- Based on isoxazole substitution of benzamide derivatives and anti-prostate cancer drug applications
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The present invention discloses a class (I), formula (II) structure based on isoxazole substituted benzamide derivatives and antiprostate cancer drug applications, such isoxazole substituted benzamide derivatives, can effectively inhibit the activity of a
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Paragraph 0065; 0073-0074
(2022/01/10)
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- Nucleus-independent chemical shift (NICS) as a criterion for the design of new antifungal benzofuranones
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The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p –1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 μg·mL–1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.
- González-Chávez, Marco Martín,González-Chávez, Rodolfo,Méndez, Francisco,Martínez, Roberto,Ni?o-Moreno, Perla Del Carmen,Ojeda-Fuentes, Luis Enrique,Richaud, Arlette,Zerme?o-Macías, María de los ángeles
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- Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents
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(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 μM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 μM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 μM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.
- Bangalore, Pavan K.,Vagolu, Siva K.,Bollikanda, Rakesh K.,Veeragoni, Dileep K.,Choudante, Pallavi C.,Misra, Sunil,Sriram, Dharmarajan,Sridhar, Balasubramanian,Kantevari, Srinivas
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supporting information
p. 26 - 35
(2020/01/03)
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- Synthesis and Evaluation of 2-Azetidinone and 1H-Pyrrole-2,5-dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress
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Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one of the most active inhibitors, 3-(4-fluorophenyl)-1-[(3S)-3-hydroxy-3-(4-hydroxyphenyl)propyl]-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione (14q), showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated that 14q inhibited considerably the amount of TNF-α, ROS, MDA, and LDH in vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.
- Xia, Yineng,Zhu, Lijuan,Yuan, Xinrui,Wang, Yubin
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- METALLOENZYME INHIBITOR COMPOUNDS
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Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
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Page/Page column 223
(2018/09/28)
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- Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
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Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.
- Mikami, Satoshi,Nakamura, Shinji,Ashizawa, Tomoko,Nomura, Izumi,Kawasaki, Masanori,Sasaki, Shigekazu,Oki, Hideyuki,Kokubo, Hironori,Hoffman, Isaac D.,Zou, Hua,Uchiyama, Noriko,Nakashima, Kosuke,Kamiguchi, Naomi,Imada, Haruka,Suzuki, Noriko,Iwashita, Hiroki,Taniguchi, Takahiko
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supporting information
p. 7677 - 7702
(2017/10/06)
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- SUBSTITUTED HETEROCYCLIC ACETAMIDES AS KAPPA OPIOID RECEPTOR (KOR) AGONISTS
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The present invention relates to a series of substituted compounds having the general formula (I), including their ste reoisomers and/or their pharmaceutically acceptable salts, wherein R1, R2, R3. R4, R5, and R6 are as defined herein. This invention also relates to methods of making these compounds including intermediates. The compounds of this invention are effective at the kappa (κ) opioid receptor (KOR) site. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic pain, and associated disorders, particularly functioning peripherally at the CNS.
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Page/Page column 128
(2013/09/26)
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- Synthesis and evaluation of non-dimeric HCV NS5A inhibitors
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Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).
- Amblard, Franck,Zhang, Hongwang,Zhou, Longhu,Shi, Junxing,Bobeck, Drew R.,Nettles, James H.,Chavre, Satish,McBrayer, Tamara R.,Tharnish, Philip,Whitaker, Tony,Coats, Steven J.,Schinazi, Raymond F.
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p. 2031 - 2034
(2013/05/09)
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- Synthesis, spectral characterization and biological evaluation of a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazines
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On account of the reported anticancer activity of triazolothiadiazines, we have synthesized a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl) propan-2-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and tested for in-vitro cytotoxicity by trypan blue exclusion and MTT assay. These compounds were also evaluated for their in-vivo anthelmintic activity, as well as in-vitro antimicrobial studies. Amongst the tested compounds, the compound 7j was the most promising cytotoxic agent with IC50 value of 10.54 μM in MCF-7 cells. The compounds 7l and 7q exhibited excellent anthelmintic activity. The compounds 7d, 7f, 7j, 7l, 7o, 7p and 7r showed good antibacterial activity, whereas compounds 7e and 7k exhibited excellent antifungal activity. The structures of newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and LCMS analysis.
- Puthiyapurayil, Pushpan,Poojary, Boja,Chikkanna, Chandrashekhar,Buridipad, Sunil Kumar
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p. 407 - 416
(2013/01/15)
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- Synthesis and discovery of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines as a novel class of potent cholesteryl ester transfer protein inhibitors
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2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50 = 26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F = 53%) and long human liver microsome stability (t1/2 = 62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.
- Wang, Aihua,Prouty, Catherine P.,Pelton, Patricia D.,Yong, Maria,Demarest, Keith T.,Murray, William V.,Kuo, Gee-Hong
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scheme or table
p. 1432 - 1435
(2010/07/06)
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- Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationships
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A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4- disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6- phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.
- Huang, Horng-Chih,Li, James J.,Garland, Danny J.,Chamberlain, Timothy S.,Reinhard, Emily J.,Manning, Robert E.,Seibert, Karen,Koboldt, Carol M.,Gregory, Susan A.,Anderson, Gary D.,Veenhuizen, Amy W.,Zhang, Yan,Perkins, William E.,Burton, Earl G.,Cogburn, J. Nita,Isakson, Peter C.,Reitz, David B.
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p. 253 - 266
(2007/10/03)
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- Thiadiazinones
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Compounds of formula I STR1 in which R1 and R2 are each independently of one another H or A, R3 is H, OA or O--Cm H2m+1-n Xn, R4 is --O--Cm H2m+1-n Xn, X is F or Cl, A is alkyl having 1-6 C atoms, m is 1, 2, 3, 4, 5 or 6 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, and their salts have positive ionitropic activity and vasodilating action, and promote circulation. In addition, the compounds can be employed for the treatment of asthmatic disease and memory disorders, and have anti-depressive and anti-inflammatory properties.
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