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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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(A) Plot of cellular potency vs enzymeaffinity for all members of this series tested in both assays. (B)Plot of cellular potency vs enzyme affinity for all compounds witha LELP of >10. (C) Plot of cellular potency vs enzyme affinityfor all compounds with a LELP of <10.
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fig6: (A) Plot of cellular potency vs enzymeaffinity for all members of this series tested in both assays. (B)Plot of cellular potency vs enzyme affinity for all compounds witha LELP of >10. (C) Plot of cellular potency vs enzyme affinityfor all compounds with a LELP of <10.

Mentions: The metric LELP was used to guide the developmentof this compound series, based on the hypothesis that compounds witha low LELP (ideally <10) will have fewer off-target effects andas a result are more druglike.29 In anattempt to assess if LELP is a useful metric in this regard, the cellularEC50 against the 3D7 parasite line was plotted againstNMT affinity for all tested members of this series. Analysis of theEC50/Ki correlation is shownin Figure 6.


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)

(A) Plot of cellular potency vs enzymeaffinity for all members of this series tested in both assays. (B)Plot of cellular potency vs enzyme affinity for all compounds witha LELP of >10. (C) Plot of cellular potency vs enzyme affinityfor all compounds with a LELP of <10.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: (A) Plot of cellular potency vs enzymeaffinity for all members of this series tested in both assays. (B)Plot of cellular potency vs enzyme affinity for all compounds witha LELP of >10. (C) Plot of cellular potency vs enzyme affinityfor all compounds with a LELP of <10.
Mentions: The metric LELP was used to guide the developmentof this compound series, based on the hypothesis that compounds witha low LELP (ideally <10) will have fewer off-target effects andas a result are more druglike.29 In anattempt to assess if LELP is a useful metric in this regard, the cellularEC50 against the 3D7 parasite line was plotted againstNMT affinity for all tested members of this series. Analysis of theEC50/Ki correlation is shownin Figure 6.

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