Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction
- 1Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
- 2Shandong Engineering Research Center of Pharmaceutical Green Intelligent Technology, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
Abstract
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.
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BibTeX
@article{liu2026design,
title = {{Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction}},
author = {Wentao Liu and Bin Zhang and Yuping Jia and Xiangyu Kong and Yuxiao Deng and Xinqiang Cui and Li Yang and Wenjie Ren and Xuan Tang and Daizhou Zhang and Lingwen Xu},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203785},
url = {https://www.mdpi.com/1420-3049/31/20/3785},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction
AU - Wentao Liu
AU - Bin Zhang
AU - Yuping Jia
AU - Xiangyu Kong
AU - Yuxiao Deng
AU - Xinqiang Cui
AU - Li Yang
AU - Wenjie Ren
AU - Xuan Tang
AU - Daizhou Zhang
AU - Lingwen Xu
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203785
UR - https://www.mdpi.com/1420-3049/31/20/3785
AB - 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.
SN - 1420-3049
ER -