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 Ni2+ 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 1H 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 -.

Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity: Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry

“…The design and synthesis of the pyridinopolyamine scaffold 1 and its combinatorialization with a set of meta-substituted benzyl bromide functionalities has been reported. 12 The resulting 13 sublibraries of 126 members, prepared by a fix last synthesis method, are suitable for iterative deconvolution. The position A of pyridinopolyamine 1 (Chart 1) was selected as the site to place the differentiating functionalities (fix last) for a first-round iterative deconvolution process.…”

“…Having position A fixed with a hydrogen atom, as determined by iterative deconvolution, we next elected to determine the optimal functionality residing in positions B and C by positional scanning of positions B-D. Positions B and D were combinatorialized with the six meta-substituted functionalities (Chart 2), while position C was fixed with each of the functionalities to provide six sublibraries (10)(11)(12)(13)(14)(15) of 36 members (Table 3, Scheme 2). In this "second"-round deconvolution, a CH 2 C 6 H 4 CF 3 -m group in the C position was a clear winner (library 15, Table 3).…”

“…We have reported the synthesis a 1638-member novel pyridinopolyamine library, consisting of 13 sublibraries (1a-m) of 126 members (Chart 1), by the solution-phase simultaneous addition of functionalities (SPSAF) approach. 12 The 13 sublibraries are differentiated by the functional groups selected to be placed in the chosen fixed position A (see Chart 1 to identify combinatorial positions). Six of the sublibraries (1d-i) were derived from placing each functionality of the six-member set, used to combinatorialize the three open positions, in position A.…”

“…In this report, we describe a strategy involving iterative and positional scanning to completely deconvolute these active sublibraries. The SPSAF approach [10][11][12] was used to generate all sublibraries during the deconvolution.…”

Combinatorial Chemistry Libraries, Analysis of

“…Analysis of nonpeptide libraries by ESIMS has focused mainly on the characterization of single compounds cleaved from individual resin beads, 87 -89 or single compounds obtained from parallel synthesis. 90,91 The ESIMS spectra of low-molecularweight organic compounds generally are characterized by singly charged molecular ions, and multiply charged ions are only rarely observed. Compounds containing basic functional groups yield intense positively charged molecular ions with little fragmentation.…”