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—Derivatives of the compound 2,5-di-tert-butylhydroquinone (BHQ) are inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA). Previous work identified BHQ analogs with two alkyl substituents composed of four to six carbon atoms as the most potent representatives from this inhibitor class. In this study, we explored the effects of introducing two cycloalkyl substituents on the hydroquinone scaffold. Since these substituents have limited conformational flexibility, the entropy penalty upon binding of these compounds to SERCA was expected to be smaller than for non-cyclic BHQ analogs, potentially conveying higher inhibitory potency. We synthesized a congeneric series of four 2,5-disubstituted BHQ analogs and determined their inhibitory potencies against SERCA in bioassays. Potencies were found in the low micromolar and submicromolar concentration ranges, making the new compounds some of the most potent hydroquinone-based inhibitors to date. Computational docking facilitated a detailed analysis of enzyme/inhibitor interactions at the molecular level and showed that the entropic effect was noticeable but too small to increase potency in a substantial manner.

Hydroquinones with Conformationally Constrained Substituents: Synthesis, Characterization, and Evaluation as Calcium–ATPase Inhibitors