Common pharmacophore of structurally distinct small-molecule inhibitors of intracellular retrograde trafficking of ribosome inactivating proteins

We reported previously (±)-2-(5-methylthiophen-2-yl)-3-phenyl-2,3- dihydroquinazolin-4(1H)-one [(±)-Retro-2^cycl[ as the chemical structure of Retro-2 that showed mouse protection against ricin, a notorious ribosome inactivating protein (RIP). Herein we report our chemical resolution of (±)-Retro-2^cycl, analog synthesis, and cell-based evaluation showing that the two optically pure enantiomers and their achiral analog have nearly the same degree of cell protection against ricin as (±)-Retro-2 ^cycl. We also report our computational studies explaining the lack of stereo preference and revealing a common pharmacophore of structurally distinct inhibitors of intracellular retrograde trafficking of RIPs. This pharmacophore comprises a central aromatic ring o-substituted by an aromatic ring and a moiety bearing an O or S atom attached to sp² C atom(s). These results offer new insights into lead identification and optimization for RIP antidote development to minimize the global health threat caused by ribosome-inactivating proteins.