1,721,014 research outputs found
Modulation of Prion by Small Molecules: From Monovalent to Bivalent and Multivalent Ligands
No full textPrion diseases are fatal neurodegenerative disorders that affect humans and animals and for which no pharmacological treatment is available. Compounds consisting of two identical moieties joined via an appropriate spacer (i.e. bivalent compounds) have turned out to be effective tools to prevent prion fibril formation and exhibit an improved biological profile with regard to the corresponding monovalent derivatives. In this review we discuss the importance of the bivalent strategy as a viable approach to design new chemical entities to combat prion diseases
Remembering Marie Curie’s legacy
No full textThe April issue of ChemMedChem is dedicated to women in chemistry, medicinal chemistry in particular. Two of ChemMedChem's Board members, Professors Gloria Cristalli, University of Camerino, Italy, and Maria Laura Bolognesi, University of Bologna, Italy, introduce this issue with their Editorial, Remembering Marie Curie's Legacy, which highlights a few of the many examples in which female chemists have contributed enormously to their field
BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease
No full textThe amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the beta-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with More complex mechanisms of actions and improved efficacy. Herein, we review the major advances in. BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better. understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease
Synthesis and evaluation of a library of 2,5-bisdiamino-benzoquinone derivatives as probes to modulate protein-protein interactions in prions
No full textA small library combining two different benzoquinone cores with seven (L) amino acid methyl esters (alanine, Nomega-nitro-arginine, Nepsilon-BOC-lysine, isoleucine, methionine, phenylalanine and tryptophan) was prepared and tested for prion replication inhibition in ScGT1 cells. The most potent hit, 6a, displayed an EC(50) value of 0.87 microM, which is very close to that of quinacrine (0.4 microM)
Quinolinetrione-tacrine hybrids as multi-target-directed ligands against Alzheimer's disease
Full text linkMulti-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multitarget-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2-6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors
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