Novel triazine-tyrosine hybrids containing thiyazol or pyridine fragment as anti-multiple sclerosis agents: Design, synthesis, biological evaluation, and molecular docking study

Abstract

In this study novel triazine-tyrosine hybrids containing thiazole or pyridine fragments were introduced as anti- Multiple Sclerosis agents. The compounds were designed according to the structure of the Sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, fingolimode. At first, docking studies was performed using crystal structures of S1P1 and Sphingosine-1-phosphate receptor subtype 3 (S1P3) to theoretically identify the selectivity of the compounds towards the S1P1 isoform. The docking results showed better binding energy (lower DeltaG(b)) and therefore higher selectivity for S1P1 receptor than S1P3 receptor. Subsequently the designed compounds were synthesized according to proper chemical reactions and structurally analyzed with FTIR and NMR spectrophotometers. Considering the importance of the S1P1 receptor in release of lymphocytes and therefore inflammation produced in Multiple Sclerosis disease, the synthesized compounds were investigated to study lymphocyte reduction in an animal model. Compound (8e) with 2-mercaptobenzothiazole substitution at doses of 1 and 3 mg/kg showed significant reduction effect on the percentage of lymphocytes (68.80 , 56.75 ) compared to the fingolimod (65.73 , 20.66 ), as the positive control group.