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.

There is an urgent need for novel and improved drugs against several tropical diseases caused by protozoa. The marine sponge (Agelas sp.) metabolite agelasine D, as well as other agelasine analogs and related structures were screened for inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and T. cruzi, as well as for toxicity against MRC-5 fibroblast cells. Many compounds displayed high general toxicity towards both the protozoa and MRC-5 cells. However, two compounds exhibited more selective inhibitory activity against L. infantum (IC₅₀ <0.5 mg/mL) while two others displayed IC₅₀ <1 mg/mL against T. cruzi in combination with relatively low toxicity against MRC-5 cells. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), these compounds could be classified as hits for leishmaniasisand for Chagas disease, respectively. Identification of the hits as well as other SAR data from this initial screening will be valuable for design of more potent and selective potential drugs against these neglected tropical diseases.