Design and Synthesis of Benzylidene Phenylacetamide-based Derivatives as Potential Antibacterial Agents Targeting Staphylococcus Aureus Thymidylate Kinase

Objective : There has been a significant global surge in antimicrobial resistance in recent years, with Staphylococcus aureus infections proving particularly challenging to treat. The bacterium has resisted various antibiotics, including β-lactams. The primary objective is to identify antibacterial agents targeting Staphylococcus aureus Thymidylate kinase (TMK). Methods: Six molecules were conceived through a process involving molecular docking (glide module), Qikprop screening for ADME (absorption, distribution, metabolism, and excretion) prediction, and prime MMGBSA (Molecular Mechanics Generalized Born Surface Area) analysis to assess binding free energy employing Schrödinger suite 2021-4. in -vitro studies MIC, MBC, and TIME KILL were performed to evaluate the antibacterial activity. The designed molecules are evaluated based on glide score binding affinity and in-vitro results. Findings: The six molecules exhibited hydrophobic and hydrogen bonding interactions with the Staphylococcus aureus Thymidylate kinase (4HLC.pdb). Thymidylate kinase (TMK) enzyme, as identified in the Protein Data Bank entry. Among these, compound C ₃ displayed XP-docking Glide score and ΔBind of -4.39 kcal/mol and -76.93 kcal/mol respectively. To explore the dynamic behaviour of the C ₃ /4HLC complex, a 100-nanosecond molecular dynamics simulation was conducted. Gram-positive strains of S. aureus (NCIM 5021) Ic ₅₀ values (1.91 µM), clinical MRSA strains (ATCC 43300) Ic ₅₀ values (3.91 µM) shown in the in-vitro study. Interpretation: Based on all studies in the performance of C ₃ demonstrated with favourable outcomes, Benzylidene phenyl acetamide-based derivatives are anticipated to be potential future inhibitors of the SATMK , suggesting their potential role as antibacterial agents. Funding: We have no funding for this project.