Solution phase combinatorial chemistry. Discovery of novel polyazapyridinophanes with potent antibacterial activity by a solution phase simultaneous addition of functionalities approach

被引:74
作者
An, HY [1 ]
Cummins, LL [1 ]
Griffey, RH [1 ]
Bharadwaj, R [1 ]
Haly, BD [1 ]
Fraser, AS [1 ]
WilsonLingardo, L [1 ]
Risen, LM [1 ]
Wyatt, JR [1 ]
Cook, PD [1 ]
机构
[1] ISIS PHARMACEUT,DEPT MED CHEM,CARLSBAD,CA 92008
关键词
D O I
10.1021/ja964153r
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Chemical modification of pre-formed asymmetric polyazaphane scaffolds by simultaneous addition of Functionality (letters) in solution has been developed for the preparation of tertiary nitrogen-based combinatorial chemistry libraries. This approach has some significant advantages over the more commonly employed solid phase bead splitting/resction/mixing procedures for the preparation of libraries. Three novel, asymmetric polyazaphanes 32, 33, and 37 have been synthesized in high yields by an efficient cyclization of 2,6-bis(bronzomethyl)pyridine (31) with new orthogonally protected triamines 29, 30, and 35, respectively. Selective deprotection of 32, 33, and 37 provided mono-t-Boc-protected scaffolds 1-3 suitable for solution phase, simultaneous addition of functionalities. Model studies of small libraries of scaffold 2 using CZE analyses indicated that simultaneous addition of 10 benzylic bromide alkylating functionalities would result in libraries containing approximately equimolar amounts of all possible compounds. Sixteen purified tertiary amine libraries 4-19 (total complexity of 1600 compounds) were generated by this procedure from scaffold 2. A ''fix-last'' combinatorial method was devised to minimize chemical reactions. Several first-round sublibraries of scaffold 2, containing a mixture of 100 compounds, exhibited potent antimicrobial activities. Twenty single compounds 63-82 with uniform functionalities at the combinatorialized sites were synthesized. Some of these pure compounds were more active, while others were less active, compared with the parent mixtures 5 and 10.
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收藏
页码:3696 / 3708
页数:13
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