Design and Synthesis of 8-Trifluoromethyl-Substituted Heterocyclic Small Molecule  Mitochondrial Uncouplers for the Treatment of Metabolic Diseases

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dc.contributor.authorKrinos, Emilyen
dc.contributor.committeechairSantos, Websteren
dc.contributor.committeememberMevers, Emily Elizabethen
dc.contributor.committeememberFigg, Charles Adrianen
dc.contributor.committeememberGentry, Emily Christineen
dc.contributor.departmentChemistryen
dc.date.accessioned2026-02-28T09:00:16Zen
dc.date.available2026-02-28T09:00:16Zen
dc.date.issued2026-02-27en
dc.description.abstractgeneralMetabolism occurs mainly in the mitochondria, or "the powerhouse of the cell." Here, nutrients and sugars from food are broken down and converted into energy through a process called mitochondrial respiration. Through this process, mitochondria provide over 90% of cellular energy. However, during inflammatory events, mitochondrial respiration is less efficacious and could cause or progress diseases such as obesity, type 2 diabetes, or metabolic dysfunction-associated liver disease (MAFLD). In response to the progression of these diseases, cells activate uncoupling proteins to increase the rate of mitochondrial respiration and reduce inflammation. Thus, small molecule mitochondrial uncouplers have been developed to mimic the effects of uncoupling proteins and reduce inflammation. Our lab has focused on designing small molecule mitochondrial uncouplers to treat metabolic diseases. We take inspiration from the efficacious uncoupler, BAM15. BAM15 has proven to be effective against obesity, type 2 diabetes, liver disease, and several other conditions in animal models. However, BAM15 has not been in clinical trials due to its poor druglike properties, such as circulating drug concentration and half-life. Herein, we disclose four mitochondrial uncoupler designs that improve the druglike properties of BAM15, while maintaining its efficacy. We report the discovery of N-substituted 8-trifluoromethyl-9H-purin-6- amines where lead compound SHK1112218 was identified as a highly potent mitochondrial uncoupler. Additionally, in an obesity reversal study in mice, treatment with lead compound SHK589 was observed to decrease body fat and maintain muscle mass. Together, these findings encourage the further exploration of mitochondrial uncouplers for the treatment of metabolic diseases.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:45778en
dc.identifier.urihttps://hdl.handle.net/10919/141608en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectmitochondrial uncouplersen
dc.subjectobesityen
dc.subjectmetabolismen
dc.subjectmitochondriaen
dc.subjectprotonophoreen
dc.titleDesign and Synthesis of 8-Trifluoromethyl-Substituted Heterocyclic Small Molecule  Mitochondrial Uncouplers for the Treatment of Metabolic Diseasesen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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