Macrooxazoles A–D, New 2,5-Disubstituted Oxazole-4-Carboxylic Acid Derivatives from the Plant Pathogenic Fungus Phoma macrostoma

Abstract

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1–4) for which we proposed the trivial names macrooxazoles A–D together with two known tetramic acids (5–6) were isolated from the plant pathogenic fungus Phoma macrostoma. Their structures were elucidated based on high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The hitherto unclear structure of macrocidin Z (6) was also confirmed by its first total synthesis. The isolated compounds were evaluated for their antimicrobial activities against a panel of bacteria and fungi. Cytotoxic and anti-biofilm activities of the isolates are also reported herein. The new compound 3 exhibited weak-to-moderate antimicrobial activity as well as the known macrocidins 5 and 6. Only the mixture of compounds 2 and 4 (ratio 1:2) showed weak cytotoxic activity against the tested cancer cell lines with an IC50 of 23 µg/mL. Moreover, the new compounds 2 and 3, as well as the known compounds 5 and 6, interfered with the biofilm formation of Staphylococcus aureus, inhibiting 65%, 75%, 79%, and 76% of biofilm at 250 µg/mL, respectively. Compounds 5 and 6 also exhibited moderate activity against S. aureus preformed biofilm with the highest inhibition percentage of 75% and 73% at 250 µg/mL, respectively.

Dual Agents: Fungal Macrocidins and Synthetic Analogues with Herbicidal and Antibiofilm Activities

“…Removal of the N -Boc-protecting group from compounds 16 and 13 using TFA left test candidates 4 and 5 as pure stereoisomers. For the synthesis of larger quantities of 16 , another route was developed also starting from tetramic acid 11 in analogy to our syntheses of macrocidins A and Z [ 4 , 5 ]. 3-Acyltetramic acid 15 was built up by 4- O -acylation of 11 with 6-heptenoic acid and subsequent rearrangement of tetramate 14 .…”

“…Ring-closing metathesis of 15 with Grubbs type-II catalyst afforded key intermediate 16 in 54% total yield over three steps. Enantiopure dihydromacrocidin Z ( 3 ) was obtained from N -Boc-protected macrocidin Z 17 by hydrogenation and removal of the N -Boc-protecting group from 18 in 99% yield over two steps [ 5 ].…”

“…So far, only two total syntheses of macrocidin A ( 1 ) have been published [ 3 , 4 ]. Macrocidin Z ( 2 ), which carries an E -alkene in lieu of the expoxide, was isolated from Phoma macrostoma cultures and synthesised in parallel by us only recently [ 5 ]. Although 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.…”

“…Although 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 now 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 groups other than epoxide. We tested them for herbicidal, antibacterial, and antibiofilm activities, and for cytotoxicity to human cells.…”

Five Tetramic Acid Derivatives Isolated from the Iranian Fungus Colpoma quercinum CCTU A372

“…Tetramic acid is known to possess broad bioactivity. For example, macrocidins are known to have herbicidal activity [ 32 ] and recently have also been found to have an antibiofilm effect against Staphylococcus aureus [ 33 ]. Although only weak to moderate antimicrobial activity was observed from our compounds, further investigation of another biological assay remains necessary.…”