Title:Bis-1,3,4-Oxadiazole Derivatives as Novel and Potential Urease Inhibitors;
Synthesis, In Vitro, and In Silico Studies
Volume: 18
Issue: 7
Author(s): Sana Shah, Momin Khan*, Mahboob Ali, Abdul Wadood, Ashfaq Ur Rehman, Zarbad Shah, Muhammad Yousaf, Uzma Salar and Khalid Mohammed Khan
Affiliation:
- Department of Chemistry, Abdul Wali Khan University, Mardan 23200, Khyber Pakhtunkhwa, Pakistan
Keywords:
Bis-oxadiazole, urease inhibition, structure-activity relationship, molecular docking, oxidative cyclization, urease.
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.