Discovery of tetrahydro-ß-carboline derivatives as a new class of phosphodiesterase 4 inhibitors
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Phosphodiesterase 4 is the primary enzyme responsible for degradation of the second messenger cAMP in many of the cells releasing proinflammatory mediators. Inhibition of this enzyme could help in the management of various inflammatory conditions such as asthma, chronic obstructive pulmonary disorder, arthritis, and psoriasis. In this study, two novel series of tetrahydro-β-carbolines were designed by combining the pharmacophoric features of both tadalafil and piclamilast. Twenty-two compounds were synthesized and assessed for Phosphodiesterase 4 inhibition, four of them showed superior activity to the reference compound IBMX. Docking studies showed that the prepared compounds interact with the crucial Gln443 with variable interactions with the hydrophobic pocket Q2. This is the first report of tetrahydro-β-carbolines as a scaffold for Phosphodiesterase 4 inhibition. Currently, further optimization of the substituents is carried out to fine-tune the hydrophobic interactions and enhance the potency of this novel series of inhibitors.
KeywordsCOPD Asthma PDE4 β-Carboline Docking
This study was entirely funded by the Science and Technology Development Fund (STDF), Egypt, Grant #4711, awarded to the Principal Investigator Dr. Mohamed A. Helal. The authors would like to thank Dr. Khaled M. Darwish, Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, for his insights in the design of the target compounds and during the synthetic steps.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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