Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction

Erectile dysfunction (ED) remains a global health burden, yet the clinical utility of tadalafil is constrained by its poor aqueous solubility, cross-inhibition of homologous PDE isoforms, and an efficacy ceiling that cannot be overcome by dose adjustment alone. Herein, a series of diketopiperazine-based tadalafil analogues were designed and synthesized by decorating the amide nitrogen with flexible carbon chains and polar fragments (glycine, taurine, cysteine, and succinic/glutaric anhydride spacers), and by replacing the 3,4-methylenedioxybenzyl motif with substituted aromatic aldehydes. All target compounds were characterized by 1H/13C NMR and HR-MS and evaluated for cytotoxicity against rat aortic smooth muscle cells, calculated Log P and aqueous solubility, NO release, and phosphodiesterase type-5A (PDE5A) inhibitory activity, followed by 100 ns molecular dynamics (MD) simulations and MM/PBSA calculations on the leading analogue. Compound 18, bearing a p-methoxyphenyl group and an N-methyl amide, markedly enhanced NO release relative to tadalafil, reduced residual PDE5A activity to 38.69 ± 1.98% at 10 μM, and exhibited negligible cytotoxicity with a predicted logP of 1.53. Docking into PDE5 (PDB: 1XOZ) and MD analysis revealed a stable binding pose anchored by hydrogen bonds to Gln817 and Tyr612, reinforced by π–π stacking with Phe820 and extensive hydrophobic contacts with Leu765, Ile768, Val782, and Met816 (ΔG_bind = −9.13 ± 3.30 kcal/mol), with van der Waals contributions dominating (−41.78 ± 4.60 kcal/mol). Collectively, compound 18 emerges as a promising next-generation tadalafil-derived PDE5 inhibitor lead, and the resulting SAR picture outlines a hydrophobic-anchor-dominated optimization strategy for this scaffold.