Viayna A

References (4)

Title : In-vitro and in-silico studies of annelated 1,4,7,8-tetrahydroazocine ester derivatives as nanomolar selective inhibitors of human butyrylcholinesterase - de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
Author(s) : de Candia M , Titov AA , Viayna A , Kulikova LN , Purgatorio R , Piergiovanni B , Niso M , Catto M , Voskressensky LG , Luque FJ , Altomare CD
Ref : Chemico-Biological Interactions , :110741 , 2023
Abstract : Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment Alzheimer disease and related dementias, herein we investigated diverse newly and previously synthesized beta-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (K(i) = 7.8 +/- 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC(50) of 0.27 microM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes.
ESTHER : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedSearch : de Candia_2023_Chem.Biol.Interact_14ChEPon_110741
PubMedID: 37839515

Title : Three to Tango: Inhibitory Effect of Quercetin and Apigenin on Acetylcholinesterase, Amyloid- Aggregation and Acetylcholinesterase-Amyloid Interaction - Alvarez-Berbel_2022_Pharmaceutics_14_
Author(s) : Alvarez-Berbel I , Espargaro A , Viayna A , Caballero AB , Busquets MA , Gamez P , Luque FJ , Sabate R
Ref : Pharmaceutics , 14 : , 2022
Abstract : One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid- plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid- aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on A40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the A40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.
ESTHER : Alvarez-Berbel_2022_Pharmaceutics_14_
PubMedSearch : Alvarez-Berbel_2022_Pharmaceutics_14_
PubMedID: 36365159

Title : Interplay between Ionization and Tautomerism in Bioactive beta-Enamino Ester-Containing Cyclic Compounds: Study of Annulated 1,2,3,6-Tetrahydroazocine Derivatives - Viayna_2020_J.Phys.Chem.B_124_28
Author(s) : Viayna A , Antermite SG , de Candia M , Altomare CD , Luque FJ
Ref : J Phys Chem B , 124 :28 , 2020
Abstract : Depending on the chemical scaffold, a bioactive species could reflect the interplay between ionization and tautomerism, which is often complicated by the possibility of populating different conformational states, in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for beta-enamino esters of 1,2,3,6-tetrahydroazocino-fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental pKa values (i.e., alpha,beta-diesters and beta-esters ranging within 6.1-7.3 and 8.2-9.0 pKa intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual pKa values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between the calculated and experimental pKa values was found when the tautomeric preference of the protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism, and conformational preferences in multifunctional (bio)organic compounds.
ESTHER : Viayna_2020_J.Phys.Chem.B_124_28
PubMedSearch : Viayna_2020_J.Phys.Chem.B_124_28
PubMedID: 31841339

Title : Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein-huprine hybrids - Perez-Areales_2017_Future.Med.Chem_9_965
Author(s) : Perez-Areales FJ , Betari N , Viayna A , Pont C , Espargaro A , Bartolini M , De Simone A , Rinaldi Alvarenga JF , Perez B , Sabate R , Lamuela-Raventos RM , Andrisano V , Luque FJ , Munoz-Torrero D
Ref : Future Med Chem , 9 :965 , 2017
Abstract : AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS &
METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Abeta42 and tau aggregation, of antioxidant activity, and of brain permeation.
RESULTS: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Abeta42 and tau antiaggregating and antioxidant activities. CONCLUSION: Second-generation naphthyridine- and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.
ESTHER : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedSearch : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedID: 28632395