Project Summary/Abstract Per 2019 Alzheimer’s report, Alzheimer’s disease (AD) dire statistics include: a current patient load of 5.8 million that is projected to expand to 14 million by 2050 in the US, increases in deaths by 145% (per 2000-2017 data), and climbing healthcare costs - $290 billion in 2019. In terms of pharmacotherapy, five clinical drugs [i.e., three cholinesterase inhibitors (ChEIs), one N-methyl-D-aspartate receptor antagonist (NMDRA), and one ChEI/NMDRA combo-drug] are indicated for AD and these drugs only provide symptomatic relief - they do not slow disease progression. A triad of poor health outcomes, lack of effective drugs, and high failure rates of pipeline molecules in clinical trials has therefore increased the urgency to discover more robust anti-AD molecules with novel mechanisms for slowing disease progression. The overall objective of this grant application is to 1) synthesize derivatives of Tubastatin A (a highly selective HDA6 inhibitor, IC50 = 15 nM), 2) evaluate each derivative for binding/functional activities at individual sigma (σ) receptors, and 3) determine each compound’s ability to inhibit histone deacetylase-6 (HDAC6). Central hypothesis: single molecules designed using the multi-target-directed ligands (MTDL) paradigm could more effectively mitigate AD’s neurodegenerative pathogenic cascades and repair cognitive deficits. Evidently, in AD animal models, independent σ-1 activation or σ-2 blockade or HDAC6 inhibition commonly result in decreased neurodegeneration and improved cognitive function. Therefore, our synthesized derivatives are expected to exhibit a de-novo σ-1/HDAC6 or σ- 2/HDAC6 combo-mechanistic anti-neurodegenerative approach towards slowing AD progression or potentially modifying the disease.