Abstract
Eight analogues of the bioherbicides macrocidin A (1) and Z (2) with structural variance in the size of the macrocycle, its para- or meta-cyclophane character, and its functional groups were synthesized on two modular routes and tested for herbicidal, antibiotic, and antibiofilm activities. Apart from the lead compounds 1 and 2, the structurally simplified dihydromacrocidin Z (3) and normacrocidin Z (4) showed high herbicidal activity in either thistles, dandelions or in both. The derivatives 2, 3, and dibromide 9 also inhibited the growth of Staphylococcus aureus biofilms by ca 70% when applied at subtoxic concentrations as low as ca 20 µM, which are unlikely to induce bacterial resistance. They also led to the dispersion of preformed biofilms of S. aureus, exceeding a similar effect by microporenic acid A, a known biofilm inhibitor. Compounds 3 and 9 showed no noticeable cytotoxicity against human cancer and endothelial cells at concentrations below 50 µM, making them conceivable candidates for application as anti-biofilm agents in a medicinal context.
Highlights
Macrocidins are polycyclic tetramic acid macrolactams (PTMs)
L-tyrosine, yet differ in their modular routes. They share the same tetramic acid derived from L-tyrosine, yet differ in degree of resemblance to thetolead macrocidins
Z (2) on two efficient modular routes, which allow the introduction of various functionalities and scaffold modifications on a few key intermediates
Summary
Macrocidins are polycyclic tetramic acid macrolactams (PTMs). Macrocidin A (1; Figure 1) was first isolated from the fungus Phoma macrostoma Montagne in 2003 by a Dow. AgroSciences group headed by Graupner [1]. E-alkene in lieu of the expoxide, was isolated from Phoma macrostoma cultures and synthesised in parallel by us only recently [5]. Concentrated Phoma macrostoma cultures, formulated as broadcast granules, are being used as bioherbicides for environment-friendly weed management in the US and Canada, efforts towards the synthesis of simplified macrocidin derivatives with improved herbicidal properties were sporadically made (e.g., by Graupner’s group [6] and Syngenta [7]), albeit without disclosing details. As 3-acyltetramic acids from a broad range of sources were found to have antibiotic or biofilm inhibitory effects [8,9,10,11,12] (e.g., by us in the case of macrocidin Z (2) [5]), we synthesised analogues of the natural macrocidins with variation of the structural key features such as the size of the macrocycle, its para- or meta-cyclophane character, and its decoration with functional
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