RT Journal Article
T1 Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties
A1 Pont, Caterina
A1 Sampietro, Anna
A1 Pérez-Areales, F. Javier
A1 Cristiano, Nunzia
A1 Albalat, Agustí
A1 Pérez, Belén
A1 Bartolini, Manuela
A1 De Simone, Angela
A1 Andrisano, Vincenza
A1 Barenys, Marta
A1 Teixidó, Elisabet
A1 Sabaté, Raimon
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Muñoz-Torrero, Diego
K1 Alzheimer’s disease
K1 BACE-1 inhibitors
K1 DMPK properties
K1 Acetylcholinesterase inhibitors
K1 Butyrylcholinesterase inhibitors
K1 Multitarget drugs
K1 Tau anti-aggregating agents
K1 Zebrafish embryos
K1 β-amyloid anti-aggregating agents
AB Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein-huprine hybrid lead by hydroxy group removal-ring contraction-ring opening-ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification.
PB MDPI
SN 1999-4923
YR 2024
FD 2024-07-25
LK https://hdl.handle.net/10347/45089
UL https://hdl.handle.net/10347/45089
LA eng
NO Pont C, Sampietro A, Pérez-Areales FJ, Cristiano N, Albalat A, Pérez B, Bartolini M, De Simone A, Andrisano V, Barenys M, Teixidó E, Sabaté R, Loza MI, Brea J, Muñoz-Torrero D. Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties. Pharmaceutics. 2024 Jul 25;16(8):982. doi: 10.3390/pharmaceutics16080982. PMID: 39204327; PMCID: PMC11359831
NO This research was funded by MICIU/AEI/10.13039/501100011033, grant numbers PID2020- 118127RB-I00 and PID2021-127863OB-I00, AGAUR, grant number 2021SGR00357, the Spanish Min- istry of Science and Innovation with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan (PRTR-C17.I1), Fundació Bosch i Gimpera, project number 300155, and the Autonomous Community of Galicia within the framework of the Biotechnol- ogy Plan Applied to Health, and also Xunta de Galicia (ED431C 2022/20) and European Regional Development Fund (ERDF).
NO Fellowships from Ministerio de Educación, Cultura y Deporte to C.P. (FPU15/01131) and from Ministerio de Universidades to A.S. (grant FPU21/00810) are gratefully acknowledged. FJP- A and ET are Serra Hunter Fellows, Serra Hunter Programme, Catalonia, Spain. The Authors thank Laura Castro and the staff of the zebrafish facility (CCiTUB) for their technical support and INSA-UB María de Maeztu Unit of Excellence (Grant CEX2021-001234-M) funded by MICIN/AEI/FEDER, UE, for institutional support.
DS Minerva
RD 30 abr 2026