A parallel synthesis demonstration library of tri-substituted indazoles containing new antimutagenic/antioxidant hits related to benzydamine.
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.
Menon
Sanjay
S
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA.
Vaidya
Hemin
H
Pillai
Segaran
S
Vidya
Ramdas
R
Mitscher
Lester A
LA
D016587:Antimutagenic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
D016587:Antimutagenic Agents; D000975:Antioxidants; D007191:Indazoles