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

Metabolism 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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2026

Author dc:creator

• Krinos, Emily

Chair dc:contributor.committeechair

• Santos, Webster

Committee members dc:contributor.committeemember

• Mevers, Emily Elizabeth
• Figg, Charles Adrian
• Gentry, Emily Christine

• mitochondrial uncouplers
• obesity
• metabolism
• mitochondria
• protonophore

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:45778

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/141608