Research in pharmaceutical sciences · 2026
Synthesis, in vitro and in silico evaluation of quinazoline and triazoloquinazoline derivatives as PDE7A inhibitors.
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El-Malah Afaf A, Gineinah Magdy M, Khayat Maan T, Neamatallah Thikryat, Sonousi Amr, Mahmoud Zeinab, Hassan Rasha A
Аннотация
BACKGROUND AND PURPOSE: Phosphodiesterase 7A (PDE7A) is an attractive therapeutic target for the treatment of inflammatory, autoimmune, and neurodegenerative disorders through modulation of intracellular cAMP levels. However, the development of highly potent and selective PDE7A inhibitors remains challenging. This study aimed to design, synthesize, and evaluate 2-chloroquinazoline and fused 1,2,4-triazolo[4,3-c]quinazoline derivatives as potential PDE7A inhibitors, supported by molecular docking, molecular dynamics simulations, and in silico toxicity prediction.
EXPERIMENTAL APPROACH: A series of 2-chloroquinazoline derivatives 4a-f and their fused 1,2,4-triazolo[4,3-c]quinazoline counterparts 5a-d were synthesized as phosphodiesterase 7A (PDE7A) inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory activity against phosphodiesterase 7A (PDE7A) and were compared with theophylline and BRL50481, a selective PDE7 inhibitor.
FINDINGS/RESULTS: All compounds demonstrated enzyme inhibition ranging from 0.062 to 1.35 μM;. Derivatives 5c and 5d exhibited the most potent inhibitory effects, with IC50 values of 0.076 and 0.062 μM;, respectively, and were not significantly different from BRL50481 (IC50 = 0.034 μM;), while being significantly more potent than theophylline (IC50 = 0.539 μM;). These compounds, together with 4c and 5a, showed superior inhibitory activity compared with theophylline. Molecular docking and molecular dynamics studies were performed to investigate binding interactions and stability within the PDE7A active site.
CONCLUSION AND IMPLICATIONS: Compounds 5c and 5d displayed high binding affinity and stability within the active site. Their interactions with key amino acid residues support their potential as effective PDE7A inhibitors. Predicted toxicity data indicated a favorable safety profile across 30 toxicity endpoints, supporting their further development.
EXPERIMENTAL APPROACH: A series of 2-chloroquinazoline derivatives 4a-f and their fused 1,2,4-triazolo[4,3-c]quinazoline counterparts 5a-d were synthesized as phosphodiesterase 7A (PDE7A) inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory activity against phosphodiesterase 7A (PDE7A) and were compared with theophylline and BRL50481, a selective PDE7 inhibitor.
FINDINGS/RESULTS: All compounds demonstrated enzyme inhibition ranging from 0.062 to 1.35 μM;. Derivatives 5c and 5d exhibited the most potent inhibitory effects, with IC50 values of 0.076 and 0.062 μM;, respectively, and were not significantly different from BRL50481 (IC50 = 0.034 μM;), while being significantly more potent than theophylline (IC50 = 0.539 μM;). These compounds, together with 4c and 5a, showed superior inhibitory activity compared with theophylline. Molecular docking and molecular dynamics studies were performed to investigate binding interactions and stability within the PDE7A active site.
CONCLUSION AND IMPLICATIONS: Compounds 5c and 5d displayed high binding affinity and stability within the active site. Their interactions with key amino acid residues support their potential as effective PDE7A inhibitors. Predicted toxicity data indicated a favorable safety profile across 30 toxicity endpoints, supporting their further development.