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Issue 41, 2012
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A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase

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Abstract

Seven new benzyl (3–9) and four new phenethyl (10–13) amino analogues of ansa-macrolide rifampicin (1) were synthesized using the optimised method of reductive amination. Structures of 3–13 in solution were determined by 1D and 2D NMR and FT-IR methods whereas the energetically most favoured conformation of amino analogues was calculated with the use of the PM5 method. Spectroscopic and semi-empirical studies revealed the presence of zwitterionic forms of all 3–13 analogues in solutions containing water traces. 1H–15N HSQC and 1H–15N HMBC in combination with 1H–1H COSY and 1H–13C HMBC two dimensional spectroscopic methods unambiguously evidenced that the presence of the zwitterionic form of ansa-macrolides was a consequence of proton transfer from the O(8)–H phenolic group to the secondary amine moiety within 3–13 structures. 1H–1H NOESY studies indicated two different orientations of the substituent introduced at the C(3) position for benzyl and phenethyl amino analogues of rifampicin and their similar conformation within the ansa-bridges in solution. FT-IR studies of the deprotonation of molecule 1 and comparison of these data with those for 3–13 indicated C(8)[double bond, length as m-dash]O double bond character after formation of zwitterions in solution. Results of an antibacterial test against Gram-(−) and Gram-(+) strains were compared with detailed structural information on new analogues of 3–13 to indicate some structure–activity relationships. Molecular recognition studies of 1 and 12 inhibitors at the binding site of bacterial RNA polymerase (RNAP) as zwitterions revealed key intermolecular interactions and led to the proposition of a new model of RNAP inhibition, which explains significant differences in antibacterial properties of rifampicin and its analogues.

Graphical abstract: A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase

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Article information


Submitted
10 Jul 2012
Accepted
16 Aug 2012
First published
17 Aug 2012

Org. Biomol. Chem., 2012,10, 8283-8297
Article type
Paper

A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase

K. Pyta, P. Przybylski, K. Klich and J. Stefańska, Org. Biomol. Chem., 2012, 10, 8283
DOI: 10.1039/C2OB26317C

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