Synthesis and antimycobacterial activity of agelasine E and analogs

Abstract

Agelasine E, previously isolated from the marine sponge Agelas nakamurai, has been synthesized for the first time, together with analogs with various terpenoid side chains. Treatment of N⁶-methoxy-9-methyl-9H-purin-6-amine with allylic bromides gave the desired 7,9-dialkylpurinium salts together with minor amounts of the N⁶-alkylated isomer. The N⁶-methoxy group was finally removed reductively. ¹H–¹⁵N HMBC and ¹H–¹⁵N HSQC NMR spectroscopy gave additional information on tautomerism and charge delocalization in the purine derivatives studied. The heterocyclic products were screened for activity against Mycobacterium tuberculosis and agelasine analogs carrying a relatively long terpenoid substituent in the purine 7-position and a methoxy group at N-6 were potent inhibitors of bacterial growth. Since agelasine analogs with the geranylgeranyl chain at N-7 exhibited antimicrobial activity, several strategies for synthesis of geometrically pure (2E,6E,10E)-geranylgeranyl bromide from geranyllinalool were evaluated.