Synthesis of Novel 7-Phenyl-2,3-Dihydropyrrolo[2,1- b]Quinazolin-9(1 H)-ones as Cholinesterase Inhibitors Targeting Alzheimer's Disease Through Suzuki-Miyaura Cross-Coupling Reaction

Abstract

An important field of research in medicinal and organic chemistry involves halogen-containing heterocyclic synthones, which form the backbone of more complex organic compounds. This study aimed to design and synthesize 28 novel derivatives of 7-aryl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one. The derivatives were created from 7-bromoquinoline intermediates to evaluate their potential as cholinesterase inhibitors for treating neurodegenerative diseases such as Alzheimer's disease. The conditions for the Suzuki-Miyaura cross-coupling reaction were optimized to improve yield and purity. The derivatives were evaluated for their anticholinesterase activity using Ellman's method, revealing that it most effectively inhibited cholinesterase within the micromolar range. 7-(3-Chloro-4-fluorophenyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one derivative exhibited the highest inhibitory potency, with an IC₅₀ value of 6.084 ± 0.26 μM. Additionally, molecular dynamics simulations provided insight into how this lead compound interacts with the enzyme, suggesting its potential as a drug candidate for Alzheimer's disease.

Keywords: Acetylcholinesterase (AChE); Alzheimer’s disease; Butyrylcholinesterase (BChE); Pd catalyst; Suzuki–Miyaura cross-coupling; carbon–carbon bond (C-C); deoxyvasicinone; mackinazolinone; quinazoline.

Figure 1

Structures of AChE inhibitors for managing AD.

Figure 2

The structures of deoxyvasicinone and mackinazolinone alkaloids and the design of the present work.

Scheme 1

General synthetic route for the target compounds. Reagents and conditions: (a) lactams, POCl₃, toluene, reflux 5 h; (b) boronic acids, Pd catalyst.

Scheme 2

Synthetic route for the target compounds 3a-3n. Reagents and conditions: (a) 2-Pyrrolidone, POCl₃, toluene, reflux 5 h; (b) boronic acids, Cs₂CO₃, Pd(PPh₃)₄, PhCH₃/H₂O = 3:1, 110 °C, reflux 8 h.

Scheme 3

Synthetic route for the target compounds 4a–4n. Reagents and conditions: (a) 2-Piperidinone, POCl₃, toluene, reflux 5 h; (b) boronic acids, Cs₂CO₃, Pd(PPh₃)₄, PhCH₃/H₂O = 3:1, 110 °C, reflux 8 h.

Figure 3

Crystal structure of compound 3j (CCDC: 2392852).

Figure 4

The analysis of the SAR by compound 3k.

Figure 5

Molecule docking results: 3D docking models of compound 3k with AChE (PDB code: 4ey7).

Figure 6

RMSD plot of 3k–4ey7 complex (black), 4ey7 (red), and 3k (green) across 100 ns MD simulation trajectory.

Figure 7

RMSF plot of protein 4ey7 across 100 ns MD simulation trajectory.

Figure 8

Radius of gyration plot of 3k–4ey7 complex across 100 ns MD simulation trajectory.

Figure 9

Number of H-bonds in 3k–4ey7 complex across 100 ns MD simulation trajectory.