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However, their impact on skeletal muscle and GABAergic pathways remains poorly understood. We synthesized a focused library of benzothiazole derivatives via oxidative electrophilic substitution and profiled their activity in C2C12 skeletal muscle cells, assessing cytotoxicity, proliferation, myogenic differentiation, and GABA-related signaling using cell-based assays, real-time PCR, and transcriptomics. Omics-guided analyses revealed that selected benzothiazole derivatives differentially modulate myogenic differentiation and prostaglandin E2, and simultaneously bidirectionally regulate GABAergic and glutamatergic signaling genes, including synaptic subunits and transporters. Notably, a lead derivative downregulated Gabrg2, a GABA-A receptor subunit implicated in epilepsy and other disorders of inhibitory synapses, highlighting a potential link between skeletal muscle signaling and neuropsychiatric disease. 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