- Comprehensive study on structure-activity relationships of rifamycins: Discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O
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The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component analysis is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of molecular rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by molecular modeling techniques. Methyl C34 is found to play a key role for determining the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidation of rifamycin B and is studied by X- ray single-crystal diffractometry, by solution IR and NMR spectroscopy, and by thermal analysis. Surprisingly the oxidation process is totally stereospecific, and an explanation is given based on solution spectroscopic evidence. The conformation found in the solid state is typical of nonactive compounds, and molecular mechanics calculations show that a molecular rearrangement to the active conformation would require about 15 kcal/mol. Thermal analysis confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chemical modification prior to reaching the enzyme or to conformational activation.
- Bacchi, Alessia,Pelizzi, Giancarlo,Nebuloni, Marino,Ferrari, Pietro
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- Process Investigations on the One-Pot Synthesis of Rifamycin S Avoiding Chlorinated Solvents
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The facile synthesis of rifamycin S from rifamycin B, a member of the ansamycin family of antibiotics, via the oxidation of rifamycin B was developed. Currently on an industrial scale, this oxidation is performed using harsh pH conditions and chlorinated solvents. With the development of a suitable buffer/methanol system, a similar yield and space-time-yield in comparison to the current process can be obtained renouncing chlorinated solvents. Employment of methanol as a reaction medium in this process is crucial for attaining high yields under mild reaction conditions. With this method a space-time-yield of 189 g L-1 h-1 of rifamycin S was achieved in one step.
- L?w, Sebastian A.,Nestl, Bettina M.,Weissenborn, Martin J.,Zepeck, Ferdinand,Hauer, Bernhard
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p. 1544 - 1547
(2015/12/01)
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- A FACILE PREPARATION OF RIFAMYCIN DERIVATIVES BY USE OF MANGANESE DIOXIDE
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Rifamycin O, rifamycin S and rifamycin SV were prepared in good yields (88-94percent) by the oxidation and hydrolytic cleavage of rifamycin B in the presence of manganese dioxide.
- Seong, Baik Lin,Han, Moon Hi
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p. 627 - 628
(2007/10/02)
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