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2014年9月4日木曜日

Rhodanine (2-thioxothiazolidin-4-one) as reductase inhibitors

Rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors By Tyr-OH Hydrogen Bonding Activation;


Abstract

Abstract Image
 
 
 

Enoyl acyl carrier protein (ACP) reductase,

one of the enzymes of the type II fatty acid biosynthesis pathway,

has been established as a promising target for the development of new drugs for malaria.

 

 

Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization.

 

 

The most potent inhibitor exhibits an IC50 of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC50 value of 750 nM.

 

 

Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure−activity relationship of these rhodanine compounds is discussed.

 
 
 

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This article has been cited by 4 ACS Journal articles (4 most recent appear below).
  • Cover Image

    Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease

    Bruno Bulic, Marcus Pickhardt, and Eckhard Mandelkow
    Journal of Medicinal Chemistry2013 56 (11), 4135-4155

    • Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease

      BrunoBulic, MarcusPickhardt, and EckhardMandelkow
      Journal of Medicinal Chemistry2013 56 (11), 4135-4155
      Pharmacological approaches directed toward Alzheimer disease are diversifying in parallel with a growing number of promising targets. Investigations on the microtubule-associated protein tau yielded innovative targets backed by recent findings about the ...
      Abstract | Full Text HTML | PDF | PDF w/ Links
  • Cover Image

    Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes

    Jeffrey L. Romine, Denis R. St. Laurent, John E. Leet, Scott W. Martin, Michael H. Serrano-Wu, Fukang Yang, Min Gao, Donald R O’Boyle, II, Julie A. Lemm, Jin-Hua Sun, Peter T. Nower, Xiaohua (Stella) Huang, Milind S. Deshpande, Nicholas A. Meanwell, and Lawrence B. Snyder
    ACS Medicinal Chemistry Letters2011 2 (3), 224-229

    • Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes

      Jeffrey L.Romine, Denis R.St. Laurent, John E.Leet, Scott W.Martin, Michael H.Serrano-Wu, FukangYang, MinGao, Donald RO’Boyle, II, Julie A.Lemm, Jin-HuaSun, Peter T.Nower, Xiaohua (Stella)Huang, Milind S.Deshpande, Nicholas A.Meanwell, and Lawrence B.Snyder
      ACS Medicinal Chemistry Letters2011 2 (3), 224-229
      The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in a genotype 1b replicon assay via a high-throughput screening campaign. A more potent analogue, BMS-824 (18), was used in resistance mapping studies, which ...
      Abstract | Full Text HTML | PDF | PDF w/ Links
  • Cover Image

    New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

    Jonathan B. Baell and Georgina A. Holloway
    Journal of Medicinal Chemistry2010 53 (7), 2719-2740

    • New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

      Jonathan B.Baell and Georgina A.Holloway
      Journal of Medicinal Chemistry2010 53 (7), 2719-2740
      This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are ...
      Abstract | Full Text HTML | PDF | PDF w/ Links
  • Cover Image

    Synthesis and Antimicrobial Properties of Novel Silver/Polyrhodanine Nanofibers

    Hyeyoung Kong and Jyongsik Jang
    Biomacromolecules2008 9 (10), 2677-2681 
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2014年8月21日木曜日

Benzisothiazole- and Indolizine-β-d-glucopyranoside Inhibitors of SGLT2



Abstract

Abstract Image
 
 
 
A series of benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure−activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM.

Keywords:

Benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors; SAR; SGLT2; benzisothiazole-C-glucoside
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2014年8月8日金曜日

Micro-Tublle Stabilizing Alkaloids CERATAMINE Congeners

Summary;

Sequential metalation onto the  tribromoimidazole followed by  functionalization led to the efficiently generate a key imidazole intermediate containing the vinyl bromide and the amide functionalities, thar are keys to the success to the total synthesis described herein.

Abstract

Abstract Image
 
Two synthetic approaches to the microtubule-stabilizing ceratamine alkaloids are described. The first approach involved attempts to graft an aminoimidazole moiety onto an azepine ring to form partially hydrogenated versions of the unprecedented aromatic imidazo[4,5-d]azepine core of the ceratamines.
 
 
This route ultimately failed because it was not possible to aromatize the partially hydrogenated ceratamine intermediates.
 
 
A second approach started with tribromoimidazole that was sequentially metalated and functionalized to efficiently generate a key imidazole intermediate containing vinyl bromide and amide functionalities.
 
 
An intramolecular Buchwald vinyl amidation reaction converted this key intermediate into a bicyclic imidazo[4,5-d]azepine that was at the same oxidation state as the aromatic core of the ceratamines.
 
 
The 2-amino functionality present on the imidazole ring of the ceratamines was installed using a Buchwald/Hartwig amination reaction on a 2-chloroimidazole precursor.
 
 
Deprotection and aromatization resulted in the first synthesis of desbromoceratamine A (55) and desmethyldesbromoceratamine A (60).
 
 
An unanticipated addition of atmospheric oxygen was encountered during deprotection of the imidazole ring in the last step of the synthesis leading to C-11 oxygenated ceratamine analogues as byproducts.
 
 
Evaluation of the synthetic ceratamines in a TG3 cell-based assay for mitotic arrest revealed that the C-14 and C-16 bromine substituents in ceratamine A (1) play a major role in the antimitotic potency of the natural product.
 
 
The synthetic route to ceratamine analogues has provided sufficient quantities of desbromoceratamine A (55) for testing in mouse models of cancer.
 
 
 
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2014年5月29日木曜日

The Danshen extracts against transient cerebral ischemic damage

Abstract

We observed neuroprotective effects of five major lipophilic diterpenes derived from Danshen (Radix Salvia miltiorrhiza) extract,

 

 

such as cryptotanshinone (CTs), dihydrotanshinone I (DTsI),

tanshinone I (TsI), tanshinone IIA (TsIIA)

and tanshinone IIB (TsIIB), in the hippocampal CA1 region (CA1)

against transient ischemic damage in gerbils.

 

 

These diterpenes were administered 30 min before ischemia–reperfusion and the animals were sacrificed 4 days after ischemia–reperfusion.

 

 

In the vehicle-treated-group, cresyl violet positive (CV+) cells and neuronal nuclei (NeuN)+ neurons were significantly decreased in the CA1. However, in the TsI- and CTs-treated-ischemia-groups, CV+ and NeuN+ neurons were abundant in the CA1. In the other groups, the number of CV+ and NeuN+ neurons was less than the TsI- and CTs-treated-ischemia-groups.

 

 

In addition, gliosis induced by ischemic damage was apparently blocked in the TsI- and CTs-treated-ischemia-groups. These results suggest that TsI and CTs among five major lipophilic diterpenes have strong potentials for neuroprotection against ischemic damage.

 
 
 

Graphical abstract

Keywords

  • Transient cerebral ischemia;
  • Hippocampal CA1 region;
  • Neuronal death;
  • Gliosis;
  • Neuroprotection
Corresponding author contact information
Corresponding author. Tel.: + 82 33 248 2583.
Corresponding author contact information
Corresponding author. Tel.: + 82 33 250 8891; fax: + 82 33 256 1614.
1
Ok Kyu Park and Jung Hoon Choi contributed equally to this article.
Copyright © 2012 Elsevier B.V. All rights reserved.
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2014年5月25日日曜日

Yasuhiro Torisawa@ Google Scholar

Please See the Selected Lists in Google Scholar<1994-2014>

 

 

 

20 Years of Research By Yasuhiro Torisawa

During 1994-2014:

 

 

http://scholar.google.co.jp/scholar?start=10&q=Yasuhiro+Torisawa&hl=ja&as_sdt=0,5&as_ylo=1990&as_yhi=2013

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2013年10月5日土曜日

Tau Aggregation Inhibitors

Abstract Image







Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer’s disease.
 
 
Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels.
 
 
Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors
 
and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice.
 
 
 
Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.


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Tau Complex Inhibition by Prototype Inhibitors


Kinetic Studies of Cdk5/p25 Kinase:

Phosphorylation of Tau and Complex Inhibition by Two Prototype Inhibitors



Abstract Image




These studies served as a necessary kinetic backdrop for investigations of the mechanism of inhibition by prototype inhibitors :

N4-(6-aminopyrimidin-4-yl)-sulfanilamide (APS) and 1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-5-yl-urea (CTIU).


We found that the cdk5/p25-catalyzed phosphorylation of tau follows a rapid equilibrium, random kinetic mechanism, as evidenced by initial velocity analysis indicating sequential addition of tau and ATP, and studies of the mechanism of inhibition by substrate analogue AMP, product ADP, and analogues of peptide substrate H1P. Identical mechanistic conclusions were drawn when H1P was the phosphoryl acceptor.



Subsequent studies of inhibition by APS and CTIU revealed that
both compounds can bind to all four steady-state forms of the enzyme,
to form the complexes E:I, E:I:tau, E:I:ATP, and E:I:tau:ATP.



These results contrast with reported claims that APS and CTIU are competitive inhibitors of the binding of ATP.
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Type II Kinase Inhibitors


Abstract Image
 
 
 
A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S.
 
 
We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2.
 
 
The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT.
 
 
 
Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics.
 
 
 
The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the conformational barrier between the active and inactive forms of the enzyme and a relative stabilization of the active form.
 
 
The conformational bias toward the active form of LRRK2 mutants has two primary consequences. (1)
 
 
 
The mutant enzyme becomes hyperactive, a known contributor to the Parkinsonian phenotype, as a consequence of being “locked” into the activated state, and (2) the mutation creates an unusual allosteric pocket that can bind type II inhibitors but in an ATP-competitive fashion.
 
 
 
Our results thus suggest that developing type II inhibitors, which are generally considered superior to type I inhibitors because of desirable selectivity profiles, might be especially challenging for the G2019S LRRK2 mutant.
 
 
 
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