- Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin
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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 β-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.
- Sooriyaarachchi, Sanjeewani,Chofor, René,Risseeuw, Martijn D. P.,Bergfors, Terese,Pouyez, Jenny,Dowd, Cynthia S.,Maes, Louis,Wouters, Johan,Jones, T. Alwyn,Van Calenbergh, Serge,Mowbray, Sherry L.
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p. 2024 - 2036
(2016/10/22)
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- ALPHA-KETO HETEROCYCLES AS FAAH INHIBITORS
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The invention provides a series of -alpha ketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.
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Page/Page column 109
(2010/04/03)
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- Optimization of the central heterocycle of α-ketoheterocycle inhibitors of fatty acid amide hydrolase
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The synthesis and evaluation of a refined series of α- ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity. 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
- Garfunkle, Joie,Ezzili, Cyrine,Rayl, Thomas J.,Hochstatter, Dustin G.,Hwang, Inkyu,Boger, Dale L.
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supporting information; experimental part
p. 4392 - 4403
(2009/06/17)
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- METHODS AND COMPOSITIONS FOR MODULATING SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR ACTIVITY
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The present invention relates to compounds which modulate the activity of the SI P1 receptor, the use of these compounds for treating conditions associated with signaling through the S1 P1 receptor, and pharmaceutical compositions comprising these compounds.
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Page/Page column 100
(2010/10/20)
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