Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
- MeSH
- chalkon chemie farmakologie MeSH
- chalkonoidy chemie farmakologie MeSH
- glutathion-S-transferasa fí * antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů farmakologie chemie MeSH
- kumariny * chemie farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- protinádorové látky farmakologie chemie MeSH
- simulace molekulového dockingu * MeSH
- sulfonamidy * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 μg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 μM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.
- MeSH
- antituberkulotika farmakologie chemie MeSH
- bakteriální proteiny metabolismus MeSH
- chinoliny * farmakologie MeSH
- isatin * farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- oxidoreduktasy metabolismus MeSH
- protein přenášející acyl farmakologie MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Heterocyclic compounds have been featured as the key building blocks for the development of biologically active molecules. In addition to being derived from renewable raw materials, fatty acids possess a variety of biological properties. The two bioactive ingredients are being combined by many researchers to produce hybrid molecules that have a number of desirable properties. Biological activities and significance of heterocyclic derivatives of fatty acids have been demonstrated in a new class of heterocyclic compounds called heterocyclic fatty acid hybrid derivatives. The significance of heterocyclic-fatty acid hybrid derivatives has been emphasized in numerous research articles over the past few years. In this review, we emphasize the development of synthetic methods and their biological evaluation for heterocyclic fatty acid derivatives. These reports, combined with the upcoming compilation, are expected to serve as comprehensive foundations and references for synthetic, preparative, and applicable methods in medicinal chemistry.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The 7-chloro-4-(piperazin-1-yl)quinoline structure is an important scaffold in medicinal chemistry. It exhibited either alone or as hybrid with other active pharmacophores diverse pharmacological profiles such as: antimalarial, antiparasitic, anti-HIV, antidiabetic, anticancer, sirtuin Inhibitors, dopamine-3 ligands, acetylcholinesterase inhibitors, and serotonin antagonists. In the presented review, a comprehensive discussion of compounds having this structural core is surveyed and illustrated.
- MeSH
- chinoliny chemie farmakologie MeSH
- lidé MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
