Abstract
Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a ‘drug hunters’ quest to discover new leads and a chemical biologists search for effective molecular tools in ‘cell perturbation’ studies. At the front end of the drug discovery flow chart, the last 5–10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 107 derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis.
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Abbreviations
- IMCR:
-
Isonitrile based multicomponent reaction
- PCT:
-
Patent cooperation treaty
- AIDS:
-
Acquired Immune Deficiency Syndrome
- GPCR:
-
G protein-coupled receptor
- ATP:
-
Adenosine triphosphate
- AMP:
-
Adenosine monophosphate
- GMP:
-
Guanosine monophosphate
- CRF:
-
Corticotropin releasing factor
- PDE:
-
Phosphodiesterase
- BZ:
-
Benzodiazepine
- GABA:
-
γ-Aminobutyric acid
- TFA:
-
Trifluoroacetic acid
- HBTU:
-
O-Benzotriazole-N,N,N′,N′-tetramethyl- chronium-bona fluoro-phosphate
- HOBt:
-
N-Hydroxybenzotriazole
- DIEA:
-
Diisopropylethylamine
- HATU:
-
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3- tetramethyl uronium hexafluorophosphate
- UDC:
-
Ugi/Deprotection/Cyclization
- RAM:
-
Aminomethylated resin
- CCR5:
-
Chemokine (C-C motif) receptor 5
- DOE:
-
Design of experiment
- MAOS:
-
Microwave assisted organic synthesis
- TMSCN:
-
Trimethylsilylcyanide
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Hulme, C., Lee, YS. Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]-heterocycles. Mol Divers 12, 1–15 (2008). https://doi.org/10.1007/s11030-008-9072-1
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DOI: https://doi.org/10.1007/s11030-008-9072-1