Development of novel nitric oxide production inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold

Nitric oxide (NO), the smallest signaling molecule known, can be excessively produced by overexpressed inducible nitric oxide synthase (iNOS), and eventually leads to multiple inflammatory related diseases. Thus, reducing the overexpression of NO represents as very potential anti-inflammatory strategy. In current study, a series of compounds were designed and synthesized based on the hybridization of 7H-pyrrolo[2,3-d]pyrimidine and cinnamamide fragments in order to develop novel NO production inhibitors. Among them, compound S2h displayed a vigorous inhibitory activity on NO production with an IC₅₀ value of 3.21 ± 0.67 µM, which was much lower than that of the positive control N^ω-nitro-L-arginine (L-NNA, IC₅₀ = 28.36 ± 3.13 µM). Due to its obeying Lipinski's and Veber's rules that guarantee compounds with good oral bioavailability, S2h effectively suppressed the paw swelling in carrageenan-induced mice. Additionally, compound S2h formed clear interactions with iNOS protein according to the docking analysis. Therefore, compounds S2h is a promising lead compound for further development of potent iNOS inhibitors or anti-inflammatory agents.