Abstract:We report herein the synthesis of six diterpene derivatives, three of which are new, generated through known organic chemistry reactions that allowed structural modification of the existing natural products kaurenoic acid (1) and copalic acid (2). The new compounds were fully characterized using high resolution mass spectrometry, infrared spectroscopy, 1 H-and 13 C-NMR experiments. We also report the evaluation of the anti-tuberculosis potential for all compounds, which showed some promising results for Micobacterium tuberculosis inhibition. Moreover, the toxicity for each of the most active compounds was also assessed.

The labdane diterpenes copalic acid, 3β-acetoxy-copalic acid, 3β-hydroxy-copalic acid and ent-agathic acid were isolated from Copaifera langsdorffii oleoresin. These four compounds were submitted to structural modifications by reduction with hydrogen/palladium, esterification with diazomethane, esterification with methanol/sulfuric acid and conversion into sodium salt, furnishing 15 compounds. All compounds were assayed in vitro against Mycobacterium tuberculosis (H37Rv, ATCC 27294). The four compounds displayed minimum inhibitory concentration (MIC) value of 125 µg mL -1 , and were not considered active. A methylated derivative of compound 3β-hydroxy-copalic acid, and a sodium salt of copalic acid displayed MIC values of 25 µg mL -1 (71.7 µM) and 6.25 µg mL -1 (19.2 µM), respectively. The sodium salt of copalic acid stood out by displaying similar activity in comparison with streptomycin (MIC 6.25 µg mL -1) and a better activity compared to µM value of pyrazinamide (MIC 3.12 µg mL -1 ; 25.34 µM). Therefore, the methylated derivative of compound 3β-hydroxy-copalic acid and the sodium salt of copalic acid should be considered for further studies.

A set of seven diterpenes, three kauranes and four trachylobanes, isolated from the African plant Psiadia punctulata were assayed against Mycobacterium tuberculosis and reached activity comparable with cycloserine, a second line drug used to treat tuberculosis (TB). Several structural properties of those diterpenes, such as lipophilicity, HOMO and LUMO energies, charge density, and intramolecular hydrogen bond (IHB) formation, were obtained by theoretical calculations and compared with their activities. Peculiar correlations were observed, especially between activity, lipophilicity and IHB formation.