Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer’s disease

• Published in: Bioorganic chemistry 2024-06, Vol.147, p.107373-107373, Article 107373
• Main Authors: Das, Bhanuranjan, TK Baidya, Anurag, Chakrabarti, Sourabh, Chouhan, Deepak, Thakur, Banita, Darreh-Shori, Taher, Chen, Gefei, Tiwari, Vinod, Kumar, Rajnish
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amyloid Beta; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; DFT; Dose-Response Relationship, Drug; Humans; In Vitro; In Vivo; Male; Medicin och hälsovetenskap; Mice; Molecular Docking; Molecular Docking Simulation; Molecular Dynamic; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Protein Aggregates - drug effects; Structure-Activity Relationship; Tau; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism; α-ketoamide
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107373

[Display omitted] •A series of α-ketoamide derivatives synthesized from β,γ-unsaturated α-keto thioesters achieved high purity and yield.•Thioflavin T assay identified promising compounds (BD19, BD23, BD24, and BD27) with significant Aβ inhibitory effects.•BD23, selected for solubility (0.045 ± 0.0012 mg/ml), demonstrated BBB permeability (Pe) of 10.66 ± 8.11 × 10 − 6 cm/s.•In vivo assays showed enhanced cognitive functions in Aβ-induced mouse model, particularly with 5 mg/kg BD23. The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aβ) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from β,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aβ aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aβ aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10−6 cm/s. In addition to its Aβ inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aβ induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23′s interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.