Design, synthesis, and biological evaluation of furosemide analogs as therapeutics for the proteopathy and immunopathy of Alzheimer's disease.

β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer's disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.