Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase

• Published in: European journal of medicinal chemistry Vol. 253; p. 115288
• Main Authors: Yelamanda Rao, Kandrakonda, Jeelan Basha, Shaik, Monika, Kallubai, Sreelakshmi, Mothukuru, Sivakumar, Irla, Mallikarjuna, Gunti, Yadav, Ranay Mohan, Kumar, Sandeep, Subramanyam, Rajagopal, Damu, Amooru Gangaiah
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-05-2023
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Antioxidant and anti Alzheimer's disease; Cholinesterase Inhibitors - chemistry; DNA; DNA nicking and protection; Humans; Hydrogen Peroxide; Molecular Docking Simulation; Novel α-Amino phosphonates; Novel α-Amino phosphonates; DNA nicking and protection; Antioxidant and anti Alzheimer's disease
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115288

Pleiotropic interference may be a prerequisite for the efficient limitation of the progression of multi-factorial diseases such as Alzheimer's disease (AD). Concept of designing the single chemical entity acting on two or more targets of interest has potential advantage in AD therapy. In line with this, rational design and synthesis of frame work of hybrids bearing 2,3-disubstituted quinazolinone, vanillin and α-amino phosphonate scaffolds (5a─v) were carried out. A congeneric set of twenty-two synthetic derivatives (5a─v) were evaluated for their cholinesterase inhibitory, antioxidant, DNA nicking, DNA protection, neuroprotective and Aβ aggregation modulatory activities. Amongst tested activities, the most significant and worth mentioning is that the analogues 5m, 5p and 5u were found to be the most potent, selective, and mixed type inhibitors of EeAChE with IC50 values of 0.296 ± 0.030, 0.289 ± 0.027, and 0.306 ± 0.028 μM, respectively. Further, the biophysical approaches indicated that the compounds 5m, 5p, and 5u have a strong binding affinity towards AChE. Kinetic and Molecular docking studies have revealed that the most active congeners were well oriented in the AChE active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). A few parameters derived from molecular dynamics (MD) simulation trajectories emphasized the stability of AChE-5p and 5m complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of AChE-5p and 5m complexes. Further, these derivatives significantly impacted ABTS radical scavenging capacities and maximal DNA protection activity. Importantly, Thioflavin T (ThT) assay and FE-SEM study demonstrated compounds 5m, 5p and 5u as effective Aβ1−42 fibril modulators at molecular level by the formation of micro size co-assembled mature structures, thus efficiently abolishing the cytotoxicity of Aβ1–42. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines. Furthermore, in silico ADMET prediction studies have revealed that the targeted analogues satisfied most of the characteristics of CNS acting drugs. These multi-functional efficacies indicated worthiness of these α-amino phosphonate derivatives being chosen for further pharmacokinetics, toxicity, and behavioral research to test their potential for AD treatment.
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•Novel α-amino phosphonate derivatives were evaluated as multitarget directed ligands against AD.•Analogues 5m, 5p and 5u were found to be most potent, selective, and mixed type inhibitors of EeAChE.•Analogue 5u has significant ABTS radical scavenging and maximal DNA protection capacities.•ThT assay and FE-SEM studies demonstrated 5m, 5p and 5u as effective Aβ1−42 fibril modulators.•They had no obvious cytotoxicity and exhibited effective neuroprotective activity.