63624-40-8Relevant articles and documents
Novel C-3-(N-alkyl-aryl)-aminomethyl rifamycin SV derivatives exhibit activity against rifampicin-resistant Mycobacterium tuberculosis RpoBS522L strain and display a different binding mode at the RNAP β-subunit site compared to rifampicin
Brucoli, Federico,Gupta, Megha,Parish, Tanya,Zloh, Mire
, (2021)
Antimicrobial resistance is a main concern in tuberculosis treatment and is often associated with the emergence of Mycobacterium tuberculosis strains resistant to rifampicin (RIF), which is one of the cornerstones of tuberculosis chemotherapy. In this study, aminoalkyl-aromatic ring tails were appended to the C3 position of rifamycin core to assess the role of C3 substitutions to the anti-mycobacterial activity of the rifamycin antibiotics. The typical hydrazone unit of RIF was replaced by an amino-alkyl linkage to connect the aromatic ring tails with the rifamycin naphthoquinone core. Eight novel C3-(N-alkyl-aryl)-aminoalkyl analogues of rifamycin SV were synthesised and screened in vitro against wild-type HR37Rv and “hypervirulent” HN-878 strains, and a panel of rifampicin-resistant M. tuberculosis clinical isolates carrying mutations at the 522, 531 and 455 positions of the rpoB gene (RpoBS522L, RpoBS531L and RpoBH455D strains). The analogues exhibited anti-tubercular activity against H37Rv and HN-878 at submicromolar or nanomolar concentrations, and against clinical H37Rv isolates bearing the S522L mutations at low micromolar concentration. Benzylamine moiety-including analogue 8 was as active as rifampicin against HN-878 with a MIC90 value of 0.02 μM, whereas 14 and 15, which included tryptamine and para-methyl-sulfonylbenzylamine C3-substituents, respectively, showed higher anti-tubercular activity (MIC90 = 3 μM) compared to rifampicin against the S522L mutated H37Rv strain. Detailed in silico analysis of different RNAP molecular systems predicted a distinct, possibly novel, binding mode for the new rifamycin analogues. These were found to occupy a different space in the binding pockets of both wild type and mutated RNAP proteins compared to that of rifampicin. Moreover, the molecular modelling experiments investigated the ability of the novel analogues aromatic tails to establish key interactions at the RNAP binding site. These interesting findings might pave the way for generating rifamycin analogues that can overcome anti-microbial resistance in M. tuberculosis.
A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase
Pyta, Krystian,Przybylski, Piotr,Klich, Katarzyna,Stefanska, Joanna
, p. 8283 - 8297,15 (2012/12/12)
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)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.
3-N-substituted aminomethyl derivatives of rifamycin SV. A convenient method of synthesis, cyclization of certain derivatives, and anticellular and antiviral activities of several derivatives
McCarthy,Moore,Wysong,Aldrich
, p. 1272 - 1276 (2007/10/21)
A new synthesis of Mannich bases of rifamycin SV using the Borch procedure with rifaldehyde is described. This new synthesis offers two advantages over the previously published method. It provides a route to monoalkyl-aminomethylrifamycins (1e-h) and to unsubstituted aminomethylrifamycins that were not accessible by the old procedure. The new method also offers a preparative route to Mannich bases 1a and 1b which were needed in multigram quantities for biological testing. In addition, the cyclization of certain of the monoalkylaminomethylrifamycins to the novel N,15 didehydro 15 deoxo 3,15 epi[methano(alkylimino)]rifamycin SV derivatives is described. The anticellular and antiviral effects of representatives of both series of compounds against cultured mouse cells and murine oncornavirus are discussed.
