The effect of complexation of 3-formylrifamycin SV macrocyclic ether derivatives with metal cations and small nitrogen-containing organic molecules on antibacterial activity against S. aureus and S. epidermidis Piotr Przybylski a,⇑ , Krystian Pyta a , Dominika Czerwonka a , Marcelina M. Kubicka b , Marzena Gajecka b,c a Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland b Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, S ´ wie ˛cickiego 4, 60-781 Poznan, Poland c Institute of Human Genetics, Polish Academy of Science, Strzeszynska 32, 60-479 Poznan, Poland article info Article history: Received 2 June 2015 Revised 15 July 2015 Accepted 16 July 2015 Available online 22 July 2015 Keywords: Rifamycin antibiotics Bacterial RNA polymerases Complexes Antibacterial Solubility Log P abstract Spectroscopic studies of ether rifamycins (1–9) have shown that all these compounds tend to be zwitterions with different localizations of intramolecularly transferred proton, which influences their solubility and log P values. According to ESI MS studies, rifamycins 3 and 4 form complexes with Li + or Na + , while the other ones (7–9) coordinate small organic molecules, which can be further replaced by Na + cation. Biological assays revealed that the use of 7–9 in the form of complexes with small organic molecules improves their antibacterial potency as a result of changed: log P, solubility and binding mode with bacterial RNA polymerases. Ó 2015 Elsevier Ltd. All rights reserved. Rifamycin B (Fig. 1), as a structural precursor of 3-formyl rifa- mycin SV, was isolated by Professor Sensi group in the last century after analysis of the extract from maritime pine containing bacteria Actinomycete mediterranei, finally reclassified as Amycolatopsis mediterranei. 1 Semisynthetic 3-formyl rifamycin SV, obtained from rifamycin B via other rifamycins S, O and SV, is an example of ansa-macrolide antibiotics having a characteristic structural motif, that is, the ansa bridge which joins non-adjacent positions of the naphthalene rifamycin core. 2 The presence of functional groups and conformation of the ansa-bridge strongly contribute to unique antibacterial properties of rifamycins. It has been found earlier that with hydroxyls at C(21) and C(29) directed to the outside, rifamy- cins have shown antibacterial activity, whereas with the hydroxyls directed toward the aromatic core, rifamycins were inactive. 3 The presence of hydroxyls at C(21) and C(23) within the rifamycins’ structures is as important as that of phenols at C(1) and C(8) as well as one acetate at C(25) which enable stable binding of rifamy- cin to the bacterial RNA polymerases (RNAP). 4 There are several known resistance mechanisms of bacteria to the rifamycin antibi- otics. One such mechanism involves amino acid mutations at the binding site of RNAP. 4g–i Interestingly, all key amino acids can be substituted or deleted from the enzyme sequence except for E 445 /E 565 4,5 whose negatively charged carboxylate group participates in a strong intermolecular hydrogen bonding with the positively charged protonated basic substituent at C(3) of rifamycins. 4a,e,f To prevent stable docking of rifamycins at RNAP binding pocket other resistance mechanisms are realized via structural modifications such as: hydrolysis of C(3) 6 tail and ribosylation, glycosylation or phosphorylation of hydroxyls at C(21) and C(23). 7 Up to now a number of rifamycin SV or 3-formylrifamycin SV derivatives at C(3) or and C(4) atoms with primary and secondary amines or ketones 4e,f,8 as well as those derivatives containing hydrazone 9 and heterocyclic moieties, 4f,10 sulphonium and phosphonium ylides, 11 oximes, 12 have been obtained. Some of the above-mentioned rifamycin derivatives revealed interesting antibacterial, antimycobacterial and antiviral properties while the semisynthetic rifampicin (U.S. rifampin) became the first-line antitubercular drug used in combination with other ones as, for example, isoniazid to limit the bacteria resistance. 13 Recently Manning et al. have reported that the appli- cation of rifampicin in the form of its complexes with Cu 2+ cation, polyethylene glycol (PEG) or with Cu 2+ cation and PEG taken together resulted in the retained or slightly decreased activity http://dx.doi.org/10.1016/j.bmcl.2015.07.043 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +48 61 8291693; fax: +48 61 829 1505. E-mail address: piotrp@amu.edu.pl (P. Przybylski). Bioorganic & Medicinal Chemistry Letters 25 (2015) 3903–3909 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl