Fragment-Based Drug Discovery (FBDD) is a powerful drug discovery technique that uses small (&lt;300 amu) molecules (fragments) as a starting point for dug discovery. FBDD is contrasted with other methods of drug discovery through its use of small fragments, rather than fully elaborate molecules, such as those employed in High-Throughput Screening. Vital to this technique of FBDD is a high-quality library full of fragments that cover a broad range of chemical space, can easily be synthesized, and can readily be optimized in a modular fashion in the lead optimization stage. The ideal fragment will satisfy these demands along with possessing good physiochemical properties such as cLogP, number of rotatable bonds, and H-bond donors and acceptors. To meet these criteria, a molecule consisting of a hydrophobic core, a hydrophilic moiety, and a synthetic handle for rapid optimization would be ideal. The synthesis of underrepresented heterocyclic compounds and known heterocyclic structures with novel spatial arrangements requiring synthetic routes is a worthwhile endeavor. One such molecule is 2-ethynyl-1-phenyl-1<i>H</i>-imidazole-4-carboxylic acid. This hydrophobic imidazole possesses a hydrophilic carboxylic acid, a phenyl ring, and an alkyne substituent in an underrepresented 3-D spatial arrangement that would provide a high quality, synthetically tractable fragment for a drug discovery library if a known synthesis were available. To this end, a straightforward, modular synthesis of 2-ethynyl-1-phenyl-1<i>H</i>-imidazole-4-carboxylic acid and more broadly 1,2,4-substituted imidazoles was explored.

Synthesis of 1,2,4-substituted imidazoles for a fragment-based drug discovery library

253rd National Meeting (2017)

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