2. Academic Validation
  3. Chromone-based small molecules for multistep shutdown of arachidonate pathway: Simultaneous inhibition of COX-2, 15-LOX and mPGES-1 enzymes

Chromone-based small molecules for multistep shutdown of arachidonate pathway: Simultaneous inhibition of COX-2, 15-LOX and mPGES-1 enzymes

  • Eur J Med Chem. 2024 Jan 10:266:116138. doi: 10.1016/j.ejmech.2024.116138.
Perihan A Elzahhar 1,  Rebecca Orioli 2,  Nayera W Hassan 1,  Silvia Gobbi 2,  Federica Belluti 2,  Hala F Labib 3,  Ahmed F El-Yazbi 4,  Rasha Nassra 5,  Ahmed S F Belal 6,  Alessandra Bisi 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy of Science Technology and Maritime Transport, Alexandria, Egypt.
  • 4 Faculty of Pharmacy and the Research and Innovation Hub, Alamein International University, Alamein, 5060335, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
  • 5 Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: [email protected].
  • 7 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: [email protected].
PMID: 38219658 DOI: 10.1016/j.ejmech.2024.116138
Abstract

As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices. They also showed appreciable 15-LOX inhibition, in comparison to quercetin. Further testing of these compounds for mPGES-1 inhibition displayed promising activities. Intriguingly, compounds 2a-c were capable of suppressing edema in the formalin-induced rat paw edema assay. They exhibited an acceptable gastrointestinal safety profile regarding ulcerogenic liabilities in gross and histopathological examinations. Additionally, upon treatment with the test compounds, the expression of the anti-inflammatory cytokine IL-10 was elevated, whereas that of TNF-α, iNOS, IL-1β, and COX-2 were downregulated in LPS-challenged RAW264.7 macrophages. Docking experiments into the three enzymes showed interesting binding profiles and affinities, further substantiating their biological activities. Their in silico physicochemical and pharmacokinetic parameters were advantageous.

Keywords

15-LOX; COX; Chromone; Inflammation; N-acylhydrazone; mPGES-1.

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