2. Academic Validation
  3. Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

  • Bioorg Chem. 2024 Oct 24:153:107911. doi: 10.1016/j.bioorg.2024.107911.
Ahmed M Moussa 1,  Heba Abdelrasheed Allam 2,  Mohamed K El-Ashrey 3,  Marwa A Fouad 4,  Ahmed A Al-Karmalawy 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt. Electronic address: heba.abdelkhalek@pharma.cu.edu.eg.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt; Medicinal Chemistry Department, Faculty of Pharmacy, King Salman International University, South Sinai 46612, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt; Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq, Baghdad 10023, Iraq. Electronic address: akarmalawy@horus.edu.eg.
PMID: 39467506 DOI: 10.1016/j.bioorg.2024.107911
Abstract

In this study, we designed and synthesized novel analogues of roflumilast that exhibit selective inhibition of PDE-4B. To accomplish this target; synthesis of novel series (4a-u, 5a-i, and 6) was done, aiming at obtaining new PDE-4B inhibitors hits based on the proposed pharmacophore, 1-(cyclopropylmethoxy)-2-(difluoromethoxy) benzene moiety. Enzyme assay was used to measure the IC50 values for the PDE-4B inhibition of all the synthesized compounds along with roflumilast as a reference drug. The results demonstrated that most of the examined candidates exhibited considerable inhibitory activity against the PDE-4B Enzyme. The four compounds (4i, 4k, 4p, and 4q) exhibited the highest potency (IC50 = 7.25, 7.15, 5.50, 7.19 nM, respectively) with no significant inhibition difference from roflumilast (no statistical difference at p < 0.05). Interestingly, compound 4p with 3-OH and 4-OCH3 substituents was found to be the most potent against PDE-4B Enzyme (IC50 = 5.50 nM), compared to that of roflumilast (IC50 = 2.36 nM). Moreover, the most potent derivatives 4i, 4k, 4p, and 4q were further tested for PDE-4D inhibitory activity to investigate their PDE-4D/PDE-4B selectivity ratio. Compound 4k showed the highest selectivity towards PDE-4B isozyme more than the reference drug roflumilast (PDE-4D/4B IC50 ratio for compound 4k and roflumilast = 3.22 and 3.02, respectively). Additionally, compound 4p was chosen to test its selectivity for PDE-4B over PDE-8A, PDE-11A, and PDE-1B compared to thereference drug roflumilast. Compound 4p showed approximately 6-fold selectivity for PDE-4B over PDE-8A, about 5-fold selectivity for PDE-4B over PDE-11A, and about 11-fold selectivity of PDE-4B over PDE-1B. Compound 4p showed a higher selectivity towards PDE-4B than PDE-1B, more than the reference compound roflumilast. Furthermore, the most potent compounds (4i, 4k, 4p, 4q) were subjected to further investigation, and their effects on the cAMP level and percentage of inhibition of tumor necrosis factor-alpha (TNF-α) were studied and compared with reference drug roflumilast. Compound 4q showed the highest increase in the level of intracellular cAMP (6.55 ± 0.37 pmol/mL) and compound 4i showed the highest % of TNF-α inhibition (77.22 %). On the other side, a molecular docking study against PDE-4B clarified that all the examined candidates achieved nearly similar binding modes with similar orientations to that of the native roflumilast ligand and showed higher docking scores than roflumilast.

Keywords

Chronic obstructive pulmonary disease; Phosphodiesterase 4B inhibitor; Roflumilast; TNF-α; cAMP.

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