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Synthesis of macrolones with central piperazine ring in the linker and its influence on antibacterial activity

2011; Elsevier BV; Volume: 19; Issue: 23 Linguagem: Inglês

10.1016/j.bmc.2011.07.010

1464-3391

Samra Kapić, Hana Čipčić Paljetak, Ivana Palej Jakopović, Andrea Fajdetić, Marina Ilijaš, Vlado Štimac, Karmen Brajša, David Holmes, John M. Berge, Sulejman Alihodžić,

Pneumonia and Respiratory Infections

Three macrolides, clarithromycin, azithromycin and 11-O-Me-azithromycin have been selected for the construction of a series of new macrolone derivatives. Quinolone-linker intermediates are prepared by Sonogashira-type C(6)-alkynylation of 6-iodoquinolone precursors. The final macrolones, differing by macrolide moiety and substituents at the position N-1 of the quinolone or by the presence of an ethyl ester or free acid on the quinolone unit attached via a linker. The linker comprises of a central piperazine ring bonded to the 4″-O position of cladinose by 3-carbon ester or ether functionality. Modifications of the linker did not improve antibacterial properties compared to the previously reported macrolone compounds. Linker flexibility seems to play an important role for potency against macrolide resistant respiratory pathogens.