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  3. Furazanopyrazine-based novel promising anticancer agents interfering with the eicosanoid biosynthesis pathways by dual mPGES-1 and sEH inhibition

Furazanopyrazine-based novel promising anticancer agents interfering with the eicosanoid biosynthesis pathways by dual mPGES-1 and sEH inhibition

  • Eur J Med Chem. 2025 May 5:289:117402. doi: 10.1016/j.ejmech.2025.117402.
Gianluigi Lauro 1,  Michela Aliberti 1,  Mauro De Nisco 2,  Silvana Pedatella 3,  Giacomo Pepe 1,  Manuela Giovanna Basilicata 4,  Maria Giovanna Chini 5,  Katrin Fischer 6,  Robert K Hofstetter 6,  Oliver Werz 6,  Maria Grazia Ferraro 7,  Marialuisa Piccolo 8,  Carlo Irace 8,  Anella Saviano 9,  Pietro Campiglia 1,  Alessia Bertamino 1,  Carmine Ostacolo 1,  Tania Ciaglia 1,  Michele Manfra 10,  Giuseppe Bifulco 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, Fisciano, 84084, Italy.
  • 2 Department of Health Sciences, University of Basilicata, Viale dell'Ateneo Lucano, Potenza, I-85100, Italy.
  • 3 Department of Chemical Sciences, University of Napoli Federico II, Via Cintia 4, I-80126, Napoli, Italy.
  • 4 Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138, Naples, Italy.
  • 5 Department of Biosciences and Territory, University of Molise, C.da Fonte Lappone, Pesche, 86090, Italy.
  • 6 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, Jena, 07743, Germany.
  • 7 Department of Molecular Medicine and Medical Biotechnologies, School of Medicine and Surgery, University of Naples, Via Domenico Montesano 49, Naples, 80131, Italy.
  • 8 BioChem Lab, Department of Pharmacy, School of Medicine and Surgery, University of Naples, Via Domenico Montesano 49, Naples, 80131, Italy.
  • 9 ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
  • 10 Department of Health Sciences, University of Basilicata, Viale dell'Ateneo Lucano, Potenza, I-85100, Italy. Electronic address: michele.manfra@unibas.it.
  • 11 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, Fisciano, 84084, Italy. Electronic address: bifulco@unisa.it.
PMID: 40010271 DOI: 10.1016/j.ejmech.2025.117402
Abstract

We report the identification of a new set of compounds based on the furazanopyrazine core interfering with eicosanoid biosynthesis and acting as potentially effective anti-inflammatory and Anticancer agents. Based on our previous promising results on a set of furazanopyrazine-based compounds against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme, we here identified derivatives with improved pharmacokinetic properties by replacing the ester moiety with a more stable ether group. A focused virtual library of 1 × 104 molecules was built and screened against mPGES-1 through molecular docking experiments, leading to the selection of 10 candidates for synthesis and biological evaluation. Several molecules were found to inhibit mPGES-1 and, among them, two items featured IC50 values in the low micromolar range. Additional computational studies on the collection of synthesized compounds demonstrated that compound 3b, previously emerged as an mPGES-1 inhibitor, interfered with soluble Epoxide Hydrolase (sEH) activity, thus emerging as a valuable dual mPGES-1/sEH inhibitor. The pharmacokinetic features of the most potent compounds were accurately estimated. Unfortunately, poor outcomes were obtained for 3b; on the Other hand, compound 7e exhibited promising mPGES-1 inhibition and excellent pharmacokinetic profile, demonstrating that the novel furazanopyrazine-based items with ether moiety possess improved pharmacokinetic properties compared to the ester-based compounds reported in our previous study. Additionally, the Anticancer properties of 7e and 7d, the latter emerged as the most active mPGES-1 inhibitor, were evaluated and both compounds showed promising activities against HCT-116 human colorectal Cancer (CRC) cells. These findings highlight the furazanopyrazine core as a promising scaffold for disclosing new anti-inflammatory drugs with the ability to inhibit targets belonging to arachidonic acid cascade.

Keywords

Cancer; Furazanopyrazine; Inflammation; Virtual screening; mPGES-1; sEH.

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