Synthesis and antimycobacterial activity of agelasine E and analogs

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 N-6- 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. H-1 - (NHMBC)-N-15 and H-1 - N-15 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.