SOLUTION-PHASE COMBINATORIAL CHEMISTRY - DISCOVERY OF NOVEL POLYAZAPYRIDINOPHANES WITH POTENT ANTIBACTERIAL ACTIVITY BY A SOLUTION-PHASE SIMULTANEOUS ADDITION OF FUNCTIONALITIES APPROACH

Chemical modification of pre-formed asymmetric polyazaphane scaffolds by simultaneous addition of Functionality (letters) in solution has be en developed for the preparation of tertiary nitrogen-based combinator ial chemistry libraries. This approach has some significant advantages over the more commonly employed solid phase bead splitting/resction/m ixing procedures for the preparation of libraries. Three novel, asymme tric polyazaphanes 32, 33, and 37 have been synthesized in high yields by an efficient cyclization of 2,6-bis(bronzomethyl)pyridine (31) wit h new orthogonally protected triamines 29, 30, and 35, respectively. S elective deprotection of 32, 33, and 37 provided mono-t-Boc-protected scaffolds 1-3 suitable for solution phase, simultaneous addition of fu nctionalities. Model studies of small libraries of scaffold 2 using CZ E analyses indicated that simultaneous addition of 10 benzylic bromide alkylating functionalities would result in libraries containing appro ximately equimolar amounts of all possible compounds. Sixteen purified tertiary amine libraries 4-19 (total complexity of 1600 compounds) we re generated by this procedure from scaffold 2. A ''fix-last'' combina torial method was devised to minimize chemical reactions. Several firs t-round sublibraries of scaffold 2, containing a mixture of 100 compou nds, exhibited potent antimicrobial activities. Twenty single compound s 63-82 with uniform functionalities at the combinatorialized sites we re synthesized. Some of these pure compounds were more active, while o thers were less active, compared with the parent mixtures 5 and 10.