A Role for Janus Cyclohexyl Ring Motifs in Medicinal Chemistry. Incorporation Into G‐Quadruplex Ligands and Anti‐ Trypanosoma brucei Activity

The naphthalene diimide (NDI) ring system is recognized as a privileged motif for binding to G‐quadruplex DNA. Accordingly, compounds with peripheral groups attached to the NDI core are being explored as antiparasitic and anticancer candidates. In this study, we have synthesized and explored a series of NDIs with peripheral all‐ cis ring fluorinated cyclohexyl rings to assess their relative stabilization potential for G‐quadruplex and double‐stranded DNA. This was explored through FRET melting experiments and measuring changes in melting temperatures (Δ T m ). Compounds were also assayed against Trypanosoma brucei to assess their in vitro potency (EC 50 ) against the causative parasite of human African trypanosomiasis or African Sleeping Sickness. The study revealed significant differences in activity when changing the nature of fluorine substitutions on the cyclohexane ring and also the length and nature (ether (O) or methylene (CH 2 )) of the linker to the core aromatic motif. The most active compound of the series was ether 12a which displayed nanomolar activity (EC 50 = 40 nM) against T. brucei although with a modest selectivity (14‐fold) for the parasite over HeLa (human model) cells. The study reveals good prospects for exploring fluorinated Janus cyclohexanes in a medicinal chemistry context.