Synthesis, Biological Evaluation, and Computational Study of Pyridine- and Indazole-Based Inhibitors of the Inducible Nitric Oxide Synthase as Promising Antipsoriatic Agents

The dysregulation of inducible nitric oxide synthase (iNOS) is linked to various diseases, including psoriasis, where it contributes to imbalanced nitro-oxidative stress. iNOS is primarily produced in the skin's epidermal layer and can be activated by cytokines elevated in psoriatic lesions, such as TNF-α and IL-17. Macrophages also play a role in psoriasis by producing cytokines and iNOS, and patients show increased levels of these immune cells in lesions. Given the association of iNOS with psoriasis severity, it is seen as a potential therapeutic target. However, no specific iNOS Inhibitor has been reported as a treatment for psoriasis. The study describes the synthesis of new compounds based on prior iNOS inhibitors, their potency and selectivity of action, and the evaluation of the most interesting compounds in different in vitro and ex vivo cell models of psoriasis. Moreover, a computational analysis was performed that sheds light on the binding mode of the most promising molecule into both the iNOS and the constitutive endothelial NOS (eNOS). Compound 10 demonstrated significant effectiveness with respect to known iNOS inhibitors, reducing nitric oxide release, cytokine-induced inflammation, and cell necrosis, also shifting macrophages from a pro-inflammatory to a resolving phenotype. Its reasonable metabolic stability, along with the absence of significant in vivo toxicity, supports its further evaluation as a promising candidate for antipsoriatic drug development.

inducible nitric oxide synthase; inflammation; keratinocytes; macrophages; psoriasis; synthesis; zebrafish embryos.