Nitric oxide production inhibition and anti-mycobacterial activity of extracts and halogenated sesquiterpenes from the Brazilian red alga laurencia dendroidea J. Agardh

Abstract

Background:Red algae of the genus Laurencia J. V. Lamouroux are a rich source of secondary metabolites with important pharmacological activities such as anti-tumoral, anti-inflammatory, anti-fungal, anti-viral, anti-leishmanial, anti-helminthic, anti-malarial, anti-trypanosomal, anti-microbial as well as anti-bacterial against Mycobacterium tuberculosis.Objective:In the present study, we evaluated the inhibition of nitric oxide (NO) and tumor necrosis factor-α production and the anti-mycobacterial activity of crude extracts from the red Alga Laurencia dendroidea (from the South-Eastern coast of Brazil). Halogenated sesquiterpenes elatol (1), obtusol (2) and cartilagineol (3), previously isolated from this Alga by our group, were also studied.Materials and Methods:The lipopolysaccharide-activated macrophage cells (RAW 264.7) were used as inflammation model. Cytotoxic effect was determined using a commercial lactate dehydrogenase (LDH) kit and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The growing Mycobacterium inhibition was verified against Mycobacterium bovis Bacillus Calmette–Guérin and M. tuberculosis H37 Rv strains.Results:The crude extract from Alga collected at Angra dos Reis, RJ, Brazil, was the most active inhibitor of both mycobacterial growth (half maximal inhibitory concentration [IC50] 8.7 ± 1.4 μg/mL) and NO production by activated macrophages (IC50 5.3 ± 1.3 μg/mL). The assays with isolated compounds revealed the anti-mycobacterial activity of obtusol (2), whereas (-)-elatol (1) inhibited the release of inflammatory mediators, especially NO. To our knowledge, this is the first report describing an anti-mycobacterial effect of L. dendroidea extract and demonstrating the association of this activity with obtusol (2).Conclusion:The described effects of active compounds from L. dendroidea are promising for the control of inflammation in infectious diseases and specifically, against mycobacterial infections associated with exacerbated inflammation.SUMMARY Inflammation is strongly involved in the pathogenesis of most infectious diseases, including TB. The treatment of TB is based on the use of anti mycobacterial drugs, however the most severe forms of TB, require additional anti inflammatory therapy to prevent excessive inflammation. A combination of these properties in one compound could provide additional therapeutic benefits. In this work, we studied L. dendroidea extracts and purified compounds and demonstrated that the LDA extract and (-)-elatol (1) were potent in inhibiting NO production by macrophages through the specific inhibition of iNOS expression. The LDA and LDM extracts and obtusol (2) were active against virulent strain of M. tuberculosis. This is the first report demonstrating that the anti-inflammatory activities of L. dendroidea were associated with the presence of (-)-elatol (1), whereas anti-mycobacterial activities of L. dendroidea extracts were associated with obtusol (2).

Antimycobacterial Activity of Laurinterol and Aplysin from Laurencia johnstonii

“…Despite the urge to find new anti-NTM treatments, marine natural products have been weakly evaluated; Biá Ventura et al investigated the antimycobacterial activity of two extracts of Laurencia dendroidea and three of its halogenated sesquiterpenes against Mycobacterium bovis, noting obtusol (3) with a half-maximal inhibitory concentration (IC 50 ) of 31.4 µg/mL [39]. Previously, laurinterol and aplysin were evaluated for their toxicity against murine macrophages and they exhibited half-maximal cytotoxic concentration (CC50) of 23.7 and 323.7 μg/mL, respectively [17].…”

“…To date, algae metabolites represent over 2% of the marine anti-TB compounds reported. Among the metabolites isolated from Laurencia that have been tested against Mtb (Figure 2), obtusol (3), elatol (4), and deschloroelatol (5) exhibited MICs of 32 μg/mL, debromolaurinterol (6) and isolaurenisol 7showed MICs of 64 and 38 μg/mL, respectively, and allolaurinterol (8) and allolaurinterol acetate (9) presented MICs of 16 and 9 μg/mL, respectively [38][39][40]. Axisonitrile-3, a sesquiterpene isonitrile isolated from the sponge Acanthella klethra, is one of the most active marine compounds against Mtb and exhibited a MIC of 2 μg/mL [38].…”

“…Despite the urge to find new anti-NTM treatments, marine natural products have been weakly evaluated; Biá Ventura et al investigated the antimycobacterial activity of two extracts of Laurencia dendroidea and three of its halogenated sesquiterpenes against Mycobacterium bovis, noting obtusol (3) with a half-maximal inhibitory concentration (IC50) of 31.4 μg/mL [39]. Laurencia-derived sesquiterpenes with chamigrane (compounds 3-5), cyclolaurane (compound 6), and laurane (compounds 7-9) skeletons have shown antitubercular properties.…”

Antimycobacterial Activity of Laurinterol and Aplysin from <i>Laurencia johnstonii</i>

“…To date, algae metabolites represent over 2% of the marine anti-TB compounds reported, and among the metabolites isolated from Laurencia that have been tested against Mtb (Fig. 2), obtusol (3), elatol (4) and deschloroelatol (5) exhibited MICs of 32 µ g/mL; debromolaurinterol (6) and isolaurenisol (7) showed MICs of 64 and 38 µ g/mL, respectively and, allolaurinterol (8) and allolaurinterol acetate (9) of 16 and 9 µ g/mL, respectively [38][39][40]. Axisonitrile-3, a sesquiterpene isonitrile isolated from the sponge Acanthella klethra, is one of the most active marine compounds against Mtb, which exhibited MIC of 2 µ g/mL [38].…”

Enzymes associated with anti-inflammatory potentialities of purified terpenoid extracts from the selected sea weeds

“…Neorogioltriol, a tricyclic brominated diterpenoid isolated from the organic extract of the red algae Laurencia glandulifera, showed anti-inflammatory effects under in vitro condition in LPS-treated RAW 264.7 macrophages, and also in vivo using the carrageenan-induced paw edema model (38). In addition, anti-inflammatory effects of lipid extract of Tetraselmis chuii, Chlorella sorokiniana and Chondrus crispus in RAW 264.7 macrophages (39).…”