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. Guani...

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Bibliographic Details
Published inTetrahedron Vol. 54; no. 16; pp. 3999 - 4012
Main Authors An, Haoyun, Wang, Tingmin, Mohan, Venkatraman, Griffey, Richard H., Cook, P.Dan
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 16.04.1998
Elsevier
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
SMALL ORGANIC-MOLECULES
SMALL-MOLECULE LIBRARIES
GENERATION
TEMPLATE
STRATEGY
CHEMICAL LIBRARIES
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Summary: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. Forty polar combinatorial libraries (total 4275 compounds) with high diversity were synthesized from novel polyazaphane pharmacophores by a SPSAF approach. Libraries with potent antibacterial activity were discovered.
ISSN:0040-4020
1464-5416
DOI:10.1016/S0040-4020(98)00131-8