Akademik Veri Yönetim Sistemi
JOURNAL OF MOLECULAR STRUCTURE, 2025 (SCI-Expanded)
Designing small organic molecules for use as multitarget enzyme inhibitors is a very stimulating idea in discovery of new single molecules that have excellent inhibition profiles on multi- targeted enzymes and other diseases. We designed and synthesized a new ketoprofen-thiourea conjugate for a thorough investigation as an inhibitor targeting six enzymes: Urease, alpha-Glucosidase, alpha-Amylase, Carbonic Anhydrase, Tyrosinase enzymes besides EFRG, DNA-topoisomerase I and Annexin V-FITC Apoptosis Assay. The novel molecule (5) was obtained from ketoprofen and 4-bromoanilne in three steps and characterized by elemental and spectroscopic analyses and three-dimensional molecular structure was determined by SC-XRD. It was found to exhibit inhibitory potential against all enzymes. Specifically, it was 2-fold more active inhibitor of Tyrosinase with IC50 in 7.38 +/- 1.17 mu M) as compared to the standard Kojic acid (IC50 =16.69 +/- 2.81 mu M); similarly, urease inhibition was more than 5 times that of the standard thiourea, however showed inhibition for Carbonic anhydrase slightly lesser than acetazolamide; for alpha-glucosidase and alpha-amylase was least active. The reversible mode of the tyrosine inhibition was evaluated through Lineweaver-Burk plots. In silico molecular docking studies were performed to support the in vitro results. The anticancer activity was examined against HCT116, MCF-7 and HepG2 cancer cell lines. The compound (5) revealed a significant cytotoxic effect, greater than the doxorubicin, the standard antibiotic drug. Mechanistic studies suggested EGFR inhibition and apoptosis as key pathways for its anticancer action. The binding mode of topo I-DNA complex indicated that amide group forms H-bonding with proline and amine group of arginine form another H-bonding with carbonyl group of ligand. Computational studies such as DFT, MEP, FMOs and energy gap were also calculated. The precise energy gap of 4.23 eV indicated the stability of the molecule at room temperature. The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H ... H, H ... C/C ... H and H ... O/O ... H interactions suggest that van der Waals interactions and H-bonding play the major roles in the crystal packing. The newly identified inhibitor of various enzymes at same time can serve as leads for further research and development.