Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors

A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A2a antagonist/MAO-B inhibitor (Ki(A2A) = 260 nM; IC50(MAO-B) = 200 nM; IC50(MAO-A) = 10 μM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson’s agents. A number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC50 of 68 and 48 nM, respectively, being 5–7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC50 = 334 nM).