Parkinson’s disease (PD) is a common degenerative disease of the central nervous system among the elderly. Istradefylline, an FDA-approved adenosine A receptor antagonist (anti-PD drug), has good efficacy. However, it has been reported that the double bond of istradefylline is easily converted into cis-configuration when exposed to an indoor environment or direct light in a dilute solution. In order to find more stable adenosine A receptor antagonists with similar pharmacological efficacy to istradefylline, the compounds series I-1 (12 compounds) was designed by maintaining the xanthine skeleton of istradefylline unchanged and replacing the trans-double bond with thiazole or benzothiazole and other biologically active heterocyclic compounds. These compounds were synthesized via multi-step experiment and successfully confirmed through different characterization techniques for their ability to inhibit cAMP formation in A AR overexpressing cells. The thiazole derivative of istradefylline (Compound I-1-11, I-1-12) exhibited significant activity (IC =16.74 ± 4.11 μM, 10.36 ± 3.09 μM ), as compared to istradefylline (IC = 5.05 ± 1.32 μM). In addition, the molecular docking of benzothiazole derivatives I-1-11 and thiazole derivatives I-1-12 with higher inhibition rate were carried out and compared with istradefylline. The molecular docking results showed that I-1-11 and I-1-12 anchored in the same site as that of XAC (3REY) with predicted affinity binding energy -6.63 kcal/mol and -6.75 kcal/mol, respectively. Validation through dynamics simulation also showed stable interactions, with fluctuations less than 3 Å and MM/GBSA energy less than -20 kcal/mol. Hence, this study could provide a basis for the rational design of adenosine A receptor antagonists with better potency.
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