\u3b1-linolenic acid-valproic acid conjugates: Toward single-molecule polypharmacology for multiple sclerosis

Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of \u3b1-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways

2-Propargylamino-naphthoquinone derivatives as multipotent agents for the treatment of Alzheimer's disease

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of “one drug, one target” has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD.This work was supported by a grant of the Ministry of Defence “Long Term Development Plan” Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence; by the Ministry of Education, Youth and Sports of Czech Republic (project ERDF IT4N no. CZ.02.1.01/0.0/0.0/ 18_069/0010054), by EU COST Action (CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)"), and by MH CZ - DRO (University HospitalHradec Kralove, No. 00179906). We also thank the Scientific Grant Agency (VEGA Project 1/0482/20) and Research and Development Support Agency (APVV-15-0079 and APVV-19-0087). Marvin was used for drawing, displaying, and characterizing chemical structures, substructures and reactions, Marvin 20.15.0, ChemAxon (https://www.chemaxon.com)

Novel Sustainable-by-Design HDAC Inhibitors for the Treatment of Alzheimer's Disease

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (1), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives 8 and 9 display a HDAC inhibitory profile similar to 1, together with a more promising safety for 9 compared to 1. Moreover, both compounds and particularly 9 were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD