Naturally Inspired Coumarin Derivatives in Alzheimer's Disease Drug Discovery: Latest Advances and Current Challenges.

The main feature of neurodegenerative diseases, including Alzheimer's disease, is the network of complex and not fully recognized neuronal pathways and targets involved in their onset and progression. The therapeutic treatment, at present mainly symptomatic, could benefit from a polypharmacological approach based on the development of a single molecular entity designed to simultaneously modulate different validated biological targets. This strategy is principally based on molecular hybridization, obtained by linking or merging different chemical moieties acting with synergistic and/or complementary mechanisms.

Chromone-based small molecules for multistep shutdown of arachidonate pathway: Simultaneous inhibition of COX-2, 15-LOX and mPGES-1 enzymes.

As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices.

Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment.

Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α.

Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold.

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events.

Hitting drug-resistant malaria infection with triazole-linked flavonoid-chloroquine hybrid compounds.

: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules were designed by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. : Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery.