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Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).

Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EW - J. Med. Chem. (2014)

Bottom Line: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria.Here we describe the discovery of 34c through optimization of a previously described series.Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.

ABSTRACT
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

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2,3-Substitutedbenzo[b]thiophene PfNMT and PvNMT inhibitor 1 and the target profile for the development of this series.Footnote a: Ki values are quoted in placeof IC50 values as a means of expressing the inhibitor affinitywhile correcting for differing Michaelis constants (Km) between enzymes. Enzyme Ki values are calculated from the IC50 values using theCheng–Prusoff equation, the definition of which is given inthe Experimental Section.23 IC50 values are the mean value of two or moredeterminations, and standard deviation is within 20% of the IC50. Footnote b: No significant difference in inhibition betweenHsNMT1 and HsNMT2 isoforms has been observed in this series; therefore,the HsNMT affinities reported in this work refer to HsNMT1. Footnotec: LELP = cLogP/LE. LE = [−log(Ki)](1.374)/(no. of heavy atoms), with cLogP determined with ChemAxon,which can be obtained from http://www.chemaxon.com/products/calculator-plugins/logp/.
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fig1: 2,3-Substitutedbenzo[b]thiophene PfNMT and PvNMT inhibitor 1 and the target profile for the development of this series.Footnote a: Ki values are quoted in placeof IC50 values as a means of expressing the inhibitor affinitywhile correcting for differing Michaelis constants (Km) between enzymes. Enzyme Ki values are calculated from the IC50 values using theCheng–Prusoff equation, the definition of which is given inthe Experimental Section.23 IC50 values are the mean value of two or moredeterminations, and standard deviation is within 20% of the IC50. Footnote b: No significant difference in inhibition betweenHsNMT1 and HsNMT2 isoforms has been observed in this series; therefore,the HsNMT affinities reported in this work refer to HsNMT1. Footnotec: LELP = cLogP/LE. LE = [−log(Ki)](1.374)/(no. of heavy atoms), with cLogP determined with ChemAxon,which can be obtained from http://www.chemaxon.com/products/calculator-plugins/logp/.

Mentions: Previouswork reported discovery of a series of benzo[b]thiophene-basedinhibitors of P. falciparum (Pf)NMT and P.vivax (Pv)NMT, exemplified by 1 (Figure 1).211 representsa promising starting point for hit to lead development but has onlymoderate enzyme affinity and high lipophilicity and contains a potentiallymetabolically labile ester group. Further development therefore focusedon removal of this high-risk functionality combined with a 100-foldimprovement in enzyme affinity, reduced lipophilicity, and controlledmolecular weight. Little is currently known of the potential for toxicityresulting from mammalian NMT inhibition, and previous data have shownthat a potent Homo sapiens (Hs)NMT inhibitor is nottoxic to mice at high doses.22 Althoughselectivity over HsNMT is desirable, selectivity at the cellular levelwas considered the more critical determinant for progression.


Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).

Rackham MD, Brannigan JA, Rangachari K, Meister S, Wilkinson AJ, Holder AA, Leatherbarrow RJ, Tate EW - J. Med. Chem. (2014)

2,3-Substitutedbenzo[b]thiophene PfNMT and PvNMT inhibitor 1 and the target profile for the development of this series.Footnote a: Ki values are quoted in placeof IC50 values as a means of expressing the inhibitor affinitywhile correcting for differing Michaelis constants (Km) between enzymes. Enzyme Ki values are calculated from the IC50 values using theCheng–Prusoff equation, the definition of which is given inthe Experimental Section.23 IC50 values are the mean value of two or moredeterminations, and standard deviation is within 20% of the IC50. Footnote b: No significant difference in inhibition betweenHsNMT1 and HsNMT2 isoforms has been observed in this series; therefore,the HsNMT affinities reported in this work refer to HsNMT1. Footnotec: LELP = cLogP/LE. LE = [−log(Ki)](1.374)/(no. of heavy atoms), with cLogP determined with ChemAxon,which can be obtained from http://www.chemaxon.com/products/calculator-plugins/logp/.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4048319&req=5

fig1: 2,3-Substitutedbenzo[b]thiophene PfNMT and PvNMT inhibitor 1 and the target profile for the development of this series.Footnote a: Ki values are quoted in placeof IC50 values as a means of expressing the inhibitor affinitywhile correcting for differing Michaelis constants (Km) between enzymes. Enzyme Ki values are calculated from the IC50 values using theCheng–Prusoff equation, the definition of which is given inthe Experimental Section.23 IC50 values are the mean value of two or moredeterminations, and standard deviation is within 20% of the IC50. Footnote b: No significant difference in inhibition betweenHsNMT1 and HsNMT2 isoforms has been observed in this series; therefore,the HsNMT affinities reported in this work refer to HsNMT1. Footnotec: LELP = cLogP/LE. LE = [−log(Ki)](1.374)/(no. of heavy atoms), with cLogP determined with ChemAxon,which can be obtained from http://www.chemaxon.com/products/calculator-plugins/logp/.
Mentions: Previouswork reported discovery of a series of benzo[b]thiophene-basedinhibitors of P. falciparum (Pf)NMT and P.vivax (Pv)NMT, exemplified by 1 (Figure 1).211 representsa promising starting point for hit to lead development but has onlymoderate enzyme affinity and high lipophilicity and contains a potentiallymetabolically labile ester group. Further development therefore focusedon removal of this high-risk functionality combined with a 100-foldimprovement in enzyme affinity, reduced lipophilicity, and controlledmolecular weight. Little is currently known of the potential for toxicityresulting from mammalian NMT inhibition, and previous data have shownthat a potent Homo sapiens (Hs)NMT inhibitor is nottoxic to mice at high doses.22 Althoughselectivity over HsNMT is desirable, selectivity at the cellular levelwas considered the more critical determinant for progression.

Bottom Line: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria.Here we describe the discovery of 34c through optimization of a previously described series.Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.

ABSTRACT
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

Show MeSH
Related in: MedlinePlus