Department of Physics, Chemistry and Material Science

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Browsing Department of Physics, Chemistry and Material Science by Subject "Antimicrobial"

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    In silico-guided design, synthesis and antimicrobial activity of piperazine-linked 8-hydroxyquinoline-isatin hybrids
    (University of Namibia, 2025) Van Wyk, Elvira; Hans, R.
    Drug-resistant pathogenic bacteria and fungi render existing antimicrobials ineffective, fuel the global antimicrobial resistance (AMR) crisis, and ultimately serve as impetus for the discovery of new antimicrobial agents. Hybrid drugs formed by covalently binding two pharmacophores, have shown promise in combating resistance. Monomers selected for this study include 8-hydroxyquinoline and isatin. There exist reports on the versatility of the 8-hydroxyquinoline ring and the antimicrobial, anticancer, and antifungal activity ascribed to its derivatives, while the isatin scaffold known for rendering high hit rates, in targeted drug discovery. The aim of the study was to synthesize piperazine-linked 8-hydroxyquinoline-isatin hybrids, with and without the thiosemicarbazide unit, and to evaluate their antimicrobial activities. In silico studies of the hybrids were done using open-source absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction platforms, SwissADME and pkCSM, to guide the selection of constructs with favourable pharmacokinetics and druglike properties. According to the docking studies, compounds 14a-c and 15a-c showed significant binding energy with Escherichia coli’s outer membrane protein A (OmpA) and DNA gyrase as the key target enzymes. Both 14c and 15c showed binding energies of -9.8 kcal/mol with OmpA. In the case of DNA gyrase, a binding energy of -8.9 kcal/mol was recorded for 14c, whereas 15c showed satisfactory interaction with a binding energy of -8.5 kcal/mol. Synthesis of the target hybrids began with the reaction of 5-chloromethyl-8-hydroxyquinoline 10 with piperazine to yield 5- (piperazin-1-ylmethyl)quinolin-8-ol 11. The Mannich reaction of unsubstituted/5- substituted isatin with 11, yielded Mannich bases 14a-c with yields ranging between 56 - 60%. Proposed structures of the novel hybrids, 14a-c were confirmed by means of infrared, 1H- and 13C-NMR spectroscopy. Antimicrobial activity testing of hybrids 14a-c and advanced intermediates, against Klebsiella pneumonia ATCC10556, Escherichia coli ATCC700928, Candida albicans ATCC13933 and Staphylococcus aureus ATC12600 was done using the agar disk diffusion method. Hybrids 14a-b as well as intermediate 10 displayed activity against all four strains. Equipotent activity with MIC values of 1.25 mg/mL against all bacterial strains was recorded for hybrid 14b and intermediate 10. This study revealed the antimicrobial activity of novel piperazine-linked 8-hydroxyquinoline-isatin hybrids and that they warrant further studies