Synthesis and Antimicrobial Evaluation of Novel Platensimycin Analogues

Abstract

Since the isolation of the natural products platensimycin and platencin as new antibiotic lead structures, several total syntheses as well as syntheses of derivatives have been developed. Most of these approaches are very laborious and the target molecules are often produced in only poor overall yields. The following approach describes the synthesis of rather simple platensimycin analogues focussing on some structure elements that have previously been identified as being essential for binding to the Fab F enzyme in fatty acid biosynthesis. Two of the new analogues show significant antimicrobial activities.

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

“…The phenol group of the methyl ester 2 was esterified with several aromatic or aliphatic carboxylic acid chlorides to give the phenol esters 3a – h . The following hydrogenation of the nitro group with Pd/C (5%) in methanol led to the amino group which reacted in the same procedure under aminolysis of the phenol ester to the resulting anilides 4a – g [ 14 – 18 ]. The olefin partial structures of 3a and 3f were hydrogenated under these conditions but the halogen substituent of 3b was stable.…”

“…Even the synthesis of the 3-amino-2,4-dihydroxy benzoic acid partial structure, which is essential for binding to the enzyme FabF ( Figure 2 ), takes several steps in these total syntheses [ 5 – 13 ]. In continuation of our work on simple platensimycin analogues [ 14 , 15 ], we hereby present the short and effective preparation of the o -hydroxy-anilide partial structure without the requirement of a protecting group.…”

Enantioselective Hydroazidation of Trisubstituted Non‐Activated Alkenes

“…To demonstrate the utility of this method, it was applied for the diastereo‐ and enantioselective synthesis of (+)‐rodocaine, whose racemate is known as an ophthalmic anesthetic (Scheme ) . Cyclohexane‐1,2‐diol was converted into cyclopentene 5 in an overall yield of 41 % by Malaprade glycol oxidative cleavage followed by intramolecular aldol condensation, thioacetalization, and Corey–Seebach alkylation . Enantioselective hydroazidation of 5 with (−)‐IpcBH 2 afforded the azide trans ‐ 6 (61 % yield, 75:25 e.r.)…”

Review of Platensimycin and Platencin: Inhibitors of β-Ketoacyl-acyl Carrier Protein (ACP) Synthase III (FabH)

“…Plesch’s group also focused on the development of novel simplified platensimycin analogues and thereby synthesized a series of compounds containing the anilide group and the ketone, both identified as essential for binding of the active components to the Fab F complex [39]. After a standardized agar diffusion assay, ketones 67 and 68 showed a broad spectrum of antibacterial activity, comparable to the antibiotics tetracycline and clotrimazol (Table 1).…”