1-Benzylindoles as inhibitors of cytosolic phospholipase A2α: synthesis, biological activity, aqueous solubility, and cell permeability

  • RSC Med Chem. 2023 Dec 13;15(2):641-659. doi: 10.1039/d3md00590a.
Imke Meyer Zu Vilsendorf  1 ,  Judith Einerhand  1 ,  Dennis Mulac  2 ,  Klaus Langer  2 ,  Matthias Lehr  1
Affiliations
  • 1. Institute of Pharmaceutical and Medicinal Chemistry, University of Münster Corrensstrasse 48 48149 Münster Germany [email protected].
  • 2. Institute of Pharmaceutical Technology and Biopharmacy, University of Münster Corrensstrasse 48 48149 Münster Germany.
PMID: 38389890 DOI: 10.1039/d3md00590a
Abstract

Cytosolic Phospholipase A2α (cPLA2α) is considered an interesting target for the development of new anti-inflammatory drugs, as it is significantly involved in the formation of pro-inflammatory lipid mediators. Recently, in a ligand-based virtual screening approach, 2,4-dichlorobenzyl-substituted 4-[2-(indol-3-ylmethylene)hydrazineyl]benzoic acid 7 was found to be an inhibitor of cPLA2α with micromolar activity. This compound has now been systematically varied to increase inhibitory potency. The studies performed led to 5-(1-benzylindol-3-ylmethyl)-2H-tetrazol-2-yl)pentanoic acid derivatives that exhibited submicromolar activity against the enzyme. The most potent compounds were also tested for their water solubility and for permeability in a Caco-2 model. Among Other things, it was found that in Caco-2 cells, the pentanoic acid chain of the molecules can be metabolised to a considerable extent to propionic acid by β-oxidation.

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