Solution phase combinatorial chemistry. Discovery of 13- and 15-membered polyazapyridinocyclophane libraries with antibacterial activity

A solution phase simultaneous addition of functionalities (SPSAF) combinatorial approach was utilized to synthesize 40 polyazacyclophane libraries (total complexity of 4275). Eighteen different functionality sets, utilizing 42 functionalities, were designed to disrupt RNA-protein interactions. Guanidine functionality sets with a greater potential to form positive charges provided the most active libraries. Differences in antibacterial activity are clearly related to different ring sizes with the more rigid 13-membered scaffold affording more active libraries compared with libraries from the 15-membered scaffold. Molecular modeling established a significant difference in the shapes of 13- and 15-membered pyridinophanes. Several libraries exhibited potent antibacterial activity. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.