Design, synthesis, in silico study, and anti-psoriatic activity of some novel Fumaric acid ester derivatives

Abstract

Psoriasis, being a chronic inflammatory and autoimmune disease, remains untreatable despite meticulous management and treatment therapies developed by scientists globally. Earlier, Fumaric acid ester derivatives were employed in clinical and preclinical settings to observe the benefits in psoriasis treatment. In the current study, some novel derivatives were designed, synthesized, formulated, and tested in the mouse tail model of psoriasis. The designed molecules were also docked on P38α-MAPK enzyme, which is believed to play an important role in generating cytokines and further other mediators responsible for psoriasis. Molecular docking was performed using Schrodinger 2024-1. Results indicated that out of fourteen designed compounds, three compounds (compounds 2 (2E)-4-(octyloxy)-4-oxobut-2-enoic acid, Compound 3 (2E)-4-(diphenylmethoxy)-4-oxobut-2-enoic acid and Compound 4 (2E)-4-(cyclopentoxy)-4-oxobut-2-enoic acid) were properly synthesized and characterized and confirmed by spectroscopic techniques and then were subjected to be evaluated pharmacologically in mouse tail model. Among them, compound 2 exhibited the highest binding energy (-1.908 kcal/mol) and convincing binding interactions and can be considered for the inhibition of the enzyme. Molecular docking results were in agreement with the in vivo study, indicating the presence of orthokeratosis and alleviating other cardinal signs of psoriasis in the mouse tail.