibited moderate cytotoxicity against the human non-small-cell lung cancer cell line A549 and the rest of the compounds show almost no cytotoxicity. Further cytotoxic evaluations were also performed on compound 7k. The in silico pharmacokinetic study predicted that the selected compounds 7l and 7h are likely to be orally active.

Research and study of 2-((4,6 dimethyl pyrimidine-2-yle) thio)-N-phenyl acetamide derivatives as inhibitors of sirtuin 2 protein for the treatment of cancer using QSAR, molecular docking and molecular dynamic simulation.

Phenyl acetamide derivatives have a wide range of biological activities, so their research and development can be useful and effective for the design production of new drugs. In this project, quantitative structure-activity relationship (QSAR) was performed. For modeling two methods of multiple linear regression (MLR) and nonlinear regression of support vector machine (SVR) were used. In the MLR stage, the best model with the values of R2train = 0.913 and R2test = 0.881 was selected by stepwise method. In this model, 4 descriptors of BELV2, GATS8p, GATS6e and RDF080m were included, which were used as input for the nonlinear support vector regression method. In the SVR model, the best results were obtained using the radial Gaussian kernel function (RBF) with R2train = 0.978 and R2test = 0.990. In the next step, using molecular docking and molecular dynamic simulation methods, the interaction between phenyl acetamide derivatives and the sirtuin 2 protein was investigated. Examining the results of molecular docking, it was observed that these derivatives formed complexes by forming hydrogen and hydrophobic bonds with the sirtuin 2 protein. Also, the results of molecular dynamic simulation show that phenyl acetamide compounds form stable complex with the sirtuin 2 protein, and it was found that the compounds with more activity have formed a number of hydrogen bonds with the protein.

Benzothiazole Derivatives Endowed with Antiproliferative Activity in Paraganglioma and Pancreatic Cancer Cells: Structure-Activity Relationship Studies and Target Prediction Analysis.

The antiproliferative effects played by benzothiazoles in different cancers have aroused the interest for these molecules as promising antitumor agents. In this work, a library of phenylacetamide derivatives containing the benzothiazole nucleus was synthesized and compounds were tested for their antiproliferative activity in paraganglioma and pancreatic cancer cell lines. The novel synthesized compounds induced a marked viability reduction at low micromolar concentrations both in paraganglioma and pancreatic cancer cells. Derivative 4l showed a greater antiproliferative effect and higher selectivity index against cancer cells, as compared to other compounds. Notably, combinations of derivative 4l with gemcitabine at low concentrations induced enhanced and synergistic effects on pancreatic cancer cell viability, thus supporting the relevance of compound 4l in the perspective of clinical translation. A target prediction analysis was also carried out on 4l by using multiple computational tools, identifying cannabinoid receptors and sentrin-specific proteases as putative targets contributing to the observed antiproliferative activity.

Synthesis and Antibacterial Activities of 2-Oxo-N-phenylacetamide Derivatives Containing a Dissulfone Moiety Target on Clp.

Rice bacterial blight and rice bacterial streak are two serious rice diseases and have caused great harm to the production of rice all over the world. To develop an efficient antibacterial agent with a novel target, a series of novel 2-oxo-N-phenylacetamide derivatives containing a dissulfone moiety were synthesized, and their antibacterial activities were evaluated. Among them, compound D14 exhibited the best antibacterial activities, especially against Xoo and Xoc with EC50 values of 0.63 and 0.79 mg/L, respectively, which were much better than the commercial control of bismerthiazol (BT) (76.59 and 83.35 mg/L, respectively) and thiodiazole copper (TC) (91.72 and 114.00 mg/L, respectively). Meanwhile, compound D14 can interact with a CRP-like protein (Clp) of Pxo99A and show strong binding activity with Xoo-Clp with a Kd value of 0.52 μM, which was far superior to the corresponding Kd values of BT (183.94 μM) and TC (222.58 μM). Treatment of D14 and deletion of the clp gene could significantly reduce the expression of the clp gene and attenuate the virulence of pathogenic bacteria. These results indicated that compound D14 could be used as a potential novel agricultural bactericide and Clp can be used as a target protein for the control of plant bacterial diseases. This work provided reliable support for developing novel antibacterial agents based on Clp as a target protein.

Synthesis, antioxidant, antimicrobial, and molecular docking studies of some N-cinnamyl phenylacetamide and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives

A series of N-cinnamyl phenylacetamides (1-8) and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives (9-12) with different active moieties have been designed, synthesized and tested for antioxidant and antimicrobial activity. The synthetic protocol was based on the formation of Schiff bases followed by chloroacetylation of imines. The chemical structures of the compounds were recognized by 1H-NMR, 13C-NMR, and MS spectral techniques. The structure and configuration of the substituents are shown to significantly influence the antioxidant and antimicrobial activity of the compounds under study. Compounds 1-4 and 6-10 exhibited superior antioxidant activity (IC50 = 9.92-19.06 µM) compared to α-tocopherol (IC50 = 26 µM). N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives (9-12) showed excellent antibacterial activities against all the tested strains with MIC values in the range of 10-230 µM comparable to those of amoxicillin (80-275 µM) against Bacillus cereus (G+), Staphylococcus aureus (G+), Escherichia coli (G-), and Pseudomonas aeruginosa (G-). Besides, the compounds also exhibited candidacidal activity against Candida albicans and (E)-2-chloro-N-(3,7-dimethylocta-2,6-dien-1-yl)-N-(2-ethyl-6-methylphenyl)acetamide 12 was the most active compound (EC50 = 423.62 µM). Molecular docking, drug-likeness data, physicochemical properties, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters of the compounds were in silico computed. The derivatives presented good properties for Lipinski's parameters, poor solubility in the aqueous medium (Log S of -4.06 to -5.97), and PSA <140, indicating good permeability in biological membranes and gastrointestinal absorption. Molecular docking to the active sites of NADPH oxidase (PDB: 1W6X), penicillin-binding protein 2a (PDB: 1VQQ), and lanosterol 14-alpha demethylase (PDB 1EA1) revealed that most compounds displayed minimal binding energy and have a good affinity toward the active pocket of each enzyme. This is the first article to describe the antioxidant and antimicrobial properties of N-cinnamyl phenylacetamide and N-(3,7-dimethylocta-2,6-dien-1-yl) phenylacetamide derivatives.

Neuroprotective activity studies of some phenylacetamide derivatives bearing 1H-pyrazole or 1H-1,2,4-triazole

Neuroprotective activity studies of some phenylacetamide derivatives bearing 1H-pyrazole or 1H-1,2,4-triazole

Synthesis and Evaluation of Aryl/Heteroaryl Benzohydrazide and Phenylacetamide Derivatives as Broad‐Spectrum Antibacterial Agents

AbstractA series of novel aryl/heteroaryl benzohydrazide (3 a–d) and aryl/heteroaryl phenylacetamide derivatives (5 a–g) were designed, synthesized and characterized by spectral techniques. The synthesized compounds were screened against pathogenic bacteria to assess their in vitro antibacterial properties. From the eleven synthesized compounds, 3 b(0.7 μg/mL) and 3 c(0.6 μg/mL) exhibited potent activity against a panel of organisms especially against S. aureus. Further, time‐kill study confirmed the bactericidal activity of 3 b and 3 c against S. aureus, that may be because of conjoined benzothiazole and benzohydrazide moieties in their structures. Extra‐precision docking and binding free energy calculation were also performed for the title compounds, in which 3 c(‐6.23 kcal/mol) exhibited higher binding affinity against S. aureus ParE (SaParE). Molecular dynamic simulation of 50 ns was used to find out the stability of predicted binding conformation of 3 c/SaParE. Besides, assessment of in silico ADMET properties illustrates that the title compounds were in agreement with Lipinski's rule parameters. The study could offer a unique framework that may lead to the discovery of novel antibacterials.

Novel 1,2,4-triazole analogues as mushroom tyrosinase inhibitors: synthesis, kinetic mechanism, cytotoxicity and computational studies.

We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a-l) were synthesized by the reaction of 4- and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a-c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a-d) under basic condition. By using the analytical techniques for instance, FTIR, LC-MS, 1H NMR and 13C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a-l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC50 = 0.0048 ± 0.0016µM) exhibits 3500 times more activity compared with standard drug kojic acid (IC50 = 16.8320 ± 1.1600µM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25µM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.

Synthesis and Antibacterial Evaluation of N-phenylacetamide Derivatives Containing 4-arylthiazole Moieties.

A series of new N-phenylacetamide derivatives containing 4-arylthiazole moieties was designed and synthesized by introducing the thiazole moiety into the amide scaffold. The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. Their in vitro antibacterial activities were evaluated against three kinds of bacteria—Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac) and X.oryzae pv. oryzicola (Xoc)—showing promising results. The minimum 50% effective concentration (EC50) value of N-(4-((4-(4-fluoro-phenyl)thiazol-2-yl)amino)phenyl)acetamide (A1) is 156.7 µM, which is superior to bismerthiazol (230.5 µM) and thiodiazole copper (545.2 µM). A scanning electron microscopy (SEM) investigation has confirmed that compound A1 could cause cell membrane rupture of Xoo. In addition, the nematicidal activity of the compounds against Meloidogyne incognita (M. incognita) was also tested, and compound A23 displayed excellent nematicidal activity, with mortality of 100% and 53.2% at 500 μg/mL and 100 μg/mL after 24 h of treatment, respectively. The preliminary structure-activity relationship (SAR) studies of these compounds are also briefly described. These results demonstrated that phenylacetamide derivatives may be considered as potential leads in the design of antibacterial agents.

Synthesis and biological activity of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]-N-phenylacetamide derivatives as antimalarial and cytotoxic agents

A novel series of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]- N-phenylacetamide derivatives is synthesized via substitution with 2-mercapto-4-methyl-5-thiazoleacetic acid at position 4 of 4,7-dichloroquinoline to obtain an intermediate acetic acid derivative. The chemical behavior of these reactants was investigated using different reaction conditions to optimize the nucleophilic substitution at position 4. The final compounds are prepared using a modified version of the Steglich esterification reaction between the acetic acid intermediate 3 and different anilines. The structures are confirmed by infrared, 1H, 13C, distortionless enhancement by polarization transfer 135°, Correlated Spectroscopy, heteronuclear correlation spectroscopy and (Long range HETCOR using three BIRD pulses) FLOCK-NMR spectral studies, and by elemental analysis. The synthesized compounds are tested in vitro and in vivo for their potential antimalarial and anticancer activities, with derivative 11 being the most promising candidate.

Discovery of phenyl acetamides as potent and selective GPR119 agonists

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Synthesis and Evaluation of Phenyliminoindolin-Containing Phenylacetamide Derivatives with the Antidepressant and Anticonvulsant Effects

To discover a novel antidepressant-like effect and anticonvulsant compound, seventeen new 2-oxo-3-phenyliminoindolin-1-Nphenylacetamide compounds were synthesized and screened for the antidepressant activity and anticonvulsant effects. 2-oxo-3-phenyliminoindolin-1-N-phenylacetamide derivatives were synthesized with indoline-2, 3-dione as the starting material, through a nucleophilic substitution reaction and a nucleophilic addition-elimination reaction. The target derivatives 2a-2q were evaluated the antidepressant-like activity using the FST, TST, and evaluated anticonvulsant effect by MES test. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC-ECD. It was observed that 13 compounds showed significant reductions in the immobility time in the FST at a concentration of 50 mg/kg. Compound 2b was found to have the most potent antidepressant activity in the FST and the TST for 30 min after treatment. Compound 2b significantly increased the concentrations of the main neurotransmitters 5-HT, NE and the metabolite (5-HIAA, suggesting that the effects of compound 2b may be mediated through these neurotransmitters. As assessed using maximal electroshock, 13 compounds showed the anticonvulsant effects administered at the concentration levels of 100 or 300 mg/kg. Compound 2b showed anticonvulsant effect. Compound 2b could potentially be used as adjuncts of the antidepressants to treat depression in patients with epilepsy. In conclusion, compound 2b produced significant antidepressant-like activity and the mechanism of action may be due to increased 5-HT and NE in the mouse. Compound 2b showed more anticonvulsant effect. Compound 2b could potentially be used as adjuncts of the antidepressants to treat depression in patients with epilepsy.

Expression and in Vitro Binding of Protease Activated Receptor1 (PAR1) with Novel Anti-PAR1 Molecules: Data on Fresh Myeloma Marrow Plasma Cells and Human Myeloma Cell Lines

Introduction and Aim: Myeloma plasma cells are dependent on stromal support which is mediated through cell adhesion. Heparanase activity has been shown to be associated with aggressive behavior or Bortezomib resistance and can lead to increased levels of proteases as well as shedding of heparan sulfate proteoglycan syndecan-1(CD138) from myeloma cells. We have recently published in vivo anti-myeloma effects of low molecular weight heparin (Beksac et al Acta Haematol 2015). Protease activated Receptor (PAR1) is a thrombin receptor. PAR1 gene and antigen expression on myeloma patient samples and cell lines (HMCL) has been recently reported by University of Arkansas (UAMS) group (Tian et al ASH 2011). They were able to find HMCLs H929, U266, JJN3 to express PAR1. Also expression was found to be highest among patients with 5q amplification where the PAR1 gene is located.Patients and Methods: We analyzed PAR1 expression (WEDE15 PE, Beckman Coulter) by flow cytometry, on CD38+CD138+/-CD27+/- cells obtained from fresh patient bone marrow samples obtained either at diagnosis (n: 84)(NDMM) or relapse (n: 54)(RRMM) and were compared with marrow samples taken from patients without MM (n: 43). Our group in Ankara University had previously synthesized and published novel benzamide and phenyl acetamide derivatives. We performed an in silico docking analysis on these molecules, and eleven (TD10,TD12,TD12A,TD12B,TD13,TD14,TD14B,XT2,XT2B,XT5,XT11) were found to bind to PAR1. These molecules were screened using 72 hour MTT assay on primary and refractory cell lines (U266BR ,U266, JJN3BR, JJN3, H929R, OPM2, OPM2R, KMS28PE).Results: PAR1 expression was highest on platelets followed by myeloma plasma cells (0-81.9%) and did not correlate with ISS. PAR1 expression (Threshold: >2.5 % or >5%) could be detected in NDMM (35 % or 14%) and RRMM (31% or 19%) of patients (Table1). PAR1+CD38+138+ cells were more frequent among patients with lower percentage of plasma cells in RRMM group (2,98 ± 4,5 vs 1,93 ± 3,96, P=0.028) but not NDMM. PAR1 was similarly highly expressed on HCML. Two of the novel PAR1 binding molecules (XT5 and XT2B) were found to have the lowest IC50. The IC50 were similar for all HMCLs, primary and refractory, with XT5. With XT2B the IC50 was less (U266) or higher (JJN3) or similar (OPM2) for refractory compared to the primary HMCL. PAR1 expression and anti-myeloma IC50 values of cell lines are summarized in Table 2.Conclusion: PAR1 expression is detectable at very low or very high percentages on CD138+plasma cells. Expression is higher on cells with CD27 expression (patient samples) or lacking CD27 (HMCL). Inverse correlation between PAR1 expression and plasma cell percentage among myeloma patients is detected among RRMM but not on NDMM samples. This finding may point to expression of PAR1 on quiescent plasma progenitors as suggested by Tian et al previously. The intensity or frequency of PAR1 expression on HMCL did not influence the anti-myeloma effects of these novel molecules. PAR1 binding molecules, in particular XT5, are promising as they are effective even on Bortezomib refractory HCML. However their mechanism of action and the role of PAR1 require further investigations.This study has been supported by a research grant from Turkish Academy of Sciences.Table 1Frequency of PAR1 expression (> 2.5 %) on total plasma cells (CD38+138+) and on quiescent plasma cells (CD38+138+27+)Control (n=43)NDMM (n=84)RRMM (n=54)PCD38+138+ (%)0,56± 0,664,48 ± 7,675,44 ± 12,130,007PAR1+ among CD38+138 (%)6,18 ± 13,144,14 ± 11,003,42 ± 8,810,394PAR1+ among CD38+138+27+(%)5,44 ± 12,133,42 ± 8,813,58 ± 8,570,207Table 1Comparison of Flow Cytometric PAR1 expression and IC50 (in uM after 72 hours)of the two novel molecules on three Human Myeloma Cell Lines.H929RPMI8221U266IC50 XT2B33.9>10034.3IC50 XT58.125.459.77CD38+138+ (total%)85 %75 %80 %PAR1% and (MFI) within CD38+138+83 %(13,6)90 % (2,1)85 % (2,1) DisclosuresBeksac:Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma.. Usmani:Millennium: Honoraria, Speakers Bureau; Sanofi: Honoraria, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Honoraria, Research Funding. Tian:University of Arkansas for Medical Sciecnes: Employment.

Synthesis and cholinesterase inhibitory activity of some phenylacetamide derivatives bearing 1H-pyrazole and 1H-1,2,4-triazole

Abstract A group of N -phenylacetamide derivatives bearing five membered heterocyclic rings, pyrazole and 1,2,4-triazole, were synthesized to investigate their cholinesterase inhibitory activities. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated by using Ellman’s spectroscopic method. Results indicated that all of the compounds displayed moderate and selective AChE inhibitory activity and the most active compound was 2-(1 H -1,2,4-triazole-1-yl)- N -(3-methoxyphenyl)acetamide with an IC 50 value of 6.68 uM. Keywords: Alzheimer’s disease, pyrazole, 1,2,4-triazole, acetamide, cholinesterase inhibitory activity Ozet Pirazol ve 1,2,4-triazol tasiyan bir grup N -fenilasetamit turevi sentezlenmis ve kolinesteraz inhibitor aktiviteleri test edilmistir. Asetilkolinesteraz ve butirilkolinesteraz inhibitor aktiviteleri Ellman’in spektroskobik metoduna gore test edilmistir. Elde edilen sonuclar, tum bilesiklerin orta derecede ve secici asetilkolinesteraz inhibitor aktivite gosterdigini ortaya koymustur. Serideki en aktif bilesik ise 6.68 uM’lik IC 50 degeriyle 2-(1 H -1,2,4-triazol-1-il)- N -(3-metoksifenil)asetamit’tir.