COMPREHENSIVE STUDY ON STRUCTURE-ACTIVITY-RELATIONSHIPS OF RIFAMYCINS- DISCUSSION OF MOLECULAR AND CRYSTAL-STRUCTURE AND SPECTROSCOPIC ANDTHERMOCHEMICAL PROPERTIES OF RIFAMYCIN-O

The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangem ent of four oxygens which can form hydrogen bonds with the enzyme. Str uctural descriptors are derived from X-ray diffraction crystal structu res of 25 active and nonactive rifamycins. Principal component analysi s is used to find the combination of structural parameters which bette r discriminate between active and nonactive rifamycins. Two possible m echanisms cf molecular rearrangement are described which can convert n onactive into active conformations. The energy involved for conformati onal rearrangements is studied by molecular modeling techniques. Methy l C34 is found to play a key role for determining the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxid ation of rifamycin B and is studied by X-ray single-crystal diffractom etry, by solution IR and NMR spectroscopy, and by thermal analysis. Su rprisingly the oxidation process is totally stereospecific, and an exp lanation is given based on solution spectroscopic evidence. The confor mation 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 an alysis confirms that rifamycin O has a sterically constrained conforma tion. Therefore, it is likely that the antibiotic activity of rifamyci n O is due either to chemical modification prior to reaching the enzym e or to conformational activation.