Bis-1,3,4-Oxadiazole Derivatives as Novel and Potential Urease Inhibitors; Synthesis, In Vitro, and In Silico Studies

Abstract

Aims: To synthesize bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors.

Background: Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bisoxadiazole derivatives (1-21) to evaluate their urease inhibitory potential.

Objective: The aim includes the synthesis of substituted bis-oxadiazole derivatives (1-21) in order to evaluate their urease inhibitory potential.

Methods: Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H₂SO₄ till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions.

Results: In vitro urease, the inhibitory activity of the synthesized compounds was evaluated and the results demonstrated good activities with IC₅₀ values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 μM as compared to the standard thiourea (IC₅₀ = 21.13 ± 0.415 μM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed.

Conclusion: Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally well. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.

Keywords: Bis-oxadiazole; molecular docking; oxidative cyclization; structure-activity relationship; urease; urease inhibition.