Future medicinal chemistry · 2026
Design and synthesis of novel antibacterial hybrids combining quinoline and thiazole moieties.
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Aref Mostafa M A, Al-Hussain Sami A, Abdel Halim Alyaa S, Ali Hamed I, Zaki Magdi E A, Abdelhamed Mennatullah N, Muhammad Zeinab A
Аннотация
AIM: The emergence of bacterial resistance underlines the urgent need for antibacterial agents with novel structures and mechanisms. We designed quinoline-thiazole hybrids by combining two privileged pharmacophores with established antibacterial properties..
METHODS: Fifteen novel derivatives were synthesized from quinoline-thiosemicarbazone precursors via reactions with phenacyl bromide and chloroacetic acid, followed by aldehyde condensation. Structures were confirmed by spectral analyses. Antibacterial activity was evaluated against MSSA, MRSA, and VRSA strains, and the most potent compounds were further assessed for antibiofilm activity, Cytotoxicity against WI38 fibroblasts (MTT assay), and potential inhibition of D-alanine-D-alanyl carrier protein ligase (SaDltA) via molecular docking.
RESULTS: Nine compounds demonstrated potent activity against MSSA (MIC: 0.59-2.2 µM) and MRSA (MIC: 1.08-9.08 µM), comparable to vancomycin (0.34 and 1.35 µM, respectively). Notably, several derivatives surpassed vancomycin in antibiofilm activity against both MSSA and MRSA. Cytotoxicity assessment revealed a favorable safety profile (IC₅₀: 410.13-3246.1 µM). Molecular docking demonstrated significant SaDltA binding (ΔG: -13.29 to -7.75 kcal/mol), suggesting a plausible mechanism for MRSA inhibition.
CONCLUSION: Quinoline-thiazole hybrids exhibited potent antibacterial and antibiofilm activities, with favorable drug-like properties, positioning them as promising candidates for the treatment of multidrug-resistant staphylococcal infections.
METHODS: Fifteen novel derivatives were synthesized from quinoline-thiosemicarbazone precursors via reactions with phenacyl bromide and chloroacetic acid, followed by aldehyde condensation. Structures were confirmed by spectral analyses. Antibacterial activity was evaluated against MSSA, MRSA, and VRSA strains, and the most potent compounds were further assessed for antibiofilm activity, Cytotoxicity against WI38 fibroblasts (MTT assay), and potential inhibition of D-alanine-D-alanyl carrier protein ligase (SaDltA) via molecular docking.
RESULTS: Nine compounds demonstrated potent activity against MSSA (MIC: 0.59-2.2 µM) and MRSA (MIC: 1.08-9.08 µM), comparable to vancomycin (0.34 and 1.35 µM, respectively). Notably, several derivatives surpassed vancomycin in antibiofilm activity against both MSSA and MRSA. Cytotoxicity assessment revealed a favorable safety profile (IC₅₀: 410.13-3246.1 µM). Molecular docking demonstrated significant SaDltA binding (ΔG: -13.29 to -7.75 kcal/mol), suggesting a plausible mechanism for MRSA inhibition.
CONCLUSION: Quinoline-thiazole hybrids exhibited potent antibacterial and antibiofilm activities, with favorable drug-like properties, positioning them as promising candidates for the treatment of multidrug-resistant staphylococcal infections.