Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood‐Stage Antimalarial Compounds
Identifieur interne : 003E26 ( Main/Exploration ); précédent : 003E25; suivant : 003E27Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood‐Stage Antimalarial Compounds
Auteurs : Sandeep Sundriyal [Royaume-Uni] ; Nicholas A. Malmquist [France] ; Joachim Caron [Royaume-Uni] ; Scott Blundell [Australie] ; Feng Liu [États-Unis] ; Xin Chen [États-Unis] ; Nitipol Srimongkolpithak [Royaume-Uni] ; Jian Jin [États-Unis] ; Susan A. Charman [Australie] ; Artur Scherf [France] ; Matthew J. Fuchter [Royaume-Uni]Source :
- ChemMedChem [ 1860-7179 ] ; 2014-10.
Descripteurs français
- KwdFr :
- MESH :
- enzymologie : Plasmodium falciparum.
- métabolisme : Histone-lysine N-methyltransferase.
- pharmacologie : Antipaludiques, Quinazolines.
- Animaux, Plasmodium falciparum.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Histone-Lysine N-Methyltransferase.
- chemical , pharmacology : Antimalarials, Quinazolines.
- drug effects : Plasmodium falciparum.
- enzymology : Plasmodium falciparum.
- Animals.
Abstract
Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1‐benzyl‐4‐piperidyl)[6,7‐dimethoxy‐2‐(4‐methyl‐1,4‐diazepin‐1‐yl)‐4‐quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose‐dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.
Url:
- https://api.istex.fr/document/3735302BFD13566F28D3977C22899ADB89834283/fulltext/pdf
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177335
DOI: 10.1002/cmdc.201402098
Affiliations:
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Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1‐benzyl‐4‐piperidyl)[6,7‐dimethoxy‐2‐(4‐methyl‐1,4‐diazepin‐1‐yl)‐4‐quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose‐dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name></noRegion><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><name sortKey="Srimongkolpithak, Nitipol" sort="Srimongkolpithak, Nitipol" uniqKey="Srimongkolpithak N" first="Nitipol" last="Srimongkolpithak">Nitipol Srimongkolpithak</name></country><country name="France"><noRegion><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name></noRegion><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name></country><country name="Australie"><noRegion><name sortKey="Blundell, Scott" sort="Blundell, Scott" uniqKey="Blundell S" first="Scott" last="Blundell">Scott Blundell</name></noRegion><name sortKey="Charman, Susan A" sort="Charman, Susan A" uniqKey="Charman S" first="Susan A." last="Charman">Susan A. Charman</name></country><country name="États-Unis"><noRegion><name sortKey="Liu, Feng" sort="Liu, Feng" uniqKey="Liu F" first="Feng" last="Liu">Feng Liu</name></noRegion><name sortKey="Chen, Xin" sort="Chen, Xin" uniqKey="Chen X" first="Xin" last="Chen">Xin Chen</name><name sortKey="Jin, Jian" sort="Jin, Jian" uniqKey="Jin J" first="Jian" last="Jin">Jian Jin</name><name sortKey="Jin, Jian" sort="Jin, Jian" uniqKey="Jin J" first="Jian" last="Jin">Jian Jin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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