Potential for Aedes aegypti Larval Control and Environmental Friendliness of the Compounds Containing 2-Methyl-3,4-dihydroquinazolin-4-one Heterocycle

Abstract

2-Methylquinazolin-4(3H)-one was prepared by the reaction of anthranilic acid, acetic anhydride, and ammonium acetate. The reaction of 2-methylquinazolin-4(3H)-one with N-aryl-2-chloroacetamides in acetone in the presence of potassium carbonate gave nine N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide compounds. The structures of these compounds were elucidated on the basis of their IR, ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and high-resolution mass spectrometry (HR-MS) spectral data. These synthesized compounds containing the 2-methyl-3,4-dihydroquinazolin-4-one moiety exhibited activity against Aedes aegypti mosquito larvae with LC₅₀ values of 2.085-4.201 μg/mL after 72 h exposure, which is also confirmed using a quantitative structure-activity relationship (QSAR) model. Interestingly, these compounds did not exhibit toxicity to the nontarget organism Diplonychus rusticus. In silico molecular docking revealed acetylcholine binding protein (AChBP) and acetylcholinesterase (AChE) to be potential molecular targets. These data indicated the larvicidal potential and environmental friendliness of these N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide derivatives.

Scheme 1. Synthetic Pathway of the Acetamides Containing 2-Methyl-3,4-dihydroquinazolin-4-one Heterocycle

Scheme 2. Synthetic Pathway of the N-Aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide

Figure 1

Optimized structures, magnitude and orientation of electric dipole moment, and the lowest infrared vibrational frequency of the compounds 4a–4i determined by B3LYP/6-311++g(d,p).

Figure 2

QSAR plots: (Left) Predicted versus experimental activities of LC₅₀ (24 h) and (right) predicted versus experimental activities of AChE.

Figure 3

Lowest-energy docked pose of 4i with Aedes aegypti acetylcholinesterase (homology model based on Drosophila melanogaster AChE, PDB 1DX4). (A) Ribbon structure of the protein with the docked ligand (CPK stick figure). (B) Key intermolecular interactions between 4i and amino acid residues in the binding site; the hydrogen bond is shown as a blue dashed line. (C) Two-dimensional interaction diagram showing key interactions of 4i in the hydrophobic binding site of Aedes aegypti acetylcholinesterase.

Figure 4

Lowest-energy docked pose of 4h with Aedes aegypti odorant binding protein (PDB 6OMW). (A) Ribbon structure of the protein with the docked ligands (colored stick figures). (B) Key intermolecular interactions between 4h and amino acid residues in the hydrophobic binding site. (C) Two-dimensional interaction diagram showing fundamental interactions of 4h in the hydrophobic binding site of Aedes aegypti odorant binding protein.