Design, Synthesis, and Biological Evaluation of Platensimycin Analogues with Varying Degrees of Molecular Complexity

Abstract

The molecular design, chemical synthesis and biological evaluation of two distinct series of platensimycin analogs with varying degrees of complexity are described. The first series of compounds (analog series I: 6, 15–18, Figure 3) probes the biological importance of the benzoic acid subunit of the molecule, whilst the second series (analog series II: 2, 3, 9–14) explores the tetracyclic cage domain. The biological data obtained reveal that while the substituted benzoic acid domain of platensimycin is a highly conserved structural motif within the active compounds with strict functional group requirements, the cage domain of the molecule can tolerate considerable structural modifications without losing biological action. These findings refine our present understanding of the platensimycin pharmacophore and establish certain structure activity relationships (SARs) from which the next generation of designed analogs of this new antibiotic may emerge.

Antibiotic discovery in the twenty-first century: current trends and future perspectives

“…55 In addition, medicinal chemistry studies have been conducted, and the design, synthesis and biological evaluation of several platensimycin analogs incorporating varying degrees of molecular complexity have been reported. [56][57][58] Preliminary Antibiotic discovery in the twenty-first century S Donadio et al data indicate that certain modifications of the intricate cage region can be made without detrimental effects on potency, whereas even small modifications of the benzoic acid region result in a drastic loss of activity ( Figure 1). Another remarkable chemical improvement in the synthesis of natural product analogs was a short and enantioselective synthetic route to a diverse range of 6-deoxytetracycline antibiotics (Figure 3a).…”

In vitro investigation of the antimicrobial activity of a series of lipophilic phenols and naphthols

“…33 Adamantyl derivative of Platensimycin was found also as extremely potent against Gram-positive methicillinresistant Staphylococcus aureus (MRSA) exhibiting activity in the range 1-2 µg/mL. 27,28 With respect to the SAR it is difficult to make a straightforward conclusion, since compounds from each library were found to be active. However, the findings of this study suggest that only compounds with two aromatic rings exert activity against Gram-positive bacteria.…”

“…21 Characterization of product 27 compares well with literature (mp = 225-228°C). (28) was obtained from 4-methoxy-4'-hydroxybiphenyl with sodium thiolate in 23 % yield according to the published procedure. 21 Characterization of product 28 compares well with literature (mp = 195-196°C).…”

“…Moreover, many of our derivatives bear an adamantyl substituent, and the antibacterial activity of a number of adamantane derivatives has been reported. [25][26][27][28][29] The in vitro antimicrobial testing was performed on five strains of microorganisms, Gram-positive Staphylococcus aureus and Bacillus subtilis, Gram-negative Escherichia coli and Klebsiella pneumoniae, and the fungus Candida albicans.…”

Platensimycin and platencin: promising antibiotics for future application in human medicine

“…Nicolaou et al 18,[30][31][32][33] reported several strategies for the total synthesis of platensimycin and related natural products. By using platensimycin/platencin as a starting point, they explored the relationship between structure and function.…”