INTRODUCTION: Diterpenes are a class of natural products that include a considerable number of active molecules. They can be related to several biological (anti-inflammatory,1 anticancer,2 antibacterial,3 antiviral,4) and ecological activities (fungicide5 and herbicide6, among others). When we compare the active profile of diterpenes, taking into account their structural differences, one can easily note that slight structural changes could be related to expressive change in activity. The aim of this work was to carry out structural modifications in the natural diterpene pimaradienoic acid (1) and to verify how is leishmanicidal activity related to those changes.

MATERIAL AND METHODS: Initially, 1 was isolated from Viguiera arenaria extract as described before.7 After that, the esterification reactions were carried out by reaction of 1 with four different alkyl halides. Reaction procedures were performed with iodomethane, benzylbromide, 4-chlorobenzyl bromide and 4-bromobenzyl bromide, giving products 2, 3, 4 and 5, respectively. Subsequent hydrogenation reaction of pimaradienoic acid (1), gave 15,16-dihydro pimaradienoic acid (6), which was also submitted to esterification. Reaction of 6 with the same halides, yielded 4 new esters, respectively 7, 8, 9 and 10. All diterpenes (1 to 10) were submitted to the evaluation of the leishmanicidal activity against the promastigote forms of Leishmania amazonensis.

RESULTS: All semi-synthetic derivatives were clearly identified by NMR. They were submitted to 1H-NMR, 13C {1H} NMR and some 2D experiments for their structure determination. The biological assay results are shown on Figure 1, together with the identified structures. Biological results will be discussed in accordance to Fokialakis,8 considering IC50 < 10 g.mL-1 as very active; while 10 < IC50 < 20 g.mL-1 as moderate activity.8 Therefore, this work started with a moderate activity precursor (1) which yielded initially one inactive derivative (2), but three very active ones (3, 4 and 5). In a second round the moderate activity derivative (6) was obtained, and then, gave four highly active esters (7, 8, 9 and 10). Among all, the activity of derivatives 3, 4, 5 and 7 are noteworthy.

CONCLUSION: The results obtained showed that the activity increased with the formation of esters. Compound 7 showed to be a promising derivative, with expressive activity against L. amazonensis. One can also conclude that structural modifications in natural compounds can lead us to some very interesting derivatives.

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8 Fokialakis, N. et al. Biol. Pharm.Bull. 2006; 29; 8; 1775-1778.