SAR of Sponge-Inspired Hemibastadin Congeners Inhibiting Blue Mussel PhenolOxidase

Abstract

Hemibastadin derivatives, including the synthetically-derived 5,5′-dibromohemibastadin-1 (DBHB), are potent inhibitors of blue mussel phenoloxidase (PO), which is a key enzyme involved in the firm attachment of this invertebrate to substrates and, thus, a promising molecular target for anti-fouling research. For a systematic investigation of the enzyme inhibitory activity of hemibastadin derivatives, we have synthesized nine new congeners, which feature structural variations of the DBHB core structure. These structural modifications include, e.g., different halogen substituents present at the aromatic rings, different amine moieties linked to the (E)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionic acid, the presence of free vs. substituted aromatic hydroxyl groups and a free vs. methylated oxime group. All compounds were tested for their inhibitory activity towards the target enzyme in vitro, and IC50 values were calculated. Derivatives, which structurally closely resemble sponge-derived hemibastadins, revealed superior enzyme inhibitory properties vs. congeners featuring structural moieties that are absent in the respective natural products. This study suggests that natural selection has yielded structurally-optimized antifouling compounds.

3- O -Methyl-Alkylgallates Inhibit Fatty Acid Desaturation in Mycobacterium tuberculosis

“…After removing the solvent, the respective 3-O-methyl-gallic acid ester was obtained. To prepare compounds 6 and 9, 3,4,5-tri-O-methyl-gallic acid (Sigma-Aldrich, Germany) was used instead of 3-Omethyl-gallic acid (45). Microplates were incubated at 37°C for 5 days essentially as described previously (46).…”

“…The resulting solution was then added to 1 ml of respective amine and stirred for 20 min at room temperature. The solvent was removed under reduced pressure to give amides 17 to 19(45).Bacterial strains and growth conditions. Cells of M. tuberculosis strains H37Rv, CDC1551, Erdman, and HN878 and of several XDR-TB clinical isolates from South Africa(29)were grown aerobically in Middlebrook 7H9 medium containing 10% (vol/vol) ADS enrichment solution (5% [wt/vol] bovine serum albumin [fraction V], 2% [wt/vol] glucose, 0.85% [wt/vol] sodium chloride), 0.5% (vol/vol) glycerol, and 0.05% (vol/vol) tyloxapol at 37°C.…”

Towards eco‐friendly biocides: preparation, antibiofilm activity of hemibastadin analogues

“…; Niemann et al . ). In view of discovering new specific and nontoxic anti‐biofilm compounds which should be used as potential friendly environmentally biocides, our group is developing an efficient approach based on the bioisosteric replacement of natural frameworks by a 1,2,3‐triazolic ring to allow SAR studies in the field of antifouling fight.…”

Sponge-Inspired Dibromohemibastadin Prevents and Disrupts Bacterial Biofilms without Toxicity

“…Bastadins have been previously isolated from a marine sponge Ianthella basta . Thirty natural bastadins were characterized and screened for their AF potencies: it was highlighted that some of these compounds were able to inhibit barnacle adhesion and adhesives synthesis by mussels [ 27 , 28 ].…”

“…DBHB consists of a hemibastadin unit composed by brominated tyrosine and a likewise brominated tyramine unit; its synthesis was previously described by Bayer et al in 2011 [ 27 ]. DBHB is selected and evaluated in our study because this compound has already been described as an inhibitor of macroorganisms (barnacles and mussels) adhesion [ 28 , 29 ] without toxicity. However, its activity on microorganisms has never been described.…”