Synthesis, biological evaluation and in silico molecular docking of novel 1-hydroxy-naphthyl substituted heterocycles

Abstract

The versatile precursor 2-acetyl-4-allyl-1-hydroxy naphthalene was synthesized efficiently via Claisen rearrangement 2-acetyl-1-allyloxynaphthalene. The Claisen-Schmidt condensation of latter precursor afforded the corresponding chalcones which were exploited to synthesize a series of potential heterocycles such as pyrazoline, isoxazoline, benzocoumarin and benzoflavone. The synthesized products showed potent antioxidant and antimicrobial activities. Chalcone 3c, naphthyl pyrazoline 6b and hydroxycoumarin 13 exhibited the highest activity as antioxidants. Their binding mode showed specialized recognition of hydroxycoumarin 13 with the triad key amino acids at the active site of the oxidoreductase enzyme (PDB code 1DXO). 1-Hydroxynaphth-2-yl pyrazoline (6b) revealed the highest efficacy against both Gram positive and negative bacterial species. In silico molecular docking of pyrazoline 6b endorsed its proper binding at the active site of the 2EX6 enzyme which explains its potent antibacterial activity in comparison with standard ampicillin.

Keywords: 1DXO active site; Biological; Docking; Hydroxyacetyl, heterocycle; Naphthyl.

Graphical abstract

Fig. 1

Naphthyl substituted antimicrobial drugs.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Fig. 2

(A) 3D crystal structure of duroquinone in the binding pocket of 1DXO. (B) Binding mode for compound 13 docked and minimized in the 1DXO binding pocket, showing the H-bond with residue Tyr128 with conserved amino acid residues and the cofactor FAD involved in its recognition. (C) Binding mode for compound 3c docked and minimized in the 1DXO binding pocket, showing the H-bond with residue Tyr126 with conserved amino acid residues and the cofactor FAD involved in its recognition. (D) Binding mode for compound 6b docked and minimized in the 1DXO binding pocket, showing the H-bond with residue Tyr128 with conserved amino acid residues.

Fig. 3

(A) The binding mode and residues involved in the recognition of ampicillin docked and geometrically optimized in the 2EX6 binding pocket. (B) The binding mode and residues involved in the recognition of compounds 6b and 8a docked and geometrically optimized in the 2EX6 binding pocket.