From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease |
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Authors: | Claudia Albertini Marina Naldi Sabrina Petralla Silvia Strocchi Daniela Grifoni Barbara Monti Manuela Bartolini Maria Laura Bolognesi |
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Affiliation: | 1.Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6/Via Selmi 3, 40126 Bologna, Italy; (C.A.); (M.N.); (S.P.); (S.S.); (B.M.); (M.B.);2.Centre for Applied Biomedical Research—CRBA, University of Bologna, St. Orsola Hospital, Via Massarenti 9, 40138 Bologna, Italy;3.Department of Life, Health and Environmental Sciences (MeSVA), University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy; |
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Abstract: | Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance. |
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Keywords: | anti-inflammatory, anti-amyloid, codrugs, drug combinations, polypharmacology, Alzheimer’ s disease |
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