Structure-Activity Relationship of Fluorinated Benzenesulfonamides as Inhibitors of Amyloid-β Aggregation

TY - JOUR

T1 - Structure-Activity Relationship of Fluorinated Benzenesulfonamides as Inhibitors of Amyloid-β Aggregation

AU - Žvirblis, Mantas

AU - Sakalauskas, Andrius

AU - Janvand, Saeid Hadi Ali

AU - Dudutienė, Virginija

AU - Žiaunys, Mantas

AU - Sniečkutė, Rūta

AU - Otzen, Daniel E

AU - Smirnovas, Vytautas

AU - Matulis, Daumantas

N1 - © 2024 Wiley‐VCH GmbH.

PY - 2024/8/7

Y1 - 2024/8/7

N2 - Amyloid-beta aggregation is considered one of the factors influencing the onset of the Alzheimer's disease. Early prevention of such aggregation should alleviate disease condition by applying small molecule compounds that shift the aggregation equilibrium toward the soluble form of the peptide or slow down the process. We have discovered that fluorinated benzenesulfonamides of particular structure slowed the amyloid-beta peptide aggregation process by more than three-fold. We synthesized a series of ortho-para and meta-para double-substituted fluorinated benzenesulfonamides that inhibited the aggregation process to a variable extent yielding a detailed picture of the structure-activity relationship. Analysis of compound chemical structure effect on aggregation in artificial cerebrospinal fluid showed the necessity to arrange the benzenesulfonamide, hydrophobic substituent, and benzoic acid in a particular way. The amyloid beta peptide aggregate fibril structures varied in cross-sectional height depending on the applied inhibitor indicating the formation of a complex with the compound. Application of selected inhibitors increased the survivability of cells affected by the amyloid beta peptide. Such compounds may be developed as drugs against Alzheimer's disease.

AB - Amyloid-beta aggregation is considered one of the factors influencing the onset of the Alzheimer's disease. Early prevention of such aggregation should alleviate disease condition by applying small molecule compounds that shift the aggregation equilibrium toward the soluble form of the peptide or slow down the process. We have discovered that fluorinated benzenesulfonamides of particular structure slowed the amyloid-beta peptide aggregation process by more than three-fold. We synthesized a series of ortho-para and meta-para double-substituted fluorinated benzenesulfonamides that inhibited the aggregation process to a variable extent yielding a detailed picture of the structure-activity relationship. Analysis of compound chemical structure effect on aggregation in artificial cerebrospinal fluid showed the necessity to arrange the benzenesulfonamide, hydrophobic substituent, and benzoic acid in a particular way. The amyloid beta peptide aggregate fibril structures varied in cross-sectional height depending on the applied inhibitor indicating the formation of a complex with the compound. Application of selected inhibitors increased the survivability of cells affected by the amyloid beta peptide. Such compounds may be developed as drugs against Alzheimer's disease.

KW - Alzheimer's disease

KW - amyloid aggregates

KW - amyloid beta peptide

KW - amyloid fibrils

KW - atomic force microscopy, artificial cerebrospinal fluid

KW - benzenesulfonamide

UR - http://www.scopus.com/inward/record.url?scp=85204544364&partnerID=8YFLogxK

U2 - 10.1002/chem.202402330

DO - 10.1002/chem.202402330

M3 - Journal article

C2 - 39109590

SN - 0947-6539

SP - e202402330

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

ER -