2. Academic Validation
  3. Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones

Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones

  • Eur J Med Chem. 2019 Apr 1:167:562-582. doi: 10.1016/j.ejmech.2019.02.034.
Perihan A Elzahhar 1,  Rana Alaaeddine 2,  Tamer M Ibrahim 3,  Rasha Nassra 4,  Azza Ismail 1,  Benjamin S K Chua 5,  Rebecca L Frkic 6,  John B Bruning 6,  Nadja Wallner 7,  Tilo Knape 7,  Andreas von Knethen 8,  Hala Labib 9,  Ahmed F El-Yazbi 10,  Ahmed S F Belal 11
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 2 Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, 33516, Egypt.
  • 4 Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Egypt.
  • 5 School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • 6 Institute for Photonics and Advanced Sensing, The School of Biological Sciences, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia.
  • 7 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany.
  • 8 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Department of Analytical & Pharmaceutical Chemistry, Faculty of Pharmacy & Drug Manufacturing, Pharos University in Alexandria, Egypt.
  • 10 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.
  • 11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: ahmed.belal@alexu.edu.eg.
PMID: 30818268 DOI: 10.1016/j.ejmech.2019.02.034
Abstract

In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ Agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX Inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the Other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

Keywords

15-Lipoxygenase; Cyclooxygenase-2; Inflammation; Multi-targeting; Peroxisome proliferator-activated receptor-γ.

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