2. Academic Validation
  3. Dialkyloxyphenyl hybrids as PDE4B inhibitors: Design, synthesis, in vitro/in vivo anti-inflammatory activity and in silico insights

Dialkyloxyphenyl hybrids as PDE4B inhibitors: Design, synthesis, in vitro/in vivo anti-inflammatory activity and in silico insights

  • Bioorg Chem. 2025 Jul 1:161:108511. doi: 10.1016/j.bioorg.2025.108511.
Aya M Almatary 1,  Mohamed S H Salem 2,  Mohamed R Elnagar 3,  Mohamed H Aboutaleb 4,  Tarek S Ibrahim 5,  Abdelrahman Hamdi 6,  Magda A-A El-Sayed 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt. Electronic address: Aelmatary@horus.edu.eg.
  • 2 SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, 4.5 Km the Ring Road, Ismailia 41522, Egypt.
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
  • 6 Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, Egypt. Electronic address: abdelrahmanhamdi2012@yahoo.com.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt; Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, Egypt.
PMID: 40311245 DOI: 10.1016/j.bioorg.2025.108511
Abstract

A series of novel dialkyloxyphenyl hybrids 11a-11h and 12a-12c were designed and synthesized as PDE4 inhibitors with anti-inflammatory activity. All compounds demonstrated nanomolar-range inhibitory activity against both PDE4B and PDE4D isoforms with notable selectivity for PDE4B. The 3,4-dimethoxyphenyl derivative 11e exhibited superior PDE4B inhibitory activity (IC50 = 2.82 nM), with nine-fold selectivity compared to 1.5 of Rolipram. In TNF-α inhibition assays, 11e demonstrated remarkable potency (IC50 = 7.20 nM), comparable to roflumilast, followed by 11d (IC50 = 15.54 nM) and 11b (IC50 = 28.52 nM). In vivo evaluation using LPS-induced sepsis model revealed that 11e achieved the highest inhibition of both TNF-α (52.19 %) and neutrophilia (56.47 %) compared to reference compounds. Molecular docking and dynamics studies revealed that hybrids 11b, 11d, and 11e exhibit a characteristic binding mode within the PDE4 active sites, rationalizing their activity through specific interactions, and demonstrating higher stability in the active site compared to Roflumilast.

Keywords

Anti-inflammatory; Drug design; Neutrophilia; PDE4 inhibitors; Selectivity; TNF-α.

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