Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA)
Copyright © 2024 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
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| Enthalten in: |
Bioorganic chemistry - 144(2024) vom: 19. Feb., Seite 107138 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Khaleel, Eman F [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 19.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2024.107138 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Biological activities | |
| 650 | 4 | |a InhA inhibitors | |
| 650 | 4 | |a Molecular docking | |
| 650 | 4 | |a Molecular dynamics Simulation | |
| 650 | 4 | |a Mycobacterium tuberculosis | |
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| 650 | 7 | |a Isatin |2 NLM | |
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| 650 | 7 | |a Quinolines |2 NLM | |
| 650 | 7 | |a Bacterial Proteins |2 NLM | |
| 700 | 1 | |a Sabt, Ahmed |e verfasserin |4 aut | |
| 700 | 1 | |a Korycka-Machala, Malgorzata |e verfasserin |4 aut | |
| 700 | 1 | |a Badi, Rehab Mustafa |e verfasserin |4 aut | |
| 700 | 1 | |a Son, Ninh The |e verfasserin |4 aut | |
| 700 | 1 | |a Ha, Nguyen Xuan |e verfasserin |4 aut | |
| 700 | 1 | |a Hamissa, Mohamed Farouk |e verfasserin |4 aut | |
| 700 | 1 | |a Elsawi, Ahmed E |e verfasserin |4 aut | |
| 700 | 1 | |a Elkaeed, Eslam B |e verfasserin |4 aut | |
| 700 | 1 | |a Dziadek, Bozena |e verfasserin |4 aut | |
| 700 | 1 | |a Eldehna, Wagdy M |e verfasserin |4 aut | |
| 700 | 1 | |a Dziadek, Jaroslaw |e verfasserin |4 aut | |
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