Synthesis and evaluation of 3′- and 4′-substituted cyclohexyl noviomimetics that modulate mitochondrial respiration

[Display omitted] •Potent Hsp90 C-terminal inhibitors based on KU-1202 were designed and synthesized.•Most compounds had an impact at modulating mitochondrial bioenergetics studied using a Seahorse Analyzer.•Compounds 78, 79 and 89 showed a significant shift in the ATP index toward OxPhos indicating its cytoprotective potential. KU-32 (2) and KU-596 (3), are first and second generation cytoprotective novologues that are derivatives of novobiocin (1), a heat shock protein 90 (Hsp90) C-terminal inhibitor. Although 2 and 3 improve mitochondrial bioenergetics and have demonstrated considerable cytoprotective activity, they contain a synthetically demanding noviose sugar. This issue was initially addressed by creating noviomimetics, such as KU-1202 (4), which replaced the noviose sugar with ether-linked cyclohexyl derivatives that retained some cytoprotective potential due to their ability to increase mitochondrial bioenergetics. Based on structure–activity relationship (SAR) studies of KU-1202 (4), the current study investigated 3′- and 4′-substituted cyclohexyl scaffolds as noviomimetics and determined their efficacy at increasing mitochondrial bioenergetic as a marker for cytoprotective potential.