Semisynthesis

Semisynthesis refers to the process of performing synthetic chemical transformations starting with a natural product, for the purpose of enhancing the pharmaceutical performance of the natural product. This approach has been most effectively used with complex microbial products, owing to the ready availability of the starting material through fermentation of highly productive variants of the parent organism. The challenge in these experiments is twofold: one, to achieve adequate selectivity in the chemical process and two, the subsequent purification of reaction mixtures. A good example of the successful application of semisynthesis is in the case of the rifamycin antibiotics, shown in Figure 6.9. Rifamycin B is the originally isolated natural product derived from Nocardia mediterranei. Rifamycins have potent activity against gram-positive bacteria and are of greatest importance to inhibit the growth of the tuberculosis causing organism Mycobacterium tuberculosis. Rifamycin B was only modestly effective when administered to infected animals and this led to investigation of derivatives in search of improved potency. Greater potency was achieved through substitutions on the aromatic portion as exemplified by rifamide, rifampicin, and rifabutin. The latter two compounds continue to be important drugs for the treatment of reemerging epidemics of tuberculosis.

Rifamycin B

Rifamide

Rifamycin B

Rifamide

Rifampicin

FIGURE 6.9 Rifamycin B and semisynthetic analogs.

Rifampicin

FIGURE 6.9 Rifamycin B and semisynthetic analogs.

Rifabutin

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