Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2360 - 2373 |
| Number of pages | 14 |
| Journal | ChemMedChem |
| Volume | 9 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds. / Sundriyal, Sandeep; Malmquist, Nicholas A; Caron, Joachim; Blundell, Scott; Liu, Feng; Chen, Xin; Srimongkolpithak, Nitipol; Jin, JIan; Charman, Susan Ann; Scherf, Artur; Fuchter, Matthew J.
In: ChemMedChem, Vol. 9, No. 10, 2014, p. 2360 - 2373.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds
AU - Sundriyal, Sandeep
AU - Malmquist, Nicholas A
AU - Caron, Joachim
AU - Blundell, Scott
AU - Liu, Feng
AU - Chen, Xin
AU - Srimongkolpithak, Nitipol
AU - Jin, JIan
AU - Charman, Susan Ann
AU - Scherf, Artur
AU - Fuchter, Matthew J
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201402098/epdf
U2 - 10.1002/cmdc.201402098
DO - 10.1002/cmdc.201402098
M3 - Article
VL - 9
SP - 2360
EP - 2373
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 10
ER -