Research paper Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones Perihan A. Elzahhar a , Rana Alaaeddine b , Tamer M. Ibrahim c , Rasha Nassra d , Azza Ismail a , Benjamin S.K. Chua e , Rebecca L. Frkic f , John B. Bruning f , Nadja Wallner g , Tilo Knape g , Andreas von Knethen g, h , Hala Labib a, i , Ahmed F. El-Yazbi b, j, * , Ahmed S.F. Belal a, ** a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt b Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, 33516, Egypt d Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Egypt e School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia f Institute for Photonics and Advanced Sensing, The School of Biological Sciences, The University of Adelaide, North Tce, Adelaide, South Australia, 5005, Australia g Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany h Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany i Department of Analytical & Pharmaceutical Chemistry, Faculty of Pharmacy & Drug Manufacturing, Pharos University in Alexandria, Egypt j Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt article info Article history: Received 10 November 2018 Received in revised form 4 February 2019 Accepted 10 February 2019 Available online 13 February 2019 Keywords: Inflammation Cyclooxygenase-2 15-Lipoxygenase Peroxisome proliferator-activated receptor- g Multi-targeting 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 PPARg ligands. Challenging our design with pre-synthetic docking experiments on PPARg showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARg agonist, potent COX-2 antagonist (nanomolar IC 50 values) and moderate 15-LOX inhibitor (micromolar IC 50 values). We envi- sioned 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 PPARg nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhi- bition 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 PPARg 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. © 2019 Elsevier Masson SAS. All rights reserved. 1. Introduction Inflammation is a complex and dynamic response to defend the host against potential threats such as pathogens or tissue insults [1 ,2]. It is associated with diverse signaling pathways involving enzymes, membrane and cellular receptors, transcription factors * Corresponding author. Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon. ** Corresponding author. E-mail addresses: ae88@aub.edu.lb (A.F. El-Yazbi), ahmed.belal@alexu.edu.eg (A.S.F. Belal). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2019.02.034 0223-5234/© 2019 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 167 (2019) 562e582