| 1. |
- Andaloussi, Mounir, et al.
(author)
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Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
- 2011
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 54:14, s. 4964-4976
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Journal article (peer-reviewed)abstract
- The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
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| 2. |
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| 3. |
- Larhed, M, et al.
(author)
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Rapid fluorous Stille coupling reactions conducted under microwave irradiation
- 1997
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In: Journal of Organic Chemistry. - UNIV PITTSBURGH,DEPT CHEM,PITTSBURGH,PA 15260. UNIV UPPSALA,CTR BIOMED,DEPT ORGAN PHARMACEUT CHEM,S-75123 UPPSALA,SWEDEN. : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 62:16, s. 5583-5587
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Journal article (peer-reviewed)abstract
- Palladium-catalyzed fluorous Stille cross-coupling reactions with organic halides or triflates require only 90-120 s for completion when conducted under microwave irradiation. Comparable thermal reactions require about 1 day. Fourteen different coupling products were synthesized and isolated in good yields after three-phase extraction (FC-84, dichloromethane, water) and chromatography. The examples extend the scope of the fluorous Stille coupling with respect to both the tin and halide/triflate components. Applications in parallel synthesis are suggested.
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| 4. |
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| 5. |
- Moberg, C, et al.
(author)
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Selectivity and reactivity in asymmetric allylic alkylation
- 1999
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In: Pure and Applied Chemistry. - Royal Inst Technol, Dept Chem, SE-10044 Stockholm, Sweden. Royal Danish Sch Pharm, DK-2100 Copenhagen, Denmark. Uppsala Univ, Ctr Biomed, Dept Organ Pharmaceut Chem, SE-75123 Uppsala, Sweden. Stockholm Univ, Arrhenius Lab, Dept Struct Chem, SE-10691 Stockholm, Sweden. : Walter de Gruyter GmbH. - 0033-4545 .- 1365-3075. ; 71:8, s. 1477-1483
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Journal article (peer-reviewed)abstract
- 2-(1-Hydroxyalkyl)-6-oxazolyl-and 2-(1-alkoxyalkyl)-6-oxazolylpyridines serve as versatile ligands in the palladium-catalyzed allylic substitution of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate as nucleophile. The enantioselectivity of the reaction is dependent on the conformation of the ligands, as deduced by NMR, X-ray crystallography and DFT calculations of palladium(II) complexes of the ligands. The reactions are slow, requiring up to four days reaction time. However, with the use of microwave flash heating, reaction times are reduced to 2 min, with only minor loss in stereoselectivity.
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| 6. |
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| 7. |
- Orrling, Kristina M., et al.
(author)
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α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
- 2009
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 17:16, s. 5933-5949
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Journal article (peer-reviewed)abstract
- The impact of moving the P1 side-chain from the β-position to the α-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising α-benzylnorstatines and α-phenylnorstatines. Twelve α-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired α-substituted norstatines as pure stereoisomers. The best compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nm in PM4 from P. ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to P. falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding affinities using the linear interaction energy method (LIE).
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| 8. |
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| 9. |
- Wan, Y Q, et al.
(author)
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Dimethylformamide as a carbon monoxide source in fast palladium-catalyzed aminocarbonylations of aryl bromides
- 2002
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In: Journal of Organic Chemistry. - Uppsala Univ, BMC, Dept Organ Pharmaceut Chem, SE-75123 Uppsala, Sweden. : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 67:17, s. 6232-6235
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Journal article (peer-reviewed)abstract
- Dimethylformamide (DMF) acts as an efficient source of carbon monoxide and dimethylamine in the palladium-catalyzed aminocarbonylation (Heck carbonylation) of p-tolyl bromide to provide the dimethylamide. Addition of amines to the reaction mixture in excess delivers the corresponding aryl amides in good yields. The amines employed, benzylamine, morpholine, and aniline, all constitute good reaction partners. The reaction proceeds smoothly with bromobenzene and more electron-rich aryl bromides, but electron-deficient aryl bromides fail to undergo aminocarbonylation. The reactions are conducted at 180-190 degreesC for 15-20 min with microwave heating in a reaction mixture containing imidazole and potassium tert-butoxide: the latter is required to promote decomposition of the DMF solvent at a suitable rate. The beneficial effects of controlled microwave irradiation as an energy source for the rapid heating of the carbonylation reaction mixture are demonstrated. The carbonylation procedure reported herein, which relies on the in situ generation of carbon monoxide, serves as a convenient alternative to other carbonylation methods and is particularly applicable to small-scale reactions where short reaction times are desired and the direct use of carbon monoxide gas is impractical.
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| 10. |
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