Synthesis and antimicrobial properties of guanidine-functionalized labdane type diterpenoids.

The occurrence of increased antibiotic resistance has reduced the availability of drugs effective in the control of infectious diseases, especially those caused by various combinations of bacteria and/or fungi that are often associated with poorer patient outcomes. In the hunt for novel antibiotics of interest to treat polymicrobial diseases, molecules bearing guanidine moieties have recently come to the fore in designing and optimizing antimicrobial agents. Due to their remarkable antibacterial and antifungal activities, labdane diterpenes are also attracting increasing interest in antimicrobial drug discovery. In this study, six different guanidines prenylated with labdanic fragments were synthesized and evaluated for their antimicrobial properties. Assays were carried out against both non-resistant and antibiotic-resistant bacteria strains, while their possible antifungal activities have been tested on the yeast Candida albicans. Two of the synthesized compounds, namely labdan-8,13(R)-epoxy-15-oyl guanidine and labdan-8,13(S)-epoxy-15-oyl guanidine, were finally selected as the best candidates for further developments in drug discovery, due to their antimicrobial effects on both Gram-negative and Gram-positive bacterial strains, their fungicide action, and their moderate toxicity in vivo on zebrafish embryos. The study also provides insights into the structure-activity relationships of the guanidine-functionalized labdane-type diterpenoids.

An Alternative Approach towards C-12 Functionalized Scalaranic Sesterterpenoids Synthesis of 17-Oxo-20-norscalaran-12α,19-O-lactone.

Scalarane sesterterpenoids emerged as interesting bioactive natural products which were isolated extensively from marine sponges and shell-less mollusks. Some representatives were also reported recently from superior plants. Many scalarane sesterterpenoids displayed a wide spectrum of valuable properties, such as antifeedant, antimicrobial, antifungal, antitubercular, antitumor, anti-HIV properties, cytotoxicity and stimulation of nerve growth factor synthesis, as well as anti-inflammatory activity. Due to their important biological properties, many efforts have been undertaken towards the chemical synthesis of natural scalaranes. The main synthetic challenges are connected to their complex polycyclic framework, chiral centers and different functional groups, in particular the oxygenated functional groups at the C-12 position, which are prerequisites of the biological activity of many investigated scalaranes. The current work addresses this problem and the synthesis of 17-oxo-20-norscalaran-12α,19-O-lactone is described. It was performed via the 12α-hydroxy-ent-isocopal-13(14)-en-15-al obtained from (-)-sclareol as an accessible starting material. The tetracyclic lactone framework was built following an addition strategy, which includes the intramolecular Michael addition of a diterpenic acetoacetic ester and an intramolecular aldol condensation reaction as key synthetic steps. The structure and stereochemistry of the target compound have been proven by X-Ray diffraction method.