Antitubercular Activity Increase in Labdane Diterpenes from Copaifera Oleoresin through Structural Modification

Aline Silva,Vladimir Heleno,Jairo Bastos,Sérgio Ambrósio,Carlos Martins,Alex De Andrade,Mirela Cabral,Marilza Da Silva,Ana Carolina Soares,Rodrigo Veneziani

doi:10.21577/0103-5053.20160268

Abstract

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, 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 (71.7 μM) and 6.25 μg mL (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) and a better activity compared to μM value of pyrazinamide (MIC 3.12 μg mL; 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.

Highlights

Tuberculosis (TB) is a severe respiratory disease which causes deaths counted in millions every year.[1,2] This contagious and airborne disease is caused by mycobacteria from the Mycobacterium tuberculosis complex and,[1,2] since it is transmitted through air, it is certainly hard to control.[3]
It is evaluated by the World Health Organization (WHO)[2] that 480 thousand people developed multidrugresistant TB (MDR-TB) in 2014
Considering the potential of this class of compounds and our research interests in terpenoids,[19,20,21] we decided to submit the previously isolated labdane diterpenes (1‐4) to structural modifications searching for more active compounds against M. tuberculosis

Summary

Introduction

Tuberculosis (TB) is a severe respiratory disease which causes deaths counted in millions every year.[1,2] This contagious and airborne disease is caused by mycobacteria from the Mycobacterium tuberculosis complex and,[1,2] since it is transmitted through air, it is certainly hard to control.[3]. Considering the potential of this class of compounds and our research interests in terpenoids,[19,20,21] we decided to submit the previously isolated labdane diterpenes (1‐4) to structural modifications searching for more active compounds against M. tuberculosis. Structural modifications were performed by submitting the isolated compounds to four different protocols: reduction with hydrogen/palladium, esterification with diazomethane, esterification with methanol/sulfuric acid and conversion into sodium salt.

Results

Conclusion