- Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors
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α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33–54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 μM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 μM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48–50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.
- Umm-E-Farwa,Ullah, Saeed,Khan, Maria Aqeel,Zafar, Humaira,Atia-tul-Wahab,Younus, Munisaa,Choudhary, M. Iqbal,Basha, Fatima Z.
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supporting information
(2021/05/10)
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- AMINO ACID DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISEASES
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The present disclosure provides certain amino acid derivatives that inhibit NF-kB activation and are therefore useful for the treatment of inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 44
(2020/08/13)
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- Design, synthesis, biological evaluation and inhibition mechanism of 3-/4-alkoxy phenylethylidenethiosemicarbazides as new, potent and safe tyrosinase inhibitors
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Tyrosinase plays important roles in many different disease related processes, and the development of its inhibitors is particularly important in biotechnology. In this study, thirty-nine 3-/4-alkoxyphenylethyli-denethiosemicarbazides were synthesized as novel tyrosinase inhibitors based on structure-based molecular design. Our experimental results demonstrated that thirty-one of them possess remarkable tyrosinase inhibitory activities with IC50 value below 1μM, and 5a, 6e, 6g and 6t did not display any toxicity to 293T cell line at the concentration of 1000μmol/L. According to the inhibitory activities, several compounds were selected for detail investigation on the structure–activity relationships (SARs), mechanisms of enzyme inhibition, inhibitory kinetics and cytotoxicity. In particular, the interaction between the selected inhibitors and the active center of tyrosinase was considered and discussed in detail based on their structural characteristics. Taken together, the results presented here demonstrated that the newly designed compounds are promising candidates for the treatment of tyrosinase-related disorders and further development of them may have significant contribution in biomedical science.
- Liao, Bing,Mai, Yuliang,Shi, Huahong,Song, Senchuan,Wang, Fei
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p. 369 - 379
(2020/05/14)
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- Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents
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3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
- Bi, Fangchao,Ji, Shengli,Venter, Henrietta,Liu, Jingru,Semple, Susan J.,Ma, Shutao
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supporting information
p. 884 - 891
(2018/02/15)
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- Homoserine lactone derivatives, preparation method thereof and pharmaceutical composition for prevention or treatment of the periodontal diseases containing the same as an active ingredient
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The present invention relates to homoserine lactone derivatives, optical isomers of the same, or pharmaceutically acceptable salts of the same. The homoserine lactone derivatives in the present invention have excellent properties as a quorum sensing antagonist which hinders communications among bacteria. According to the present invention, the homoserine lactone derivatives can hinder gene expressions of bacteria while effectively blocking formation of biofilm which is known to raise resistance against antibiotics, and suppress propagation of bacteria, thereby being useful as a pharmaceutical composition for preventing or treating periodontal diseases.
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Paragraph 0259-0262
(2017/04/14)
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- Synthesis of bruguierol A employing ring closing metathesis
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An expedient synthesis of bruguierol A encompassing a novel 2,3-benzo-8-oxabicyclo[3.2.1]octane ring system is described employing ring closing metathesis to generate the oxa-bridged tricyclic core.
- Sarkar, Debayan,Venkateswaran, Ramanathapuram V.
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scheme or table
p. 3232 - 3233
(2011/06/28)
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- PHENYLALKYLCARBOXYLIC ACID DELIVERY AGENTS
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The present invention provides phenylalkylcarboxylic acid compounds and compositions containing such compounds which facilitate the delivery of biologically active agents.
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Page/Page column 34-35
(2008/12/07)
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- Design and synthesis of low molecular weight compounds with complement inhibition activity
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An attempt was made to synthesize a series of non-cytotoxic low molecular weight compounds of varying substitutions and functionalities having pharmacophore activity like carbonyl compounds, carboxylic acid and bioisosteres like tetrazole and phenyl acrylic acid. The in vitro assay of these analogues for the inhibition of complement activity revealed significant inhibitory activity for varying substituents and, particularly, for bioisosteres, that is, tetrazole and phenyl acrylic acid derivatives.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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p. 4891 - 4899
(2007/10/03)
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- NOVEL SULFONE AMIDE DERIVATIVES CAPABLE OF INHIBITING BACE
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The present invention relates to novel derivatives of sulfone amide of Formula 1 as defined in this disclosure which inhibit the activity of BACE (or beta-secretase). These sulfone amide derivatives are useful for the treatment and prevention of Alzheimer's disease and related diseases caused by production of beta-amyloid, by inhibiting the activity of BACE.
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Page/Page column 188-189
(2010/02/11)
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- Synthesis of low molecular weight compounds with complement inhibition activity
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An attempt was made to synthesize a series of non-cytotoxic low molecular weight meta-substituted aromatic ethers (2-4, 5-7) and some of their bioisosteres (14-16) and to evaluate their activity on the activation of human complement (classical pathway) and their intrinsic hemolytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis by these analogues indicate that the aldehydic meta substituted aromatic ethers show inhibitory potency, while carboxylic acid meta substituted aromatic ethers show hemolytic activity. Some of the bioisosteres exhibit both inhibitory as well as hemolytic property.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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p. 1249 - 1251
(2007/10/03)
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- COMPOUNDS
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The invention provides compounds of formula (I): wherein A and B represent the groups -(CH2)m- and -(CH2)n- respectively;R1 represents hydrogen or C1-6alkyl;R2 represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC1-6alkyl, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C1-6alkoxy, C1-6fluoroalkoxy, -(CH2)pC3-6cycloalkyl, -(CH2)pOC3-6cycloalkyl, -COC1-6alkyl, -SO2C1-6alkyl, -SOC1-6alkyl, -S-C1-6alkyl, -CO2C1-6alkyl, -CO2NR5R6, -SO2NR5R6, -(CH2)pNR5R6, -(CH2)pNR5COR6, optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring;R3 represents optionally substituted aryl ring or optionally substituted heteroaryl ring;R4 represents hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, halogen, -OSO2CF3, -(CH2)pC3-6cycloalkyl, -(CH2)qOC1-6alkyl or -(CH2)pOC3-6cycloalkyl;R5 and R6 each independently represent hydrogen, C1-6alkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo-substituted azacycloalkyl ring;Z represents -(CH2)rX- wherein the -(CH2)r- group is attached to R3, or -X(CH2)r- wherein X is attached to R3, and wherein any of the -CH2- groups may be optionally substituted by one or more C1-6alkyl groups;X represents oxygen, -NR7 or -CH2- wherein the -CH2- group may be optionally substituted by one or more C1-6alkyl groups;R7 represents hydrogen or C1-6alkyl;m and n independently represent an integer selected from 1 and 2;p independently represents an integer selected from 0, 1, 2 and 3; q independently represents an integer selected from 1, 2 and 3; r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof.The compounds are useful in therapy, in particular as antipsychotic agents.
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- Compositions containing aromatic aldehydes and their use in treatments
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Disclosed are pharmaceutical and cosmetic compositions containing aromatic aldehyde compounds. Some of the disclosed compositions are useful as topical therapeutics for treating inflammatory dermatologic conditions. Some of the compositions are useful in transdermal and other systemic dose forms for treating other inflammatory conditions in mammals.
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- Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein
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A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [3H] cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF2CF2H (42, IC50 0.14 μM in buffer, 5.6 μM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF3 (67), and C(CF3)2OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC50 0.02 μM in buffer, 0.6 μM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.
- Durley, Richard C.,Grapperhaus, Margaret L.,Hickory, Brian S.,Massa, Mark A.,Wang, Jane L.,Spangler, Dale P.,Mischke, Deborah A.,Parnas, Barry L.,Fobian, Yvette M.,Rath, Nigam P.,Honda, Dorothy D.,Zeng, Ming,Connolly, Daniel T.,Heuvelman, Deborah M.,Witherbee, Bryan J.,Melton, Michele A.,Glenn, Kevin C.,Krul, Elaine S.,Smith, Mark E.,Sikorski, James A.
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p. 3891 - 3904
(2007/10/03)
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- Method for inhibition of HIV related viruses
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Treatment of AIDS, inhibition of the replication of HIV and related viruses thereof, and formulations using thiourea derivative compounds or salts thereof is disclosed. Also disclosed are novel thiourea derivative compounds.
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- Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs
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A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 μM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 μM. The 50% cytotoxic dose in cell culture is >380 μM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2- pyridyl)-thiourea (62; LY300046 · HCl) as a candidate for clinical evaluation. LY300046 · HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
- Bell,Cantrell,Hogberg,Jaskunas,Johansson,Jordan,Kinnick,Lind,Morin Jr.,Noreen,Oberg,Palkowitz,Parrish,Pranc,Sahlberg,Ternansky,Vasileff,Vrang,West,et al.
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p. 4929 - 4936
(2007/10/03)
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- 3-(substituted phenyl)phthalides
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Process comprises the combination of the three steps of condensing 3-N(R)2 -4-X-benzoic acid with an aromatic or heterocyclic aldehyde, Y-CHO, under acidic conditions to produce 3-Y-5-X-6-N(R)2 phthalide (II), condensing said phthalide with a compound of the formula Z-H under alkaline or acid conditions to produce 2-(α-Y-α-Z)methyl-4-X-5-N(R)2 benzoic acid (III), and oxidizing said benzoic acid to produce 3-Y-3-Z-5-X-6-N(R)2 phthalide (I) where: R is hydrogen, non-tertiary alkyl of one to four carbon atoms, benzyl or substituted benzyl; X is hydrogen or halo; Y is 4-R1 -3-R2 -2-R1 -phenyl, 1-R5 -2-R6 -5/6-R4 -3-indolyl, 9-R7 -3-carbazolyl, 9-julolidinyl, 3,4-dioxymethylenephenyl, 2-thienyl, 1-R8 -2-pyrrolyl, or 4-pyridinyl; and Z is 4-R1 -3-R2 -2-R1 -phenyl, 1-R5 -2-R6 -5/6-R4 -3-indolyl or 1-R8 -2-pyrrolyl which are useful as colorless precursor color formers in carbonless duplicating and in thermal marking systems. The intermediates, 3-Y-5-X-6-N(R)2 phthalides (II) and 2-(α-Y-α-Z)methyl-4-X-5-N(R)2 benzoic acids (III) also have utility as colorless precursor color formers in carbonless duplicating and thermal marking systems.
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- 2-Aminoalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7(phenylmethylene)-2H-indazoles
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Compounds of the following formula and their acid addition and quaternary salts and N-oxides SPC1 Wherein X is hydrogen, chloro, fluoro, trifluoromethyl, lower alkyl, or lower alkoxy, R is hydrogen or lower alkyl, A is alkylene of 1 to 8 carbons, and B is --NH2, EQU1 wherein R1 is lower alkyl and R2 is phenyl or phenyl-lower alkyl are disclosed. These compounds are useful as central nervous system depressants.
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