Phase Combinatorial Synthesis Of Quinoxaline The Alcohol Compound Chemical Library And Its Optimization And ADME Characteristics

The number of lead compounds is the vital base for drug discovery. Combinatorial chemistry, which can rapidly provide large number of compounds, has been recognized as a powerful tool for both identification and optimization of lead compounds in the post-genomic era. Two methods have been developed for synthesis of chemical library including solid-phase synthesis and solution-phase synthesis. The parallel combinatorial solution-phase synthesis is greatly benefited from solid-supported reagents, catalysts and scavengers in the past decade. The small organic molecules, especially the heterocycles containing N atom, have attracted more attention for their high order of structural diversity and more "lead-like" or "drug-like".1, 5-Difluoro-2, 4-dinitrobenzene (DFDNB) is a protein cross-linker and also a versatile reagent for diverse scaffolds. It is a symmetrical scaffold with chemical activities similar to o-fluoronitrobenzene, but more structural diversity can be introduced through asymmetrical nucleophilic substitutions. After simultaneous reduction of the two nitro groups, many kinds of heterocyclic scaffold compounds could be generated. In this paper, we have synthesized two kinds of "scaffold-directed" heterocyclic compound library, using the parallel solution-phase synthesis and solid-supported scavengers starting from DFDNB. Both scaffolds of compound behave many biological activities as literature reported. The overall procedures included quantitatively nucelophilic substitution, reduction of aromatic m-dinitro groups, benzofused ring formations and purifications using scavenger resins etc.In this paper, simultaneously converting of m-Ar(NO₂)₂ into m-Ar(NH₂)₂ with high yield is the key step for constructing the two libraries. We explored many conditions and selected the Pd/C-HCOONH₄ reduction method at last. Using this reduction method, a 2-quinoxalinol library containing 42 single compounds and a 1,2,7-trialky-1H-imidazo[4, 5-g]quinoxalin-6-ol mixture library (5 compounds/well) containing 2500 compounds and 27 single 1, 2, 7-trialky-1H-imidazo[4, 5-g] quinoxalin-6-ol compounds were synthesized. The synthesis of 3, 4-dihydro-1H-pyrazino[2, 3-g]quinoxalin-2-one compound was also explored and 7 compounds were obtained too. HPLC-MS analysis is a highly efficient method for detecting the process of the...