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Combinatorial Chemistry & High Throughput Screening


ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

A Parallel Synthesis Demonstration Library of Tri-Substituted Indazoles Containing New Antimutagenic / Antioxidant Hits Related to Benzydamine

Author(s): Sanjay Menon, Hemin Vaidya, Segaran Pillai, Ramdas Vidya and Lester A. Mitscher

Volume 6, Issue 5, 2003

Page: [471 - 480] Pages: 10

DOI: 10.2174/138620703106298644

Price: $65


A solution phase strategy for the multiple parallel synthesis of a demonstration library of indazoles is described by which regio-selectivity problems inherent to previous syntheses of this nucleus are largely overcome. Synthesis of selected components proceeded satisfactorily indicating that a fully realized library of indazole analogs could readily be produced using this methodology. Simple modifications of the basic nucleophilic aromatic substitution route unambiguously produce a range of N-1 substitutions (alkyl, aryl and aralkyl) in 50-75% yields. Next a range of substituents was introduced at the C-3 position in 50-80% yields by O-alkylation. Careful choice of reagents and reaction conditions were required to prevent by-product formation due to competing alkylation at N-2 (trace to 15% yields). When present, these contaminants were readily removed by chromofiltration. A third diversity site was sketched in at C-5 in 75-90% yield by reductive alkylation or acylation. Screening of some of the demonstration library members in vitro revealed highly active antioxidants suggesting that producing a full library would be worthwhile.

Keywords: parallel synthesis, library of tri-substituted indazoles, antimutagenic/antioxidant hits, regio-selectivity

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