Solution Phase Combinatorial Chemistry. Synthesis of Novel Linear Pyridinopolyamine Libraries with Potent Antibacterial Activity

Abstract

Novel linear pyridinopolyamine derivatives 1 − 3, 7, and 8 have been synthesized as scaffolds for combinatorial drug discovery. The mono- t -Boc- and monotosyl-protected linear scaffolds 1 and 2 were obtained by a Schiff base type cyclization of 2,6-pyridinedicarboxaldehyde ( 24 ) with monoprotected triamines 22 and 23 using Ni 2+ as a metal template, followed by reductive cleavage and decomplexation in a one-pot procedure. The unprotected linear scaffold 3 was obtained by treating 1 with TFA. Scaffold 1 was also synthesized from the orthogonally protected pyridinopolyamine 7 which was constructed from 2,6-bis(bromomethyl)pyridine ( 29 ) in four steps. Selective deprotection of the key intermediate 7 afforded 8, which was further selectively deprotected to give scaffold 1 . A combinatorial chemistry strategy involving solution phase simultaneous addition of functionalities (SPSAF) is described. Thirteen high-purity tertiary amine libraries ( 9 − 21 ) (total 1638 compounds) were synthesized by the SPSAF and fix last methodologies from linear polyamine scaffolds 1 and 2 . All libraries were examined by TLC, purified by chromatographic techniques, and characterized by 1 H NMR and ESI MS spectral data. A fix last methodology was utilized to minimize chemical reactions and perform SAR studies directly on libraries. Several first-round sublibraries of scaffold 1, containing 126 compounds each, exhibited potent antibacterial activity with MICs of 1−12 μM against Streptococcus pyogenes and Escherichia coli imp - .