Synthesis, molecular structure and urease inhibitory activity of novel bis-Schiff bases of benzyl phenyl ketone: A combined theoretical and experimental approach

Background: Urease belongs to the family of amid hydrolases with two nickel atoms in their core structure. On the basis of literature survey, this research work is mainly focused on the study of bis-Schiff base derivatives of benzyl phenyl ketone nucleus. Objective: Synthesis of benzyl phenyl ketone based bis-Schiff bases in search of potent urease inhibitors.Method: In the current work, bis-Schiff bases were synthesized through two steps reaction by reacting benzyl phenyl ketone with excess of hydrazine hydrate in ethanol solvent in the first step to get the desired hydrazone. In last, different substituted aromatic aldehydes were refluxed in catalytic amount of acetic acid with the desired hydrazone to obtain bis-Schiff base derivatives in tremendous yields. Using various spectroscopic techniques including FTIR, HR-ESI-MS, and 1H NMR spectroscopy were used to clarify the structures of the created bis-Schiff base derivatives.Results: The prepared compounds were finally screened for their in-vitro urease inhibition activity. All the synthesized derivatives (3-9) showed excellent to less inhibitory activity when compared with standard thiourea (IC50 = 21.15 & PLUSMN; 0.32 & mu;M). Compounds 3 (IC50 = 22.21 & PLUSMN; 0.42 & mu;M), 4 (IC50 = 26.11 & PLUSMN; 0.22 & mu;M) and 6 (IC50 = 28.11 & PLUSMN; 0.22 & mu;M) were found the most active urease inhibitors near to standard thiourea among the synthesized series. Similarly, compound 5 having IC50 value of 34.32 & PLUSMN; 0.65 & mu;M showed significant inhibitory activity against urease enzyme. Furthermore, three compounds 7, 8, and 9 exhibited less activity with IC50 values of 45.91 & PLUSMN; 0.14, 47.91 & PLUSMN; 0.14, and 48.33 & PLUSMN; 0.72 & mu;M respectively. DFT used to calculate frontier molecular orbitals including; HOMO and LUMO to indicate the charge transfer from molecule to biological transfer, and MEP map to indicate the chemically reactive zone suitable for drug action. The electron localization function (ELF), non-bonding orbitals, AIM charges are also calculated. The docking study contributed to the analysis of urease protein binding.& COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).