Synthesis and evaluation of polymer-drug conjugates as potential antioxidant and cholinesterase inhibitors for neurodegenerative diseases.

Mahadik, Nuruddin; Barron, Gemma A.; Kong Thoo Lin, Paul; Thompson, Colin J.

Abstract

Polymer-drug conjugates (PDCs) may offer improved water-solubility and in vitro activity of potential antioxidant and cholinesterase (ChE) inhibitor drugs compared to the drugs alone. Conjugation of these potential drugs to water-soluble polymers could increase their therapeutic efficacy. Vanillin was conjugated to poly­(allylamine hydrochloride) (NM10 and NM15) and naphthalimidohexylamine (HEXNAP) was conjugated to poly­(acrylic acid) (N5 and N10). The antioxidant and cholinesterase inhibitory activities of these novel PDCs were evaluated and compared with those of their respective starting materials. Additionally, in silico molecular modeling studies were conducted to explore the potential cholinesterase inhibitory mechanisms of these conjugates. NM15 (unadjusted and adjusted value) showed significantly enhanced in vitro antioxidant activity (p ≤ 0.0001) compared to vanillin. The adjusted value of N5 compared to HEXNAP showed significantly enhanced in vitro cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (p ≤ 0.0001). Kinetic and molecular modeling studies revealed that N5 was a competitive inhibitor of butyrylcholinesterase and interacted with the active sites of human acetylcholinesterase and human butyrylcholinesterase enzymes. NM15 and N5 were identified as lead PDCs based on their enhanced antioxidant and cholinesterase inhibitory activity, respectively. Overall, this work demonstrates the potential use of PDCs as treatment options for neurodegenerative diseases.

Citation

MAHADIK, N., BARRON, G., KONG THOO LIN, P. and THOMPSON, C. 2024. Synthesis and evaluation of polymer-drug conjugates as potential antioxidant and cholinesterase inhibitors for neurodegenerative diseases. Chemistry of materials [online], 36(21), pages 10514-10527. Available from: https://doi.org/10.1021/acs.chemmater.4c01767

• Journal Article Type: Article
• Acceptance Date: Oct 16, 2024
• Online Publication Date: Oct 23, 2024
• Publication Date: Nov 12, 2024
• Deposit Date: Nov 8, 2024
• Publicly Available Date: Nov 8, 2024
• Journal: Chemistry of materials
• Print ISSN: 0897-4756
• Electronic ISSN: 1520-5002
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Issue: 21
• Pages: 10514-10527
• DOI: https://doi.org/10.1021/acs.chemmater.4c01767
• Keywords: Conjugate acid-base pairs; Inhibition; Molecular properties; Peptides and proteins; Pharmacology
• Public URL: https://rgu-repository.worktribe.com/output/2530153
• Additional Information: This article has been published with separate supporting information. This supporting information has been incorporated into a single file on this repository and can be found at the end of the file associated with this output.