The diaryl urea is an important fragment/pharmacophore in constructing anticancer
molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a
favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor.
Many novel compounds have been synthesized and evaluated for their antitumor activity
with the successful development of sorafenib. Moreover, this structure is used to link
alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several
kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors:
it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone
amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh)
ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we
provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative
antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors
and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the
search to find new and more potent compounds.
Keywords: Diaryl urea, anticancer activity, DNA-alkylating agents, SAR, DFG-out, kinase inhibitors, heterocycles.
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