Synthesis of imidazolidin-4-one and 1H-imidazo62,1-a9isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

Abstract

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N α -protected amino acids, (ii) removal of the N α -protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1 H -imidazo[2,1- a ]isoindole-2,5(3 H ,9b H )-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1 H -imidazo[2,1- a ]isoindole-2,5(3 H ,9b H )-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly ( t 1/2 5–30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging. The synthesis of imidazolidin-4-ones derived from the antimalarial primaquine is presented. The key step was the cyclization of appropriate α-aminoacylprimaquine with a carbonyl compound. Cyclization with 2-formylbenzoic acid leads to 1 H -imidazo[2,1- a ]isoindole-2,5(3 H ,9b H )-dione in a diastereoselective fashion. The imidazolidin-4-ones are hydrolyzed very slowly to the parent α-aminoacylprimaquine in physiological pH 7.4 and thus can be considered slow-releasing prodrugs.