Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates.

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.

Diastereoselective Synthesis of Potent Antimalarial Cis-ß-lactam Agents.

Fifteen novel ß-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2- aminoethyl) ß-lactams 6a-o were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of cis-ß-lactam derivatives. These newly synthesized ß-lactams were evaluated for their antimalarial activity against p. falciparum K14 resistant strain and showed good to excellent EC50 values. Of the thirty ß-lactams tested, 5 h, 6a and 6c showed IC50 < 20 µM while 5b, 5c, 5e, 5f, 5g, 5i, 5j, 6d, 6g and 6h exhibited IC50 <50 . Compounds 5c, 5h, and 5q-t were examined for their anticancer properties against K562 Leukemia cell line and 5s showed the best activity. Compounds 3a-j, 5a-o, 6a-o, were tested against S. aureus , E. coli, C. albicans and showed no activity below 125 µg/mL.

Synthesis of New ß-Lactams Bearing the Biologically Important Morpholine Ring and POM Analyses of Their Antimicrobial and Antimalarial Activities.

Some new ß-lactams bearing biologically important morpholine ring have been synthesized by acylation of amino ß-lactams in the presence of morpholine-4-carbonyl chloride. These novel ß-lactams were prepared under mild reaction conditions without any solvent in short reaction times. Their biological activities have been examined against microbial agents such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and fungi such as Candida albicans (C. albicans) and Candida glabrata (C. glabrata). They have been also tested against Plasmodium falciparum K14 resistant strain and showed moderate to good IC50 values.