Synthesis of 2,4-dihydroxyacetophenone derivatives as potent PDE-1 and -3 inhibitors: <i>in vitro</i> and <i>in silico</i> insights

Aim: Synthesis of novel bis-Schiff bases having potent inhibitory activity against phosphodiesterase (PDE-1 and -3) enzymes, potentially offering therapeutic implications for various conditions. Methods: Bis-Schiff bases were synthesized by refluxing 2,4-dihydroxyacetophenone with hydrazine hydrate, followed by treatment of substituted aldehydes with the resulting hydrazone to obtain the product compounds. After structural confirmation, the compounds were screened for their in vitro PDE-1 and -3 inhibitory activities. Results: The prepared compounds exhibited noteworthy inhibitory efficacy against PDE-1 and -3 enzymes by comparing with suramin standard. To clarify the binding interactions between the drugs, PDE-1 and -3 active sites, molecular docking studies were carried out. Conclusion: The potent compounds discovered in this study may be good candidates for drug development. Different bis-Schiff bases of 2,4-dihydroxyacetophenone (3–32) have been synthesized successfully. These derivatives were structurally elucidated through different spectroscopic techniques including HR-ESI-MS, 1H- and 13C-NMR, and tested for their in vitro phosphodiesterase-1 and -3 inhibitory activities. Among the series, all the compounds attributed excellent to moderate inhibitory activity except seven compounds which were found inactive. However, 14 compounds were found the most potent inhibitors having IC50 values of 0.05 ± 0.11 to 8.02 ± 1.03 μM, when compared with the standard suramin. In case of phosphodiesterase-3 inhibitory activity, 11 compounds displayed excellent inhibitory activity with IC50 values from 0.012 ± 0.32 to 1.01 ± 0.22 μM better than the standard suramin (IC50 = 1.05 ± 0.28 μM). All the synthesized derivatives showed excellent to less inhibitory activity in the range of IC50 values from 1.23 ± 0.03 to 73.85 ± 0.61 μM, compared with acarbose IC50 = 873.34 ± 1.67 μM. Structure–activity relationship study to know the contribution of various attached substituents. The docking investigations regarding the phosphodiesterase-1 and -3 binding sites were implemented for the most active bis-Schiff bases and Suramin in order to attain better comprehension with respect to the pattern in which binding mechanics occur between the new compounds and the phosphodiesterase-1 and -3 active sites, which illustrated a higher binding efficacy in appraisal with reference inhibitor and suramin. The absorption, distribution, metabolism and excretion molecular characteristics, estimation of toxicity and bioactivity scores were also assessed.