Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study.

Autor: Moussa G; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Alaaeddine R; Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon., Alaeddine LM; Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon., Nassra R; Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt., Belal ASF; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: ahmed.belal@alexu.edu.eg., Ismail A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., El-Yazbi AF; Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: ae88@aub.edu.lb., Abdel-Ghany YS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Hazzaa A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2018 Jan 20; Vol. 144, pp. 635-650. Date of Electronic Publication: 2017 Dec 18.
DOI: 10.1016/j.ejmech.2017.12.065
Abstrakt: 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 IC 50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC 50 0.05 μM), diclofenac (IC 50 0.8 μM) and indomethacin (IC 50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC 50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC 50 2.41 μM) and Meclofenamate sodium (IC 50 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 IC 50 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 (IC 50  = 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.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: