Benzofurans as Acetylcholinesterase Inhibitors for Treating Alzheimer's Disease: Synthesis, in†vitro Testing, and in†silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by a progressive decline in cholinergic neurotransmission. During the development of AD, acetylcholinesterase (AChE) binds to ß-amyloid peptides to form amyloid fibrils, which aggregate into plaque deposits. Meanwhile, tau proteins are hyperphosphorylated, forming neurofibrillary tangles (NFTs) that aggregate into inclusions. These complexes are cytotoxic for the brain, causing impairment of memory, attention, and cognition. AChE inhibitors are the main treatment for AD, but their effect is only palliative. This study aimed to design and synthesize novel benzofuran derivatives and evaluate their inhibition of AChE in vitro and in silico. Results: The seven synthesized benzofuran derivatives inhibited AChE in vitro. Benzofurans hydroxy ester 4, amino ester 5, and amido ester (±)-7 had the lowest inhibition constant (Ki) values and displayed good affinity for EeAChE in molecular docking. Six derivatives showed competitive inhibition, while the best compound (5: Ki=36.53 µM) exhibited uncompetitive inhibition. The amino, hydroxyl, amide, and ester groups of the ligands favored interaction with the enzyme by hydrogen bonds. Conclusion: Three benzofurans were promising AChE inhibitors with excellent Ki values. In future research on their their application to AD, 5 will be considered as the base structure.

In silico and in vivo neuropharmacological evaluation of two γ-amino acid isomers derived from 2,3-disubstituted benzofurans, as ligands of GluN1-GluN2A NMDA receptor.

The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.

Mannich bases of hydroxycoumarins: synthesis, DFT/QTAIM computational study and assessment of biological activity.

The synthesis of six Mannich bases derived from hydroxycoumarins was carried out in moderate yields, two of these derivatives were described for the first time. Conformational analysis was performed through DFT theoretical calculations explaining the formation of stable six membered rings based on intramolecular hydrogen bonds within the structure. These findings were correlated with the antiproliferative activity. The biological activity of the Mannich bases through their antiproliferative activity in the HeLa cancer cell line is described for the first time, showing that the compounds were able to inhibit proliferation in cervical cancer by more than 60%. Likewise, the theoretical modeling of the photophysical properties was realized with promising results, showing that the HOMO-LUMO energies of the new compounds present the lowest electronic gap values for those with donor groups in their structure, which makes them potential fluorophores.

Quantum Reality in the Selective Reduction of a Benzofuran System.

Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA), were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore, theoretical calculations of global and local reactivity were performed based on Pearson's hard and soft acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for explaining the selectivity of the polar reactions. This local parameter was defined with the condensed Fukui function and redefined with the electrophilic (Pk+) Parr function. The similar patterns of both resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance hybrids showed the moieties in each compound that are most susceptible to reduction.

Brown Seaweed Egregia menziesii's Cytotoxic Activity against Brain Cancer Cell Lines.

Brown seaweeds contain bioactive compounds that show anti-tumorigenic effects. These characteristics have been repeatedly observed in the Lessoniaceae family. Egregia menziesii, a member of this family, is distributed in the North Pacific and its properties have been barely studied. We evaluated herein the cytotoxic and anti-proliferative activity of extracts of this seaweed, through toxicity assay in Artemia salina and lymphocytes, and MTT proliferation assay, in Bergmann glia cells, 3T3-L1 and brain cancer cell lines. E. menziesii's extracts inhibited the spread of all the tested cell lines. The hexane extract showed the highest cytotoxic activity, while the methanol extract was moderately cytotoxic. Interestingly, seaweed extracts displayed a selective inhibition pattern. These results suggest that E. menziesii's extracts might be good candidates for cancer prevention and the development of novel chemotherapies due to its highest cytotoxicity in transformed cells compare to glia primary cultures.

Synthesis and Biological Evaluation of Novel 2,3-disubstituted Benzofuran Analogues of GABA as Neurotropic Agents.

BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.

Synthesis of (-)-stemoamide using a stereoselective anti-aldol step.

The synthesis of (-)-stemoamide was achieved in 11 steps from 5-acetoxy-N-crotyl pyrrolidinone. A chiral N-acyl thiazolidinethione was employed in a stereoselective addition to a cyclic N-acyl iminium ion to install the required stereochemistry of carbon C9a. This iminium ion addition product was employed in a stereoselective MgBr2-catalyzed anti-aldol reaction to install the required stereochemistry of carbons C8 and C9. The X-ray crystal analysis of (-)-stemoamide confirmed the structure and the stereochemical outcome of these selective reactions.