Synthesis and Pharmacological Evaluation of 6,7-Dihydro‑3H‑Oxazolo[3,4‑a]Pyrazine-5,8-Dione Compounds as Inhibitors of Phosphodiesterases 4 and 5.

Benign prostatic hyperplasia (BPH) is a prevalent condition in aging men that negatively affects the quality of life. Current therapeutic strategies aim to reduce prostate size and smooth muscle contraction. In this study, five novel 4-oxazoline-centered compounds with potential phosphodiesterase (PDE) inhibitory activity were synthesized and tested for biochemical and pharmacological effects in isolated prostate cells and tissues. Among them, compound VIII exhibited inhibitory activity against PDE5 and two PDE4 isoforms in cell-free assays. Additionally, it relaxed isolated rat prostate tissue, enhanced nitric oxide-induced relaxation, and reduced contractile responses mediated by alpha-1 adrenoceptors. Moreover, compound VIII significantly inhibited the proliferation of a human hyperplastic prostate cell line, mimicking the effects of rolipram, a PDE4 inhibitor. With its dual inhibition of PDE4 and PDE5 and its ability to decrease both contraction and cell proliferation, compound VIII emerges as a promising candidate for further investigation as a potential treatment for BPH. Complementary molecular docking and conformational analyses provided a structural rationale for the observed activity trends, highlighting the role of hydroxyethyl substituent interactions with the PDE5A H-loop in modulating inhibitory potency. Taken together, the dual PDE4/PDE5 inhibition profile of compound VIII, combined with its favorable functional effects on smooth muscle tone and cell proliferation, identifies this scaffold as a promising starting point for further optimization toward BPH therapy.