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Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with β-arylpropyl analogues of fosmidomycin

(2016) CHEMMEDCHEM. 11(18). p.2024-2036
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Abstract
Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the -position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P.falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
Keywords
antibiotics, antiprotozoal agents, oxidoreductases, structural biology, structure-activity relationships, POTENTIAL ANTIINFECTIVE AGENTS, ISOPRENOID BIOSYNTHESIS, 5-PHOSPHATE REDUCTOISOMERASE, NONMEVALONATE PATHWAY, TERPENOID BIOSYNTHESIS, ANTIMALARIAL-DRUGS, MEP PATHWAY, INHIBITORS, MEVALONATE, MALARIA

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Citation

Please use this url to cite or link to this publication:

Chicago
Sooriyaarachchi, Sanjeewani, René Chofor, Martijn Risseeuw, Terese Bergfors, Jenny Pouyez, Cynthia S Dowd, Louis Maes, et al. 2016. “Targeting an Aromatic Hotspot in Plasmodium Falciparum 1-deoxy-d-xylulose-5-phosphate Reductoisomerase with Β-arylpropyl Analogues of Fosmidomycin.” Chemmedchem 11 (18): 2024–2036.
APA
Sooriyaarachchi, S., Chofor, R., Risseeuw, M., Bergfors, T., Pouyez, J., Dowd, C. S., Maes, L., et al. (2016). Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with β-arylpropyl analogues of fosmidomycin. CHEMMEDCHEM, 11(18), 2024–2036.
Vancouver
1.
Sooriyaarachchi S, Chofor R, Risseeuw M, Bergfors T, Pouyez J, Dowd CS, et al. Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with β-arylpropyl analogues of fosmidomycin. CHEMMEDCHEM. 2016;11(18):2024–36.
MLA
Sooriyaarachchi, Sanjeewani, René Chofor, Martijn Risseeuw, et al. “Targeting an Aromatic Hotspot in Plasmodium Falciparum 1-deoxy-d-xylulose-5-phosphate Reductoisomerase with Β-arylpropyl Analogues of Fosmidomycin.” CHEMMEDCHEM 11.18 (2016): 2024–2036. Print.
@article{8509194,
  abstract     = {Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the -position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P.falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.},
  author       = {Sooriyaarachchi, Sanjeewani and Chofor, Ren{\'e} and Risseeuw, Martijn and Bergfors, Terese and Pouyez, Jenny and Dowd, Cynthia S and Maes, Louis and Wouters, Johan and Jones, T Alwyn and Van Calenbergh, Serge and Mowbray, Sherry L},
  issn         = {1860-7179},
  journal      = {CHEMMEDCHEM},
  keyword      = {antibiotics,antiprotozoal agents,oxidoreductases,structural biology,structure-activity relationships,POTENTIAL ANTIINFECTIVE AGENTS,ISOPRENOID BIOSYNTHESIS,5-PHOSPHATE REDUCTOISOMERASE,NONMEVALONATE PATHWAY,TERPENOID BIOSYNTHESIS,ANTIMALARIAL-DRUGS,MEP PATHWAY,INHIBITORS,MEVALONATE,MALARIA},
  language     = {eng},
  number       = {18},
  pages        = {2024--2036},
  title        = {Targeting an aromatic hotspot in Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase with \ensuremath{\beta}-arylpropyl analogues of fosmidomycin},
  url          = {http://dx.doi.org/10.1002/cmdc.201600249},
  volume       = {11},
  year         = {2016},
}

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