Novel triazine-tyrosine hybrids containing thiyazol or pyridine fragment as anti-multiple sclerosis agents: Design, synthesis, biological evaluation, and molecular docking study
Parvin Asadi,
Fateme Mahdie,
Ghadamali Khodarahmi,
Leila Safaeian,
Farshid Hassanzade
Affiliations
Parvin Asadi
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran; Bioinformatics Research Center. Isfahan University of Medical science, Isfahan, Iran; Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Fateme Mahdie
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
Ghadamali Khodarahmi
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran; Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Corresponding author. Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
Leila Safaeian
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Farshid Hassanzade
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
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 ΔGb) 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.
