Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives

Abstract

A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results.

Figure 1

Predicted conformations of the docked compounds inside the binding pocket of Jack bean urease. The large blue spheres indicate the metal pharmacophores around the two nickels (Ni⁺²) which shows that the metal atoms can interact in all directions. The dotted lines indicate various types of interactions of the compounds atoms with the active site residues including hydrogen bonding and aromatic interactions.

Figure 2

Surface representation of the active site pocket of the Jack bean urease with the bound ligands shown inside the pocket in CPK model. The wide opening of the binding site pocket allows the compounds to adopt flexible conformations in this area.

Figure 3

Interaction diagram of the docked conformation of compound 4a with the active site residues of the enzyme. The dotted lines show the interactions between the compound and residues atoms.

Figure 4

Interaction diagram of the docked conformation of compound 4b with the active site residues of the enzyme. The dotted lines show the interactions between the compound and residues atoms.

Scheme 1

Synthesis of oxadiazoles (4a–r). Reagents and conditions: (a) H₂SO₄ (conc.), methanol, reflux, 8–12 h; (b) NH₂NH₂·H₂O (80%), ethanol, reflux, 8–12 h; (c) (1) CS₂/KOH, ethanol, reflux, 12 h; (2) HCl pH 5-6.