α-Helices are one of the most commonly found protein secondary structures and often play a vital role in mediating protein-protein interactions. However, helical peptide segments are prone to be damaged by entropy effect when taken out of proteins, and fall in to random coil or other structure [1]. Several approaches have been developed in order to stabilize a-helices in short peptides, such as lactam, salt and disulfide bridge formations between the i and i+4 positions of a helix [2]. An alternative approach is to achieve small molecules that mimic a-helices by using rigid and pre-organized scaffolds including terphenyls [3], trispyridylamides [4], polycyclic ethers [5], pyridazines [6], and trisbenzamides [7]. These a-helix mimetics focus on presenting only one side of a helix that comprises of the side chains of amino acids found at the i, i+3 (or i+4), and i+7 positions. On the contrary, a-helix mimetics that have a capability to represent two opposing helical faces have not been reported yet. Hence, we report a new bisbenzamide scaffold that can place four side chain functional groups, two found at the i and i+7 positions on one helical face; and the other two from the i+2 and i+5 positions on the opposite side (Figure 1). The spatial arrangement of the four substituents was fixed by two hydrogen bonds between a benzamide proton and two adjacent alkoxy groups that promote high structural rigidity and superior a-helix mimicry.
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