Novel click modifiable thioquinazolinones as anti-inflammatory agents : Design, synthesis, biological evaluation and docking study
Copyright © 2017 Elsevier Masson SAS. All rights reserved..
Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC50 0.05 μM), diclofenac (IC50 0.8 μM) and indomethacin (IC50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC50 2.41 μM) and Meclofenamate sodium (IC50 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC50 values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC50 = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
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| Enthalten in: |
European journal of medicinal chemistry - 144(2018) vom: 20. Jan., Seite 635-650 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moussa, Ghandoura [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.03.2018 Date Revised 02.03.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2017.12.065 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279532482 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC50 0.05 μM), diclofenac (IC50 0.8 μM) and indomethacin (IC50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC50 2.41 μM) and Meclofenamate sodium (IC50 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC50 values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC50 = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Click reaction | |
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| 650 | 4 | |a Docking | |
| 650 | 4 | |a Drug-likeness | |
| 650 | 4 | |a Lipooxygenase | |
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| 650 | 7 | |a Arachidonate 15-Lipoxygenase |2 NLM | |
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| 650 | 7 | |a PTGS2 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.99.1 |2 NLM | |
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| 700 | 1 | |a Alaeddine, Lynn M |e verfasserin |4 aut | |
| 700 | 1 | |a Nassra, Rasha |e verfasserin |4 aut | |
| 700 | 1 | |a Belal, Ahmed S F |e verfasserin |4 aut | |
| 700 | 1 | |a Ismail, Azza |e verfasserin |4 aut | |
| 700 | 1 | |a El-Yazbi, Ahmed F |e verfasserin |4 aut | |
| 700 | 1 | |a Abdel-Ghany, Yasser S |e verfasserin |4 aut | |
| 700 | 1 | |a Hazzaa, Aly |e verfasserin |4 aut | |
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