Neuroprotective effects of prenylated flavanones isolated from Dalea species, in vitro and in silico studies

• Published in: European journal of medicinal chemistry Vol. 206; p. 112718
• Main Authors: Santi, María D., Arredondo, Florencia, Carvalho, Diego, Echeverry, Carolina, Prunell, Giselle, Peralta, Mariana A., Cabrera, José L., Ortega, María G., Savio, Eduardo, Abin-Carriquiry, Juan A.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.11.2020
• Subjects: Animals; Cell Differentiation - drug effects; Computer Simulation; Dalea elegans; Dalea pazensis; Fabaceae - chemistry; Flavanones - chemistry; Flavanones - isolation & purification; Flavanones - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - isolation & purification; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; PC12 Cells; Prenylated flavanones; Prenylation; Rats; Structure-Activity Relationship; Prenylated flavanones; Neuroprotection; Dalea elegans; Dalea pazensis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112718

Neurodegenerative diseases (NDs) represent a global problem on public health, with a growing incidence as human longevity increases. Currently, although there are palliative strategies available for most of these diseases, there is a lack of effective therapies for their cure. Flavonoids are extensively studied for their multi-target behavior. Among numerous biological activities, it has been reported that they act at the CNS level, presenting neuroprotective activity through different mechanisms of action. Dalea L. (Fabaceae) is an American genus, with about 172 species. Dalea elegans Gillies ex. Hook. & Arn and Dalea pazensis Rusby, both South American species, are the important source of natural compounds of the prenylated flavanones type. In the present study, five prenylated flavanones isolated from Dalea species were assayed for their neuroprotective activity in two in vitro models of neurodegeneration. Flavanones 1 and 2 exhibited neuroprotective effects against oxidative stress-induced death in both models, granular cerebellar neurons and (NGF)-differentiated PC12 cells. Structure-activity relationships were also reported. Our results indicated that an 8-prenyl group at the A-ring accompanied by an unsubstituted B-ring, or a 2′,4′-dihydroxy-5′-dimethylallyl substitution, lead to the most potent flavanones. Furthermore, in silico studies were performed, and several putative targets in NDs were identified for compounds 1 and 2. Between them, the enzyme acetylcholinesterase was selected for its validation in vitro. The present in vitro and in silico results imply that prenylated flavanones 1 and 2 may be useful in the development and design of future strategies for the treatment of NDs diseases. [Display omitted] •Five flavanones isolated from roots and aerial parts of Dalea’ species were assayed.•Neuroprotective activity of natural prenyl-flavanones and pinocembrin was determined.•SAR and in silico studies were performed for those compounds for the first time.•Acetylcholinesterase inhibitory activity was validated.•Compound 2 was more potent than Physostigmine, with IC50 in the nanomolar range.