Synthesis of (<i>E</i>)‑8-(3-Chlorostyryl)caffeine Analogues Leading to 9‑Deazaxanthine Derivatives as Dual A_2A Antagonists/MAO‑B Inhibitors

Abstract

A systematic modification of the caffeinyl core and substituents of the reference compound (<i>E</i>)-8-(3-chlorostyryl)­caffeine led to the 9-deazaxanthine derivative (<i>E</i>)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1<i>H</i>-pyrrolo­[3,2-<i>d</i>]­pyrimidine-2,4-(3<i>H</i>,5<i>H</i>)-dione (<b>17f</b>), which acts as a dual human A_2a antagonist/MAO-B inhibitor (<i>K</i>_i(A_2A) = 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 A_2A 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 <b>17f</b> were synthesized and qualitative SARs are discussed. Two analogues of <b>17f</b>, namely <b>18b</b> and <b>19a</b>, 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)