Novel semisynthetic antibiotics from caprazamycins A–G: caprazene derivatives and their antibacterial activity

Abstract

Acidic treatment of a mixture of caprazamycins (CPZs) A-G isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of CPZs, in high yield. Chemical modification of the resulting caprazene was performed to give its various derivatives. The structure-activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic Gram-positive and Gram-negative bacteria were studied. Although caprazene showed no antibacterial activity, the antibacterial activity was restored for its 1'''-alkylamide, 1'''-anilide and 1'''-ester derivatives. Compounds 4b (CPZEN-45), 4d (CPZEN-48), 4f and 4g (CPZEN-51) exhibited more potent activities against Mycobacterium tuberculosis and M. avium complex strains than CPZ-B. These results suggest that caprazene would be a good precursor from which novel semisynthetic antibacterial antibiotics can be designed for the treatment of mycobacterial diseases such as tuberculosis and M. avium complex infection.

Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

“…Abbreviations of multiplicity were as follows; s: singlet, d; doublet, t: triplet, q: quartet, m: multiplet, br: broad. 1 1-(6,7-Dideoxy-2,3-O-isopropylidene-α-L-talo-hept-6-enofranosyl)uracil (18). Assignment was based on 1 H-1 H COSY, HMBC and HMQC NMR spectra.…”

“…1, 1) are nucleoside antibiotics isolated from the culture broth of Streptomyces sp. 16,17 , 18 which is a semisynthetic analogue of CPZs currently under preclinical study, 19 is the most promising derivative of the CPZs and has excellent antitubercular activity against not only drug-sensitive strains but also some multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis strains. 11,12 CPZs exhibit anti-mycobacterial activity in vitro, and their mode of action is to inhibit phospho-MurNAc-pentapeptide translocase (MraY), which is responsible for the formation of lipid I during peptidoglycan biosynthesis.…”

Liquid chromatographic determination of CPZEN-45, a novel anti-tubercular drug, in biological samples

“…Structure–activity relationships studied on a range of CPZEN derivatives against Mycobacterium tuberculosis showed excellent activity, of which CPZEN-45 (Fig. 1) was the most promising [4]. Recently the path to ease of manufacture has also been described [5,6].…”

Biosynthesis of the antituberculous agent caprazamycin: Identification of caprazol-3ʺ-phosphate, an unprecedented caprazamycin-related metabolite

“…Because caprazamycins possess such excellent antibacterial properties, they are expected to be promising compounds for the development of antituberculous drugs. For example, several semisynthetic caprazamycin derivatives, such as caprazene-1≤-alkylamides and caprazol-1≤-alkylamides, have been prepared and their evaluation has been reported (Ishizaki et al, 2013;Miyake et al, 2014;Takahashi et al, 2013).…”