3-Formyl rifamycin

Rifapentine (DL473) [61379-65-5] (40), C42H34N4O22, a pipera2inyl hydra2one of 3-formyl rifamycin SV, is similar to rifampicin. Rifapentine has activity similar to rifampicin, but its half-life is much longer (149,150). 

The biological activity of rifamycins has been described [179b]. Rifamycin S (102) results from the oxidation of rifamycin B (98) to rifamycin O (101) and final hydrolysis, and rifamycin SV (103) is given by reduction of rifamycin S (98) to the corresponding hydroquinone. The biological activity is retained by all compounds. Rifampicin, a hydrazone derivative of 3-formyl rifamycin SV, is a widely used orally active tuberculostatic agent [182]. 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

A semi-synthetic antibiotic, rifampicin (rifampin) (19), was prepared from compound 5, obtained by the formylation of the C-3 position of rifamycin SV (3), followed by the reaction of 5 with l-amino-4-methylpiperazine in tetrahydrofuran (Fig. 2) [69]. 

Inactivation of rifampicin (19) by Nocardia brasiliensis and N. otitidiscaviarum [217,218] and by Bacillus sp. [219] was reported. Rifampicin (19) was glycosylated by a pathogenic species of Nocardia, i.e., Nocardia brasiliensis. The structures of the two glycosylated compounds isolated from the culture broth of the bacterium were determined to be 3-formyl-23-(0-[P-D-glucopyranosyl])rifamycin SV (129) and 23-(0-[P-D-glucopyranosyl])rifampicin (130), respectively. On the other hand, rifampicin was converted into 2l-(0-phosphoryl)rifampicin (131) and 3-formyl-2 l-(G-phosphoryl)-rifamycin SV (132) by Bacillus sp. All these four compounds lacked antimicrobial activity against other Gram-positive bacteria, as well as the Nocardia species [215,218]. 

Rifamycins B and O can be transformed into rifamycin S, and rifamycin SV is obtained by treating rifamycin S with ascorbic acid [5]. Formylation of the C3 position of rifamycin SV, followed by the combination of this alkaloid with l-amino-4-methylpiperazine, gave the semisynthetic ansamy-cin rifampicin. Rifampicin was prepared in 1966, and it is one of the most effective antituberculosis agents at present. The chemical structures of the rifamycins were finally clarified in 1973-1974 [6,7]. 

Rifamycins - Prom lunong the scores of semisynthetic rifamycins prepared from rifamycin SV (XV) and its 3-formyl derivative (XVI), Rifampicin (rifaldazine) (XVII)stands out as a dramatic chemotherapeutic improvement over the parent compound. ... 

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