13-a

AMP-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, has been identified as a promising target for regulating vascular remodeling in pulmonary arterial hypertension (PAH) due to its capacity to promote proliferation, autophagy, and anti-apoptosis in pulmonary artery smooth muscle cells (PASMCs). However, research into AMPK inhibitors is very limited. Herein, a virtual screening strategy was employed to identify CHEMBL3780091 as a lead compound for a series of novel AMPK inhibitors by exploring the structure-activity relationship around a specific pyridine-2-one scaffold. Subsequently, the most promising 13a was observed to exhibit excellent AMPK inhibitory activity and favorable anti-proliferative activity against PASMCs through the inhibition of the AMPK signaling pathway in vitro. Moreover, compound 13a significantly reduced right ventricular systolic pressure, attenuated vascular remodeling, and improved right heart function in hypoxia-induced PAH rats in vivo. In conclusion, this study provides a novel and potential lead compound for the study of AMPK inhibitors and a new direction for the development of PAH drugs that focus on improving vascular remodeling.

In this study, 32 novel ureidopyrimidine compounds containing sulfonamide fragments were strategically designed and synthesized through active substructure combination. Postemergence herbicidal activity assays demonstrated that compounds 13a, 14d, and 15c exhibited superior efficacy against broadleaf weeds, including Zinnia elegans and Abutilon theophrasti, with compound 15c achieving a remarkable 95% control rate at 9.375 g a.i./ha, comparable to that of the commercial herbicide saflufenacil. Molecular docking simulations revealed that these compounds, along with saflufenacil, establish hydrogen bonds with protoporphyrinogen oxidase, particularly involving important amino acid residues, including ARG-98, GLY-175, and ASN-67. Structure-activity relationship analysis, supported by density functional theory calculations and molecular electrostatic potential studies, highlighted the importance of negatively charged regions in herbicidal activity. This comprehensive research provides valuable insights into the design and development of potent herbicides, establishing a strong foundation for future advancements in agricultural chemistry.