- Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents
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As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC50 values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π–π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.
- Gu, Xiaoke,Zhang, Yinpeng,Zou, Yueting,Li, Xin,Guan, Mingyu,Zhou, Qingqing,Qiu, Jingying
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- 4-Sulfamoylphenylalkylamides as Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae
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A current issue of antimicrobial therapy is the resistance to treatment with worldwide consequences. Thus, the identification of innovative targets is an intriguing challenge in the drug and development process aimed at newer antimicrobial agents. The state-of-art of anticholera therapy might comprise the reduction of the expression of cholera toxin, which could be reached through the inhibition of carbonic anhydrases expressed in Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). Therefore, we focused our interest on the exploitation of sulfonamides as VchCA inhibitors. We planned to design and synthesize new benzenesulfonamides based on our knowledge of the VchCA catalytic site. The synthesized compounds were tested thus collecting useful SAR information. From our investigation, we identified new potent VchCA inhibitors, some of them displayed high affinity toward VchCAγ class, for which few inhibitors are currently reported in literature. The best interesting VchCAγ inhibitor (S)-N-(1-oxo-1-((4-sulfamoylbenzyl)amino)propan-2-yl)furan-2-carboxamide (40) resulted more active and selective inhibitor when compared with acetazolamide (AAZ) as well as previously reported VchCA inhibitors.
- Mancuso, Francesca,De Luca, Laura,Bucolo, Federica,Vrabel, Milan,Angeli, Andrea,Capasso, Clemente,Supuran, Claudiu T.,Gitto, Rosaria
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p. 3787 - 3794
(2021/10/20)
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- Addressing hERG activity while maintaining favorable potency, selectivity and pharmacokinetic properties of PPARδ modulators
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One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.
- Lagu, Bharat,Senaiar, Ramesh S.,Kluge, Arthur F.,Mallesh,Ramakrishna,Bhat, Raveendra,Patane, Michael A.
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- Design, synthesis, and molecular docking of novel indole scaffold-based VEGFR-2 inhibitors as targeted anticancer agents
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A series of new indole derivatives 1–18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC50 value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.
- Roaiah, Hanaa M.,Ghannam, Iman A. Y.,Ali, Islam H.,El Kerdawy, Ahmed M.,Ali, Mamdouh M.,Abbas, Safinaz E-S.,El-Nakkady, Sally S.
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- PPAR AGONISTS, COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
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Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).
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Page/Page column 45
(2017/11/10)
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- Substituted pyrimidine derivatives with Akt inhibiting activity, and preparation method and application thereof
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The invention relates to novel substituted pyrimidine derivatives with Akt inhibiting activity and a preparation method thereof, a pharmaceutical composition comprising the substituted pyrimidine derivatives and salts thereof, and application of the substituted pyrimidine derivatives and salts thereof in preparing drugs for preventing and/or treating tumors. The structural formula of the compounds is disclosed as Formula (I) or Formula (II). The compounds have the advantages of novel structure, outstanding Akt inhibiting activity, high safety and low preparation cost, and have favorable application prospects in preparing antineoplastic drugs.
- -
-
Paragraph 0109; 0111
(2016/12/16)
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- Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines
-
A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702 nM against hCA I, of 0.41-288 nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines.
- Abdel Gawad, Nagwa M.,Amin, Noha H.,Elsaadi, Mohammed T.,Mohamed, Fatma M.M.,Angeli, Andrea,De Luca, Viviana,Capasso, Clemente,Supuran, Claudiu T.
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p. 3043 - 3051
(2016/06/13)
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- Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone-based sulfonamide derivatives
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Four series of sulfonamides incorporating chromone moieties were synthesized and assessed for their cytotoxic activity against MCF-7 and A-549 cell lines, considering the fact that some of these tumors overexpress isoforms of carbonic anhydrase (CA, EC 4.2.1.1) which is inhibited by sulfonamides. Most new sulfonamides showed weak inhibitory activity against the offtarget, cytosolic isoforms hCA I, II but effectively inhibited the tumor-associated hCA IX and XII. The most active compounds featured a primary SO2NH2 group and were active in the low micromolar range against MCF-7 and A-549 cell lines. Compound 4a showed IC50 of 0.72 and 0.50 1/4M against MCF-7 and A-549 cell lines, respectively, and was further evaluated for its proapoptotic activity which proved enhanced in both tumor types.
- Awadallah, Fadi M.,El-Waei, Tamer A.,Hanna, Mona M.,Abbas, Safinaz E.,Ceruso, Mariangela,Oz, Beyza Ecem,Guler, Ozen Ozensoy,Supuran, Claudiu T.
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p. 425 - 435
(2015/05/05)
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- ARYL AND HETEROARYL ETHER COMPOUNDS AS ROR GAMMA MODULATORS
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The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein Ring A, Ring B, R, R2, R3, n, and p are as defined herein, which are active as modulators of retinoid-related orpha
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Page/Page column 70; 71
(2015/11/09)
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- A convenient method for synthesis of 5-chloro-2-aryloxazole-4-carbaldehyde with vilsmeier reagent
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A convenient method for synthesis of 5-chloro-2-aryloxazole-4-carbaldehyde 3 in moderate to good yields had been developed via the Vilsmeier reaction of readily available N-arylglycine 2 at 100 °C, provided a novel route for the construction of nitrogen heterocycles. A series of these compounds were synthesized by this method and optimization of conditions was performed. The Japan Institute of Heterocyclic Chemistry.
- Jin, Can,Chen, Jun,Su, Weike
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experimental part
p. 153 - 161
(2011/04/21)
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- Phenylpropenamide derivatives: Anti-hepatitis B virus activity of the Z isomer, SAR and the search for novel analogs
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Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus (HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents, with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the activity of this class of molecules resides in the Z isomer. Further structure-activity relationship studies around the active Z isomer identified compounds that displayed potent antiviral activity against HBV with EC90 value of approximately 0.5 μM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors.
- Wang, Peiyuan,Naduthambi, Devan,Mosley, Ralph T.,Niu, Congrong,Furman, Phillip A.,Otto, Michael J.,Sofia, Michael J.
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scheme or table
p. 4642 - 4647
(2011/09/12)
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- Structural effects of N-aromatic acyl-amino acid conjugates on their deconjugation in the cecal contents of rats: Implication in design of a colon-specific prodrug with controlled conversion rate at the target site
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N-aromatic acyl-amino acid conjugates possess a colon-targeted property, implying that such conjugates are stable and are not absorbable until reaching the large intestine in which they are microbially converted (hydrolysed) to the parent drugs that are therapeutically active. To investigate the structural effect of N-aromatic acyl-amino acid conjugates on the large intestinal deconjugation, the hydrolysis of various N-aromatic acyl-amino acid conjugates was examined in the cecal contents. On incubation of conjugates with glycine,d or/andl forms of alanine or phenylalanine in the cecal contents, the conjugates withd amino acids were not hydrolysed. The other conjugates are susceptible to the hydrolysis, the rates of which decreased as the size of the substituent on the 2-position of the amino acids increased. The conjugates with alkyl analogs (2-4 carbons) of glycine and taurine were resistant to the hydrolysis, while taurine- and glycine-conjugates were hydrolysed effectively. The hydrolysis of N-aromatic acyl-glycine conjugates was enhanced by para-substitution of electron withdrawing groups on the aromatic acyl moiety and vice versa for electron-donating groups. While a methyl, methoxy or chloro group on the ortho-position retarded the hydrolysis, a hydroxyl group on the position accelerated it. Our data may provide useful information for the design of a colon-specific prodrug with controlled conversion rate in the large intestine.
- Kong, Hyesik,Kim, Hyunjeong,Do, Heejeong,Lee, Yonghyun,Hong, Sungchae,Yoon, Jeong-Hyun,Jung, Yunjin,Kim, Young Mi
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experimental part
p. 343 - 354
(2012/04/10)
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- Novel synthesis and characterization of some new-2-(R) phenyl- 4-(-4-bromo-2-fluoro benzylidene)-oxazol-5-ones
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In the present study a series of some new 2-(substituted) phenyl- 4-(4-bromo-2-fluoro benz-ylidene)-oxazol-5-ones (2a-2j) were synthesized by the condensation of selected substituted benzoyl glycine (1a-1j) with 4-bromo-2-fluoro benzaldehyde in the presence of fused sodium acetate and acetic anhydride. The constitution of the newly synthesized compounds has been supported by their physical properties, elemental analysis, colour, m.p, IR spectral analysis data.
- Pareek, Alok K.,Joseph,Seth, Daya S.
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experimental part
p. 1533 - 1536
(2011/10/12)
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- A facile synthesis of N-formylbenzamides by oxidative decarboxylation of N-aroylglycine induced by Ag+/S2O82-
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A facile method is described for the synthesis of N-formylbenzamides by oxidative decarboxylation of N-aroylglycine using catalytic silver(I) and 2 equivalents of ammonium persulfate as an oxidant in a biphasic system (CHCl 3/water).
- Huang, Wenhua,Zhang, Li'e
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p. 738 - 739
(2007/10/03)
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- Anthranilate 4H-oxazol-5-ones: Novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors
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D-optimal design and Projection to Latent Structures (PLS) analysis were used to optimize screening hit 5 (B. subtilis AcpS IC50: 15 μM, B. subtilis MIC: >200 μM) into a series of 4H-oxazol-5-one, small molecule, antibacterial, AcpS inhibitors. Specifically, 15, 16 and 18 show μM or sub-μM AcpS inhibition (IC50s: 15: 1.1 μM, 16: 1.5 μM, 18: 0.27 μM) and moderate antibacterial activity (MICs: 12.5-50 μM) against B. subtilis, E. faecalis ATCC, E. faecalis VRE and S. pneumo+.
- Gilbert, Adam M.,Kirisits, Matthew,Toy, Patrick,Nunn, David S.,Failli, Amadeo,Dushin, Elizabeth G.,Novikova, Elena,Petersen, Peter J.,Joseph-Mccarthy, Diane,McFadyen, Iain,Fritz, Christian C.
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- Synthesis of N-(morpholinomethyl) benzamides as moclobemide analogs
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Syntheses of new morpholinomethylbenzamides 6 bearing both electron-withdrawing and electron-releasing groups at the aromatic ring are described. The strategy involved synthesis of hippuric acid ethyl esters 3, their hydrolysis to hippuric acids 4, subseq
- Pessoa-Mahana, Hernan,Astudillo, Claudio I. O.,Araya-Maturana
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p. 1437 - 1445
(2007/10/03)
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- E-Z ratio and stability of halogenated benzylidene derivatives formed during the detection of glycine conjugates
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The orange fluorescing spot formed during the detection of halogenated hippuric acids with 4-N,N-Dimethylaminobenzaldehyde on TLC-plates consists of a E/Z-mixture of the corresponding benzyliden derivatives. Intermediates are the azlactones.
- Oelschlaeger,Seeling,Radman,Bockhard
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p. 825 - 828
(2007/10/03)
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- Ethanolysis of 4- (N, N-dimethylaminomemylene)-2-aryl-2-oxazolin-5-ones with sodium ethoxide in ethanol at reflux temperature: Unusual formation of N-acyl-α-amino acids
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The ethanolysis of 4-(N, N - dimethylaminomethylene)-2-aryl-2-oxazolin-5-ones 1 with sodium ethoxide in ethanol at reflux temperature leads to the formation of N-acyl-α-amino acids 3. Further, the reaction of 4-hydroxymethylene-2-phenyl-2-oxazolin-5 one 4 with sodium ethoxide in ethanol at reflux temperature also gives product 3a. The plausible mechanism has been proposed.
- Singh, Ram S.
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p. 1296 - 1299
(2007/10/03)
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- Synthesis and in Vitro Aldolase Reductase Inhibitory Activity of Compounds Containing an N-Acylglycine Moiety
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A number of N-benzoylglycines (6), N-acetyl-N-phenylglycines (7), N-benzoyl-N-phenylglycines (8), and tricyclic N-acetic acids (9-12) were synthesized as analogues of the N-acylglycine-containing aldolase reductase inhibitors alrestatin and 2-oxoquinoline-1-acetic acid.Derivatives of 6, which represent ring-simplified analogues of alrestatin, are very weak inhibitors of aldolase reductase obtained from rat lens, producing 50percent inhibition only at concentrations exceeding 100 μM.Compounds of series 7 were designed as ring-opened analogues of the 2-oxoquinolines.While this derivatives are more potent than compounds of series 6 (IC 50s of 6-80 μM), they are less active than the corresponding 2-oxoquinolines.Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxoquinoline-1-acetic acids.These compounds are substantially more potent than compounds of series 6 and 7 and display inhibitory activities comparable to or greater than alrestatin or the 2-oxoquinolines (IC 50s of 0.1-10 μM).Of the rigid analogues of 8, the most potent derivative is benzoxindol (12) with an IC 50 of 0.67 μM, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.
- DeRuiter, Jack,Swearingen, Blake E.,Wandrekar, Vinay,Mayfield, Charles A.
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p. 1033 - 1038
(2007/10/02)
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- THE CHEMISTRY OF PEPTIDES RELATED TO METABOLITES OF TRICHODERMA SPP. 3. AN UNUSUAL DEHYDRATION REACTION OF 2-METHYLALANINE PEPTIDES AFTER ELECTRON IMPACT IONIZATION
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Peptides of 2-methylalanine, where this residue is not the C-terminus, give molecular ions of low abundance on electron impact ionization, but abundant ions are formed by loss of the elements of water from the molecular ion.The dehydration reaction dose n
- Jamieson W. D.,Taylor A.
-
p. 277 - 284
(2007/10/02)
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- A Chromogen Produced in the Reaction of Glycine Derivatives with Acetic Anhydride and Pyridine
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The yellow chromogen produced in the assay of glutathione or glycocholic acid by their reactions with acetic anhydride and pyridine was found to be a conjugated compound containing pyridylidene and 2-oxazoline rings.The structure was confirmed by hydrolysis of the chromogen to 4-aminomethylpyridine.The same chromogen was formed with benzoylpeptides having C-terminal glycine.Keywords - chromogen; Glutathione; glycocholic acid; spectrophotometry; 2-oxazoline; pyridylidene
- Hirota, Kazuhiro,Ikeda, Mikiko
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p. 3100 - 3104
(2007/10/02)
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- Structure-Reactivity Studies on the Equilibrium Reaction between Phenolate Ions and 2-Aryloxazolin-5-ones: Data Consistent with a Concerted Acyl-Group-Transfer Mechanism
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The rate and equilibrium constants for the reaction between phenolate anions and 2-aryloxazolin-5-ones have been measured as a function of the structures Ar and Ar'.The change in "effective" charge on both phenol-leaving oxygen and endocyclic oxygen from ground to transition state, as determined from the relevant Broensted parameters, is substantial and essentially additive consistent with a concerted displacement mechanism.The stepwise mechanism requires a small change in effective charge on the phenol oxygen because departure of phenolate ion from the tetrahedral intermediate cannot be rate limiting.Hydroxide ion attack on the C-5 atom of the oxazolinone to yield a benzoylglycine has a Hammett ?- dependence which can only arise from a concerted displacement; the rate-limiting step for the stepwise mechanism is the addition of hydroxide and the transition state of the rate-limiting step will therefore not involve much endocyclic C-O bond fission.An inverse deuterium oxide solvent isotope effect indicates that the observed general-acid catalysis has a specific-acid/nucleophilic mechanism; both hydroxide and oxonium ion catalysis are demonstrated by using 18O-labeling experiments to involve nucleophilic attack at the carbonyl (C-5) center.The equilibrium constant for reaction of azide ion with 2-phenyloxazolin-5-ones has been measured; it is suggested that the absence of racemization during azide coupling in peptide synthesis is related to the very unfavorable equilibrium constant for oxazolinone formation compared with that of activated oxygen esters.
- Curran, Terence C,Farrar, Charles R.,Niazy, Omima,Williams, Andrew
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p. 6828 - 6837
(2007/10/02)
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