Valorisation of the diterpene podocarpic acid – Antibiotic and antibiotic enhancing activities of polyamine conjugates. (15th June 2022)

• Record Type: Journal Article
• Authors: Li, Steven A.; Cadelis, Melissa M.; Deed, Rebecca C.; Douafer, Hana; Bourguet-Kondracki, Marie-Lise; Michel Brunel, Jean; Copp, Brent R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 64(2022)
• Publication Date: 2022-06-15
• Subjects: Antimicrobial activities -- Diterpene polyamine conjugates -- Podocarpic acid -- Antibiotic adjuvant; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116762
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Library of amide and/or carbamate linked podocarpate – polyamine conjugates prepared. Amide derivative exhibited potent and selective anti-MRSA activity. Carbamate derivative exhibited potent and selective antifungal activity. Weak to modest ability to enhance the action of antibiotics towards G- bacteria. Abstract: As part of our search for new antimicrobials and antibiotic adjuvants, a series of podocarpic acid-polyamine conjugates have been synthesized. The library of compounds made use of the phenolic and carboxylic acid moieties of the diterpene allowing attachment of polyamines (PA) of different lengths to afford a structurally-diverse set of analogues. Evaluation of the conjugates for intrinsic antimicrobial properties identified two derivatives of interest: a PA3-4–3 (spermine) amide-bonded variant 7a that was a non-cytotoxic, non-hemolytic potent growth inhibitor of Gram-positive Staphylococcus aureus (MRSA) and 9d, a PA3-8-3 carbamate derivative that was a non-toxic selective antifungal towards Cryptococcus neoformans . Of the compound set, only one example exhibited activity towards Gram-negative bacteria. However, in the presence of sub-therapeutic amounts of either doxycycline (4.5 µM) or erythromycin (2.7 μM) several analogues were observed to exhibit weak to modest antibiotic adjuvant properties against Pseudomonas aeruginosa and/or Escherichia coli . The observation of strong cytotoxicity and/or hemolytic properties for subsets of the library, in particular those analogues bearing methyl ester or n -pentylamide functionality, highlighted the fine balance of structural requirements and lipophilicity for antimicrobial activity as opposed to mammalian cell toxicity.