Short and Efficient Synthesis of Alkyl- and Aryl-Ortho-Hydroxy-Anilides and Their Antibiotic Activity

Abstract

Ortho-hydroxy-anilides are part of natural products like the new antibiotics platencin (A) and platensimycin (B). An important step in the total synthesis of these antibiotics or their derivatives is the preparation of the o-hydroxy-anilide partial structure. The presented method allows the preparation of o-hydroxy-anilides and o-dihydroxy-anilides from 2-nitrophenol esters in a one-step synthesis without protecting the hydroxy group. Aryl- and alkyl-anilides were prepared following this method as simple analogues of platensimycin (A). The resulting compounds were tested in an agar diffusion assay for their antibiotic potency.

New starting points for antibiotics targeting P. aeruginosa FabF discovered by crystallographic fragment screening followed by hit expansion

“…These results indicate that the bulk of affinity of platencin and platensimycin (2.75 and 0.52 µM, respectively) 16 stems from the interactions between the apolar tail and the receptor opening, rather than the interactions close to the catalytic residues within the active site. This is in line with previous structureactivity relationships (SAR) studies, where exchanging the ketolide tail of platensimycin with short alkyl chains abolished antibacterial activity 44,45 and resulted in only weak binding compounds in vitro (KD = 650 µM for the ethyl analogue binding to E. coli FabFC163Q). 31 Consequently, it is reasonable to believe that the discovered hits can be optimized into potent inhibitors, despite their low affinities.…”

Crystal structure of 3-(4-hydroxy-3-methoxyphenyl)-N-phenylpropanamide, C16H17NO3

“…3-Aryl-N-arylpropanamides rise interest both due to synthetic applications and wide range of biological activity (e. g., they act as antitubercular [3] and antibiotic [4] agents, as well as HCA2 receptor agonists [5]). These compounds serve as starting materials for synthesis of 3-arylpropanols [6], 1,3-diarylpropan-1-ones [7], quinolines [8], β-l lactams [9], 4-aryl-2-quinolinones [10] and 1-indanones [11], as well as ligands in iridium complexes [12].…”

Bioinspired Synthesis of Platensimycin from Natural ent-Kaurenoic Acids

“…In this context, the search for new antibiotics presenting new modes of action to fight against resistant bacteria is becoming a pressing global need. In 2006, (−)-platensimycin (PTM), a meroditerpenoid from Streptomyces platensis , was isolated by Merck researchers. , Its activity has been tested against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant enterococci (VRE) among others. , Additionally, this substance possesses a unique mode of action as a suppressor of β-ketoacyl-(acyl-carrier protein) synthase II (FabF) engaged in the mechanism of fatty acid biosynthesis. , This unique mode of action, its challenging structural and functional architecture, has attracted the attention of many synthetic chemists, and consequently, a number of synthetic strategies have been developed to complete the synthesis of PTM and analogues. − Furthermore, a fermentation process for producing PTM from S. platensis SB12026 was described …”