Novel desosamine-modified 14- and 15-membered macrolides without antibacterial activity Ivana Palej Jakopovic ´ a,  , Mirjana Bukvic ´ Krajac ˇic ´ a,  , Maja Matanovic ´ Škugor a,  , Vlado Štimac a,  , Dijana Pešic ´ a,  , Ines Vujasinovic ´ a,  , Sulejman Alihodz ˇic ´ a,  , Hana C ˇ ipc ˇic ´ Paljetak b , Goran Kragol a,⇑,  a GlaxoSmithKline Research Centre Zagreb, Prilaz b. Filipovic ´a 29, Zagreb, Croatia b University of Zagreb School of Medicine, Center for Translational and Clinical Research, Šalata 2, Zagreb, Croatia article info Article history: Received 17 January 2012 Revised 19 March 2012 Accepted 21 March 2012 Available online 29 March 2012 Keywords: Macrolide 1,3-Oxazolidin-2-one N-alkylations Antibacterial activity abstract Novel modifications of the desosamine sugar of 14- and 15-membered antibacterial macrolides, in which the desosamine was fused with N-substituted-1,3-oxazolidin-2-ones, were developed in order to com- pletely suppress antibacterial activity and make them promising agents for other biological targets. The synthesis of such bicyclic desosamine derivatives, especially 1,3-oxazolidin-2-one formation, was optimized and conducted under mild conditions without a need for protection/deprotection steps for other functional groups. A focused series of novel desosamine-modified macrolide derivatives was pre- pared and their antibacterial activities tested. It was shown that these macrolide derivatives do not pos- sess any residual antibacterial activity. Ó 2012 Elsevier Ltd. All rights reserved. In recent years, the immunomodulatory properties of macrolide antibiotics were noted, revealing their very promising potential for the treatment of various diseases not connected to bacterial ac- tion. 1 For any of these novel biological applications, however, the antibacterial activity of macrolides is an undesired property due to the possibility of inducing bacterial resistance. Indeed, it has been shown that the reduction of antibacterial activity of certain macrolides through chemical modification does not necessarily diminish their immunomodulatory potential. 2 The reduction of a macrolide’s antibacterial activity can be achieved in a few ways, from simple removal of the cladinose sugar, 3 through modifica- tions of the aglycon ring including contraction, 4 to more complex modifications of the desosamine sugar. 5 However, these modifica- tions substantially alter the macrolide structures and their phys- ico-chemical properties. For this reason, new modifications that provide complete suppression of antibacterial activity with minor alterations of macrolide structures and/or physico-chemical prop- erties would be of great significance. Our goal was to modify the desosamine sugar of 14- and 15-membered antibacterial macro- lides by annelation of 1,3-oxazolidin-2-ones to the 2 0 ,3 0 -positions of desosamine. Because the desosamine sugar is directly involved in the binding of macrolides to ribosomes through a network of hydrogen bonds and ionic interactions, such a simple modification should diminish the antibacterial activity of macrolide antibiot- ics. 5a,5b Moreover, subsequent introduction of various substituents via N-alkylations of the 1,3-oxazolidin-2-one ring could com- pletely suppress antibacterial activity but also fine tune the macro- lide physico-chemical properties. These macrolides would be evaluated as potential agents for other biological targets. The annelation of a N-methyl substituted 1,3-oxazolidin-2-one ring to desosamine has been achieved previously but only together with simultaneous formation of an 11,12-cyclic carbonate moiety on the macrolactone ring. 5a,5b,6 These modifications diminished antibacterial activity but also caused a dramatic decrease in solu- bility in common organic solvents. We envisioned that the removal of both methyl groups from the 3 0 -N,N-dimethylamino group of clarithromycin 9a-lactam (1), clarithromycin (2), and azithromycin (3), would provide vicinal 2 0 ,3 0 -amino alcohols that could be bridged via 1,3-oxazolidin-2-one formation without altering the macrolactone ring. The nitrogen of the 1,3-oxazolidin-2-one ring would be then used as a position for the attachment of various alkyl substituents through N-alkylations performed in a parallel synthesis manner. As we reported previously, 7 removal of the first methyl from the 3 0 -N,N-dimethylamino group of desosamine is a fairly well known process that can be achieved using several reagents, 8 that is sodium acetate/iodine combination, 9 diethylazodicarboxylate (DEAD), 10 N-iodo succinimide (NIS), 11 and benzoylchloroformate. 12 In our hands the sodium acetate/iodine method proved effective for the preparation of 3 0 -N-demethyl-6-O-methyl-9a-aza-9a-homoery- thromycin A (4) and 3 0 -N-demethyl-6-O-methylerythromycin A 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.03.076 ⇑ Corresponding author. Tel.: +385 1 8886357; fax: +385 1 8886443. E-mail address: goran.kragol@glpg.com (G. Kragol).   Present address: Galapagos Research Centre, Prilaz b. Filipovic ´a 29, Zagreb, Croatia. Bioorganic & Medicinal Chemistry Letters 22 (2012) 3527–3530 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl