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Article

Investigation of the Anti-Methicillin-Resistant Staphylococcus aureus Activity of (+)-Tanikolide- and (+)-Malyngolide-Based Analogues Prepared by Asymmetric Synthesis

by
Joseph Breheny
1,
Cian Kingston
2,
Robert Doran
1,
Joao Anes
3,
Marta Martins
3,
Séamus Fanning
3 and
Patrick J. Guiry
1,2,*
1
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin D04 N2E5, Ireland
2
Synthesis and Solid State Pharmaceutical Centre, School of Chemistry, University College Dublin, Belfield, Dublin D04 N2E5, Ireland
3
UCD-Centre for Food Safety, University College Dublin, Belfield, Dublin D04 N2E5, Ireland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(12), 6400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126400
Submission received: 10 March 2021 / Revised: 10 June 2021 / Accepted: 10 June 2021 / Published: 15 June 2021
(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)
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Abstract

:
Herein, we report antibacterial and antifungal evaluation of a series of previously prepared (+)-tanikolide analogues. One analogue, (4S,6S)-4-methyltanikolide, displayed promising anti-methicillin-resistant Staphylococcus aureus activity with a MIC of 12.5 µg/mL. Based on the antimicrobial properties of the structurally related (−)-malyngolide, two further analogues (4S,6S)-4-methylmalyngolide and (4R,6S)-4-methylmalyngolide bearing a shortened n-nonyl alkyl side chain were prepared in the present study using a ZrCl4-catalysed deprotection/cyclisation as the key step in their asymmetric synthesis. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus, the MIC increased to 50 µg/mL.

1. Introduction

We developed a ZrCl4-catalysed one-pot deprotection/cyclisation synthetic protocol for the construction of δ-lactones [1]. The methodology was subsequently applied in the asymmetric synthesis of both enantiomers of a mosquito attractant pheromone [2], substituted tetrahydropyrans which provided useful synthons for the enantioselective synthesis of (+)-exo- and (+)-endo-brevicomin [3] and for the efficient synthesis of (−)-frontalin and (−)-exo-isobrevicomin [4]. Finally, of relevance to this report, the methodology was applied to the asymmetric synthesis of (+)-tanikolide, 1, affording the δ-lactone based natural product in an overall yield of 26.4% [5]. (+)-Tanikolide 1 displays strong toxicity against brine shrimp and snails and interesting antifungal activity against C. albicans [6]. C. albicans is the most common fungal pathogen of human diseases and together with other Candida species are responsible for ca. 400,000 life-threatening infections per annum with a mortality rate as high as 40% [7,8]. Current therapeutic drugs for Candida infections include members of five classes of compounds: polyenes, allylamines, azoles, fluoropyrimidines and echinocandins [9] with amphotericin B, terbinafine, fluconazole, 5-fluorocytosine and caspofungin being the most well-known examples [10].
(+)-Tanikolide 1 is structurally closely related to the marine antibiotic (−)-malyngolide, 2, with three key differences illustrated in Figure 1; a shortened alkyl side chain (Figure 1, 2 difference A), opposite configuration at the quaternary stereocentre (Figure 1, 2 difference B) and a methyl group α- to the carbonyl (Figure 1, 2 difference C). Interestingly, despite the similarity to (+)-tanikolide 1, (−)-malyngolide 2 displays no activity against C. albicans [6]. However, (−)-malyngolide 2 does display anti-microbial activity against Myobacterium smegmatis, Staphylococcus aureus, Bacillus subtilis and Streptococcus pyogenes [11]. The bacterium Staphylococcus aureus is among one of the most aggressive human pathogenic agents [12]. Antibiotic resistance to S. aureus is a major medical issue [13] and is the result of the widespread use of antibacterial antibiotics since the 1940s [14]. The most effective antibiotics for MRSA eradication are vancomycin, linezolid and a few others in combination with vancomycin. Daptomycin, clindamycin, doxycycline, tigecyclin and trimethoprim–sulfamethoxazole combination is also efficient against most MRSA strains [15]. The search for new compounds to act as antifungal and antimicrobial agents is an active field of research and, herein, we report our results with analogues of (+)-tanikolide 1 and (−)-malyngolide 2.
In addition, to our reported synthesis of (+)-tanikolide 1, we wished to probe the biological importance of the position of the methyl group and hence the four β-methyl modified analogues (3–6) were synthesised using the same δ-lactone forming methodology with the aim to enhance the antifungal activity against C. albicans (Figure 2) [5]. These analogues (3–6) were subsequently biologically evaluated, the results of which we report now (Table 1).

2. Results

The four β-methyl (+)-tanikolide based analogues (3-6) were submitted for biological testing to ascertain if they exhibited any antifungal and antimicrobial activity. The compounds were tested against Candida albicans and Candida parapsilosis. Unfortunately, the compounds displayed no inhibition of growth even at concentrations as high as 800 µg/mL. However, the series of compounds were also tested for activity against Gram-positive and Gram-negative bacterial strains, methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) (Table 1). Although the compounds showed no activity against E. coli, analogue 5 was found to exhibit promising results against MRSA with an MIC of 12.5 µg/mL. This compares favourably with the typical MIC values of vancomycin (4.8 µg/mL) [16] and linezolid (0.1–4 mg/L) [17]. Analogue 5 was shown to be stable for the duration of the assay. The configuration of a methyl group—to the carbonyl had a dramatic effect upon the specific activity of the compound, as shown by analogue 6 which displayed no bioactivity. Analogue 5 bears the opposite stereochemistry at the quaternary carbon centre to 1, upon which the analogues were initially designed. Interestingly, the configuration is the same as found in (−)-malyngolide 2, a known anti-microbial agent.
In an effort to further increase the efficacy of these potential anti-MRSA agents, we wished to synthesise analogues bearing the shortened n-nonyl side chain found in (−)-malyngolide 2. The optimal stereochemistry of the β-methyl group will be determined once again by the synthesis and evaluation of both diastereomers. A number of approaches to asymmetric synthesis of 2 have been published since the first report by Mukaiyama in 1980 [18], including the use of chiral auxiliary [19,20,21,22,23,24,25,26,27], chiral pool [28,29,30,31,32,33,34,35,36,37], other asymmetric syntheses [38,39,40] and catalytic asymmetric syntheses [41,42,43,44,45,46,47,48,49].
The synthesis of (−)-malyngolide based analogues 7 and 8 was adapted from our initial synthesis of (+)-tanikolide based compounds 3–6 (Figure 3) [5]. The first step was monoalkylation of phosphonate 9 which afforded intermediate 10 in a yield of 51%. A Horner-Wadsworth-Emmons reaction with 35% aqueous formaldehyde successfully gave the desired terminal alkene of intermediate 11 in a yield of 73%. DIBAL reduction of the ethyl ester provided allylic alcohol 12 in 25% yield. A Sharpless asymmetric epoxidation using Ti(OiPr)4, (−)-diisopropyltartrate and cumene hydroperoxide was used to afford intermediate 13 with the desired stereochemistry in a yield of 80%. The ee was subsequently determined after benzyl protection of the primary alcohol in 13 due to the absence of a chromophore on the unprotected epoxide. The stereochemistry of the product was assigned based on extensive NOE experiments carried out on analogues 3–6 [5]. Protection of the cohol was achieved using sodium hydride as a base with benzyl bromide in the presence of tetrabutylammonium iodide to give 14 in a yield of 86% with an ee greater than 99% (see Figure S1 for reference chiral SFC chromatograms). At this point a diol protection/bromination of crotonaldehyde 16 was carried out which provided intermediate 15 in 83% yield. Intermediate 15 was then applied in a copper-catalysed Grignard addition to epoxide 14 which, upon separation via silica gel column chromatography, provided diastereomers 18 and 21 in an overall yield of 69% [50]. 18 was subjected to our developed ZrCl4-catalysed one-pot deprotection/cyclisation technique to afford diastereomeric acetals 19 and 20 in a yield of 92%. Conversion to the desired δ-lactone 21 was achieved using the Lewis acid BF3.OEt2 and mCPBA with a yield of 52% [51,52]. Hydrogenolysis of the benzyl ether was carried out using Pearlman’s catalyst at 25 bar pressure to provide (4S, 6S)-4-methyl-malyngolide 7 in a yield of 94%. Diastereomer 21 was subjected to a similar synthetic sequence to afford (4R, 6S)-4-methyl-malyngolide 8 with yields of 89, 42 and 65% obtained for the cyclisation, oxidation and deprotection steps, respectively.
With the synthesis complete, the new analogues 7 and 8 were tested for their biological activity (Table 2). The results indicate that the n-nonyl chain had a significant deleterious effect on the anti-MRSA action of the compounds. Analogues 7 and 8 displayed similar activity with their lowest MIC and MBC values of 50 µg/mL. Further synthesis of modified analogues is currently underway in an effort to enhance the biological activity of this interesting class of compounds.

3. Conclusions

In summary, we have determined anti-methicillin-resistant Staphylococcus aureus activity (MIC of 12.5 µg/mL) by a novel β-methyl analogue 5 of (+)-tanikolide 1. In an effort to improve upon this activity, two further analogues 7 and 8 bearing a shortened n-nonyl alkyl side chain were prepared in the present study using a ZrCl4-catalysed deprotection/cyclisation as the key step. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus the MIC increased to 50 µg/mL. It is hoped the results described above will lead to further improvements in this class of potentially potent anti-methicillin-resistant Staphylococcus aureus compounds.

4. Materials and Methods—Chemistry

Unless otherwise noted, reactions were performed with rigorous exclusion of air and moisture, under an inert atmosphere of nitrogen in flame-dried glassware with magnetic stirring using anhydrous solvents. N2-flushed stainless steel cannulas or plastic syringes were used to transfer air and moisture-sensitive reagents. All reagents were obtained from commercial sources and used without further purification unless otherwise stated. All anhydrous solvents were obtained from commercial sources and used as received with the following exceptions: diethyl ether (Et2O), dichloromethane (CH2Cl2) and toluene (PhCH3) were dried by passing through activated alumina columns. Powdered activated 4 Å molecular sieves were purchased from Sigma Aldrich and were stored in an oven at 120 °C. In vacuo refers to the evaporation of solvent under reduced pressure on a rotary evaporator. Thin-layer chromatography (TLC) was performed on aluminium plates pre-coated with silica gel F254. They were visualised with UV-light (254 nm) fluorescence quenching, or by charring with Hanessian’s staining solution (cerium molybdate, H2SO4 in water), basic potassium permanganate staining solution (potassium permanganate, K2CO3 and NaOH in water), or an acidic vanillin staining solution (vanillin, H2SO4 in ethanol). Flash column chromatography was carried out using 40–63 μm, 230–400 mesh silica gel.
1H NMR spectra were recorded on a 300, 400 or 500 MHz spectrometer. 13C NMR spectra were recorded on a 400 or 500 MHz spectrometer at 101 or 126 MHz. 19F NMR spectra were recorded on a 400 MHz spectrometer at 376 MHz. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane and for 1H NMR are referenced to residual proton in the NMR solvent (CDCl3 = δ 7.26 ppm). 13C NMR are referenced to the residual solvent peak (CDCl3 = δ 77.16 ppm). All 13C spectra are 1H decoupled. NMR data are represented as follows: chemical shift (δ ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet, app. d = apparent doublet, app. t. = apparent triplet), coupling constant (J) in Hertz (Hz). High resolution mass spectra [electrospray ionisation (ESI-TOF)] (HRMS) were measured on a micromass LCT orthogonal time-of-flight mass spectrometer with leucine enkephalin (Tyr-Gly-Phe-Leu) as an internal lock mass. Infrared spectra were recorded on a FT-IR spectrometer and are reported in terms of wavenumbers (νmax) with units of reciprocal centimetres (cm−1). Microwave experiments were conducted in a CEM Discover S-class microwave reactor with controlled irradiation at 2.45 GHz using standard microwave process Pyrex vials. Reaction time reflects time at the set reaction temperature maintained by cycling of irradiation (fixed hold times). Optical rotation (α) values were measured at room temperature and specific rotation ([α]D20) values are given in deg.dm−1.cm3.g−1. Melting points were determined in open capillary tubes. Supercritical fluid chromatography (SFC) was performed on a Waters UPC2 system using a Chiralpak IB column.

4.1. Ethyl 2-(diethoxyphosphoryl)undecanoate (10)

NaH (60% in mineral oil, 6.0 g, 150 mmol) was placed in a dry 500 mL two-necked room-bottom flask (RBF) containing a magnetic stirrer bar under an inert atmosphere, was washed with anhydrous hexanes (2 × 20 mL) and dried under high vacuum. Dry THF (250 mL) was added to the reaction flask and triethylphosphonoacetate 9 (19.8 mL, 100 mmol) in dry THF (30 mL) was added dropwise over 20 min to the reaction mixture, with evolution of H2 gas. NaI (3.7 g, 25 mmol) was added to the reaction flask followed by dropwise addition of 1-bromononane (9.6 mL, 50 mmol) and the reaction mixture was heated at reflux for 24 h. The reaction mixture was quenched with H2O (100 mL) and the aqueous layer was extracted with ether (3 × 100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL) and dried with anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (pentane/ether, 9:1 → 4:1) to yield 10 as a colourless oil (8.93 g, 51%).
Spectroscopic analysis of 10: Rf = 0.20 (pentane/diethyl ether, 1:9); IR (neat): νmax = 3477, 2926, 2854, 1729, 1465, 1250, 1029 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.28–4.09 (m, 6 H), 2.92 (ddd, J = 22.5, 11.1, 3.7 Hz, 1 H), 2.04–1.90 (m, 1 H), 1.90–1.77 (m, 1 H), 1.50–1.09 (m, 23 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm; 13C NMR (126 MHz, CDCl3): δ 169.2 (d, J = 4.8 Hz), 62.6 (d, J = 6.6 Hz), 62.5 (d, J = 6.6 Hz), 61.2, 45.8 (d, J = 131.0 Hz), 31.8, 29.4, 29.2 (d, J = 4.6 Hz), 29.0, 28.4, 28.3, 26.9 (d, J = 5.0 Hz), 22.6, 16.3 (d, J = 4.0 Hz), 16.3 (d, J = 4.0 Hz), 14.1, 14.0 ppm; 31P NMR (162 MHz, CDCl3) δ 22.98 ppm; HRMS (ESI-TOF): calcd. for C17H35O5PNa [M + Na]+ 373.2120; found 373.2108. (see Figure S2 for 1H and 13C NMR spectra).

4.2. Ethyl 2-methyleneundecanoate (11)

Phosphate ester 10 (8.93 g, 25.5 mmol) was placed in a 250 mL two-necked RBF containing a magnetic stirrer bar, followed by deionised water (30 mL), K2CO3 (14.1 g, 101.9 mmol) and aqueous formaldehyde (16.5 mL, 37%, 203.8 mmol). The reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL) and dried with anhydrous Na2SO4. Excess solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (pentane/diethyl ether, 9:1) to yield 11 as a colourless oil (4.24 g, 73%). (see Figure S3 for 1H and 13C NMR spectra).
Spectroscopic analysis of 11: Rf = 0.70 (pentane/diethyl ether, 9:1); IR (neat): νmax = 2926, 2856, 1720, 1179, 1147 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.12 (d, J = 1.5 Hz, 1 H), 5.50 (d, J = 1.5 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 2.29 (t, J = 7.7 Hz, 2 H), 1.50–1.41 (m, 2 H), 1.37–1.19 (m, 15 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm; 13C NMR (126 MHz, CDCl3) δ 167.4, 141.2, 124.0, 60.5, 31.9, 31.8, 29.5, 29.4, 29.3, 29.2, 28.4, 22.7, 14.2, 14.1 ppm; HRMS (ESI-TOF): calcd. for C14H26O2Na [M + Na]+ 249.1831; found 249.1840.

4.3. 2-Methyleneundecan-1-ol (12)

Allylic ester 11 (4.24 g, 18.71 mmol) was placed in a dry 100 mL two-necked RBF containing a magnetic stirrer bar and dissolved in dry THF (55 mL), under an inert atmosphere. The reaction mixture was cooled to −30 °C and DIBAL (25 wt.% in toluene, 9.5 mL, 41 mmol) was added dropwise over 40 min and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with diethyl ether (5 mL) and a saturated solution of Rochelle’s salt (potassium sodium tartrate) (50 mL). The reaction mixture was stirred for 16 h at room temperature. The product was extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL) and dried with anhydrous Na2SO4. Excess solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (pentane/diethyl ether, 4:1) to yield 12 as a colourless oil (0.856 g, 25%). (see Figure S4 for 1H and 13C NMR spectra).
Spectroscopic analysis of 12: Rf = 0.19 (pentane/diethyl ether, 4:1); IR (neat): νmax = 3323, 2926, 2856, 1653, 1465, 1027 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.03–4.98 (m, 1 H), 4.88–4.83 (m, 1 H), 4.07 (s, 2 H), 2.05 (t, J = 7.6 Hz, 2 H), 1.50–1.37 (m, 2 H), 1.36–1.17 (m, 12 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm; 13C NMR (126 MHz, CDCl3) δ 148.3, 107.9, 64.9, 32.0, 30.9, 28.6, 28.5, 28.4, 28.3, 26.8, 21.7, 13.1 ppm; HRMS (EI-TOF): calcd. for C12H24O [M]+ 184.1828; found 184.1827.

4.4. (R)-(2-Nonyloxiran-2-yl)methanol (13)

Molecular sieves (4 Å, 400 mg) and dry CH2Cl2 (11.5 mL) were added to a dry 50 mL Schlenk tube containing a magnetic stirrer bar, followed by Ti(OiPr)4 (0.141 mL, 0.464 mmol) and (−)-diisopropyltartrate (0.146 mL, 0.697 mmol), at −35 °C under an inert atmosphere. The reaction mixture was stirred for 30 min. Allylic alcohol 12 (0.856 g, 4.64 mmol) was added and the mixture was stirred for 30 min. Cumene hydroperoxide (1.37 mL, 9.29 mmol) was added over 20 min. The reaction temperature was increased to −25 °C and the progress of the reaction was monitored by TLC until the consumption of the alcohol. Upon reaction completion at 18 h, the reaction mixture was quenched with saturated sodium bicarbonate solution (1 mL) and ether (5 mL) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The epoxide was purified by silica gel column chromatography (pentane/diethyl ether, 9:1 → 4:1) to yield epoxide 13 as a colourless oil (0.743 g, 80%, > 99% ee). (The ee was calculated by SFC analysis of benzyl-protected epoxide 7 (Waters Acquity UPC2, Chiracel IB, scCO2/isopropanol = 95:5, flow rate = 2 mL min−1)). (see Figure S5 for 1H and 13C NMR spectra).
Spectroscopic analysis of 13: Rf = 0.22 (pentane/diethyl ether, 3:2); SFC: Rt (R) = 1.543 min (major); Rt (S) = 2.215 min (minor); [α]D20 = + 6.3 (c = 1.0, CHCl3); IR (neat): νmax = 3430, 2926, 2856, 1466, 1047 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.75 (dd, J = 12.3, 4.4 Hz, 1 H), 3.61 (dd, J = 12.3, 8.6 Hz, 1 H), 2.86 (d, J = 4.7 Hz, 1 H), 2.64 (d, J = 4.7 Hz, 1 H), 1.83–1.66 (m, 2 H), 1.48 (dt, J = 14.0, 7.5 Hz, 1 H), 1.40–1.14 (m, 14 H), 0.85 (t, J = 6.8 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 62.7, 59.8, 49.8, 32.0, 31.8, 29.7, 29.4, 29.2, 24.6, 22.6, 14.1 ppm; HRMS (ESI-TOF): calcd. for C12H24O2Na [M + Na]+ 223.1674; found 223.1683.

4.5. (S)-2-[Benzyloxy)methyl]-2-undecyloxirane (14)

NaH (60% in mineral oil, 0.175 g, 4.379 mmol) was placed in a dry 100 mL two-necked RBF containing a magnetic stirrer bar under an inert nitrogen atmosphere, washed with anhydrous hexanes (2 × 5 mL) and dried under high vacuum. Dry THF (14.6 mL) was added and the reaction vessel cooled to 0 °C. Epoxide 13 (0.731 g, 3.649 mmol) was dissolved in dry THF (2 mL) and added to the reaction mixture, which was stirred for 30 min. Benzyl bromide (0.46 mL, 3.83 mmol) was added dropwise followed by tetra-n-butylammonium iodide (0.674 g, 1.825 mmol). The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 1 h. The reaction mixture was quenched with H2O (10 mL) and the aqueous layer extracted with diethyl ether (3 × 15 mL). The organic layers were combined and washed with H2O (25 mL) and brine (25 mL) and dried with anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by silica gel column chromatography (pentane/diethyl ether, 9:1) to yield 14 as a colourless oil (0.911 g, 86%). (see Figure S6 for 1H and 13C NMR spectra).
Spectroscopic analysis of 14: Rf = 0.60 (pentane/diethyl ether, 4:1); [α]D20 = −3.4 (c = 1.0, CHCl3); IR (neat): νmax = 2926, 2854, 1454, 1217, 1095 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.39–7.26 (m, 5 H), 4.59 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 3.61 (d, J = 11.1 Hz, 1 H), 3.47 (d, J = 11.1 Hz, 1 H), 2.71 (d, J = 4.8 Hz, 1 H), 2.64 (d, J = 4.8 Hz, 1 H), 1.87–1.75 (m, 1 H), 1.61–1.50 (m, 1 H), 1.42–1.17 (m, 14 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 138.0, 128.3, 127.7, 127.6, 73.2, 71.9, 58.6, 50.3, 32.0, 31.9, 29.7, 29.49, 29.5, 29.3, 24.6, 22.6, 14.1 ppm; HRMS (ESI-TOF): calcd. for C19H30O2Na [M + Na]+ 313.2144; found 313.2153.

4.6. 2-(2-Bromopropyl)-1,3-dioxane (15)

Anhydrous acetonitrile (50 mL) was added to a 250 mL RBF containing a magnetic stirrer bar under an inert nitrogen atmosphere and cooled to 0 °C. Crotonaldehyde (16) (4.1 mL, 50 mmol) was added followed by dropwise addition of TMSBr (7.9 mL, 60 mmol) and the reaction mixture was stirred for 5 min prior to the dropwise addition of propan-1,3-diol (17) (4.3 mL, 60 mmol). The reaction mixture was stirred for 2.5 h at 0 °C, the warmed to room temperature and quenched into a solution of pentane (150 mL) and Na2CO3 (50 mL, 10% w/v). The solution was stirred for 5 min and added to a separating funnel. Three layers were observed, the top layer containing pentane and the product, the middle layer containing acetonitrile and the product and the bottom aqueous layer. The aqueous layer was run-off and extracted with pentane (10 mL) and sodium thiosulfate (50 mL, 10% w/v). The organic fractions were combined, washed with water (3 × 60 mL) and dried with anhydrous Na2SO4. Excess solvent was removed in vacuo and the remaining yellow solution was purified by high-vacuum distillation (bath temperature 105 °C, neck temperature 72 °C) to yield 15 as a colourless oil (8.66 g, 83%). (see Figure S7 for 1H and 13C NMR spectra).
Spectroscopic analysis of 15: Rf = 0.38 (pentane/diethyl ether, 9:1); IR (neat): νmax = 2964, 2856, 1379, 1140 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.70 (dd, J = 7.1, 3.4 Hz, 1 H), 4.32–4.14 (m, 1 H), 4.13–3.98 (m, 2 H), 3.85–3.64 (m, 2 H), 2.22–1.86 (m, 3 H), 1.68 (d, J = 6.8 Hz, 3 H), 1.38–1.24 (m, 1 H) ppm; 13C NMR (101 MHz, CDCl3) δ 100.5, 66.7, 46.0, 45.6, 26.7, 25.7 ppm; HRMS (EI-TOF): calcd. for C7H12O279Br [M−H]+ 207.0021 and C7H12O281Br [M−H]+ 209.0000; found 207.0023 and 208.9995, respectively. All physical data was identical to those previously reported [5].

4.7. (2S,4S)-4-((Benzyloxy)methyl)-1-(1,3-dioxan-2-yl)-2-methyltridecan-4-ol ((2S,4S)-18) & (2R,4S)-4-((benzyloxy)methyl)-1-(1,3-dioxan-2-yl)-2-methyltridecan-4-ol ((2R,4S)-22)

The Grignard reagent was prepared by addition of bromide 15 (1.941 g, 9.285 mmol) to a dry 25 mL two-necked RBF containing a magnetic stirrer bar, magnesium turnings (0.226 mg, 9.285 mmol) and a crystal of I2 in anhydrous THF (9 mL) under an inert nitrogen atmosphere followed by heating to reflux for 1.5 h min. The solution was cooled to room temperature then transferred by cannula to a dry 25 mL two-necked RBF containing copper (I) iodide (0.059 g, 0.310 mmol) at −45 °C and stirred for 30 min. Benzyl epoxide 14 (0.899 g, 3.095 mmol) in anhydrous THF (3 mL) was added dropwise over 20 min and stirring was continued for a further 2 h at −45 °C. The reaction was quenched by the addition of solid NH4Cl (0.90 g) and saturated NH4Cl solution (5 mL) and the solution was stirred at room temperature for 10 min. The solution was extracted with ethyl acetate (6 × 30 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL) and dried with anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by silica gel column chromatography (pentane/dichloromethane/ether, 5.5:3:1.5, repeated three times) to yield (2S,4S)-18 as a colourless oil (0.397 g, 30%), (2R,4S)-22 as a colourless oil (0.424 g, 33%) and a mixture (0.072 g, 6%). (see Figure S8 for 1H and 13C NMR spectra of compound 8 and Figure S9 for 1H and 13C NMR spectra of compound 22).
Spectroscopic analysis of (2S,4S)-18: Rf = 0.38 (pentane/diethyl ether, 1:1); [α]D20 = −3.5 (c = 0.7, CHCl3); IR (neat): νmax = 3446, 2962, 2852, 1454, 1261, 1088 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38–7.24 (m, 5 H), 4.62–4.47 (m, 3 H), 4.08 (dd, J = 12.1, 4.9 Hz, 2 H), 3.72 (td, J = 12.1, 2.4 Hz, 2 H), 3.34 (d, J = 8.9 Hz, 1 H), 3.30 (d, J = 8.9 Hz, 1 H), 2.45 (s, 1 H), 2.13–1.99 (m, 1 H), 1.87 (dtd, J = 13.5, 6.8, 4.6 Hz, 1 H), 1.68–1.59 (m, 1 H), 1.58–1.42 (m, 5 H), 1.38 (dd, J = 14.5, 7.1 Hz, 1 H), 1.34–1.16 (m, 14 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 138.3, 128.3, 127.6, 127.5, 101.3, 75.6, 74.3, 73.3, 66.8, 66.8, 43.7, 43.2, 37.5, 31.9, 30.3, 29.6, 29.6, 29.3, 25.8, 24.0, 23.6, 22.7, 22.6, 14.1 ppm; HRMS (ESI-TOF): calcd. for C26H44O4 [M + Na]+ 443.3137; found 443.3120.
Spectroscopic analysis of (2R,4S)-22: Rf = 0.32 (pentane/diethyl ether, 1:1); [α]D20 = + 3.2 (c = 0.55, CHCl3); IR (neat): νmax = 3452, 2960, 2852, 1454, 1263, 1109 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37–7.22 (m, 5 H), 4.60–4.44 (m, 3 H), 4.06 (dd, J = 12.1, 4.2 Hz, 2 H), 3.71 (td, J = 12.1, 2.4 Hz, 2 H), 3.32 (d, J = 8.9 Hz, 1 H), 3.28 (d, J = 8.9 Hz, 1 H), 2.47 (s, 1 H), 2.13–1.95 (m, 1 H), 1.85 (dt, J = 13.4, 6.7, 4.6 Hz, 1 H), 1.69–1.56 (m, 1 H), 1.55–1.40 (m, 5 H), 1.36 (dd, J = 14.5, 7.0 Hz, 1 H), 1.33–1.14 (m, 14 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 138.3, 128.3, 127.5, 127.5, 101.4, 75.8, 74.3, 73.3, 66.8, 66.8, 43.5, 43.4, 37.4, 31.8, 30.3, 29.6, 29.5, 29.3, 25.8, 24.0, 23.6, 22.7, 22.6, 14.1 ppm; HRMS (ESI-TOF): calcd. for C26H44O4 [M + Na]+ 443.3137; found 443.3125.

4.8. (2S,4R)-2-((Benzyloxy)methyl)-6-methoxy-4-methyl-2-nonyltetrahydro-2H-pyran (23/24)

Dioxane (2R,4S)-22 (0.230 g, 0.547 mmol) and ZrCl4 (0.013 g, 0.055 mmol) was dissolved in anhydrous methanol (0.6 mL) in a 10 mL microwave vial containing a stirrer bar and stirred under microwave irradiation at 50 °C at 100 W for 6 min. The crude product was purified directly by silica gel column chromatography (pentane/diethyl ether, 9:1) to yield 23 and 24 as an inseparable mixture of colourless oils (0.184 g, 89%). (see Figure S10 for 1H and 13C NMR spectra of compounds 23/24).
Spectroscopic analysis carried out on pure mixture 23/24: Rf = 0.28 (pentane/diethyl ether, 9:1); [α]D20 = −31.9 (c = 1.0, CHCl3); IR (neat): νmax = 2929, 2854, 1454, 1101, 1053 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.21 (m, 5 H), 4.79 (d, J = 3.5 Hz, 1 H), 4.61–4.52 (m, 3 H), 4.49 (dd, J = 9.8, 2.3 Hz, 1 H), 3.48–3.37 (m, 4 H), 3.31–3.22 (m, 1 H), 2.12–1.94 (m, 1 H), 1.93–1.40 (m, 5 H), 1.37–0.80 (m, 25 H) ppm; 13C NMR (101 MHz, CDCl3) δ 138.8, 138.8, 128.4, 128.4, 127.8, 127.6, 127.6, 99.9, 97.9, 77.4, 77.3, 76.5, 76.0, 73.6, 56.0, 55.7, 40.5, 39.9, 39.1, 39.0, 35.3, 32.1, 30.9, 30.6, 30.4, 29.8, 29.8, 29.5, 25.2, 24.6, 22.8, 22.6, 22.3, 19.9, 14.3 ppm; HRMS (ESI-TOF): calcd. for C24H40O3Na [M + Na]+ 399.2875; found 399.2865.

4.9. (2S,4S)-2-((Benzyloxy)methyl)-6-methoxy-4-methyl-2-nonyltetrahydro-2H-pyran (19/20)

Dioxane (2S,4S)-18 (0.291 g, 0.691 mmol) was subjected to the same procedure as 22. The crude product was purified directly by silica gel column chromatography (pentane/diethyl ether, 9:1) to yield 19 and 20 as an inseparable mixture of colourless oils (0.240 g, 92%). (see Figure S11 for 1H and 13C NMR spectra of compounds 19/20).
Spectroscopic analysis carried out on pure mixture 19/20: Rf = 0.75 (pentane/ethyl acetate, 9:1); [α]D20 = −18.3 (c = 0.5, CHCl3); IR (neat): νmax = 2923, 2853, 1454, 1376 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.27 (m, 5 H), 4.73 (d, J = 3.4 Hz, 1 H), 4.58–4.51 (m, 3 H), 3.69 (d, J = 9.0 Hz, 1 H), 3.56–3.40 (m, 3 H), 3.36 (s, 3 H), 1.93 (m, 1 H), 1.83–1.47 (m, 5 H), 1.39–1.14 (m, 19 H), 1.04–0.81 (m, 9 H) ppm; 13C NMR (101 MHz, CDCl3) δ 138.9, 138.7, 128.5, 128.4, 127.7, 127.6, 127.6, 127.5, 99.7, 98.5, 77.0, 76.3, 73.5, 73.3, 72.7, 70.4, 55.9, 55.5, 40.1, 39.9, 39.6, 39.4, 39.4, 38.8, 32.1, 30.4, 30.4, 29.9, 29.8, 29.8, 29.8, 29.5, 25.5, 23.0, 23.0, 22.9, 22.5, 22.4, 20.3, 14.3 ppm; HRMS (ESI-TOF): calcd. for C24H40O3Na [M + Na]+ 399.2875; found 399.2864.

4.10. (4R,6S)-6-((Benzyloxy)methyl)-4-methyl-6-nonyltetrahydro-2H-pyran-2-one (25)

Acetals 23/24 (0.164 g, 0.436 mmol) were dissolved in CH2Cl2 (13 mL) in a dry 50 mL Schlenk tube containing a magnetic stirrer bar and cooled to 0 °C. m-CPBA (0.113 g, <77%, 0.653 mmol) was added followed by BF3·OEt2 (0.070 mL, 0.566 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled back to 0 °C, quenched slowly with Et3N (0.30 mL, 2.18 mmol) and stirred for 30 min. Excess solvent removed in vacuo. The crude product residue was purified by silica gel column chromatography (pentane/diethyl ether, 4:1) to yield 25 as a colourless oil (0.066 g, 42%). (see Figure S12 for 1H and 13C NMR spectra).
Spectroscopic analysis of 25: Rf = 0.36 (pentane/diethyl ether, 3:2); [α]D20 = −7.0 (c = 0.9, CHCl3); IR (neat): νmax = 2929, 2856, 1720, 1454, 1215, 1099 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44–7.22 (m, 5 H), 4.62 (d, J = 12.1 Hz, 1 H), 4.54 (d, J = 12.1 Hz, 1 H), 3.46 (s, 2 H), 2.62–2.51 (m, 1 H), 2.16–1.97 (m, 2 H), 1.81 (dd, J = 13.6, 3.5 Hz, 1 H), 1.74–1.54 (m, 3H), 1.48–1.17 (m, 14 H), 1.04 (d, J = 6.0 Hz, 3 H), 0.90 (t, J = 6.7 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 171.8, 138.0, 128.4, 127.6, 127.6, 85.1, 75.2, 73.6, 38.2, 37.6, 36.3, 31.8, 30.0, 29.5, 29.4, 29.2, 24.0, 23.3, 22.6, 21.2, 14.1 ppm; HRMS (ESI-TOF): calcd. for C23H36O3Na [M + Na]+ 383.2562; 383.2574.

4.11. (4.S,6S)-6-((Benzyloxy)methyl)-4-methyl-6-nonyltetrahydro-2H-pyran-2-one (21)

Acetals 19/20 (0.212 g, 0.563 mmol) were subjected to the same procedure as 23/24. The crude product residue was purified by silica gel column chromatography (pentane/diethyl ether, 4:1) to yield 21 as a colourless oil (0.106 g, 52%). (see Figure S13 for 1H and 13C NMR spectra).
Spectroscopic analysis of 21: Rf = 0.29 (pentane/ethyl acetate, 95:5); [α]D20 = + 27.75 (c = 0.55, CHCl3); IR (neat): νmax = 3017, 2963, 2855, 1717, 1455 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.26 (m, 5 H), 4.56–4.44 (m, 2 H), 3.44 (s, 2 H), 2.61–2.53 (m, 1 H), 2.22–2.08 (m, 1 H), 2.05–1.97 (m, 1 H), 1.88 (dd, J = 17.5, 12.1 Hz, 1 H), 1.72–1.53 (m, 2 H), 1.45–1.18 (m, 15 H), 0.96 (d, J = 6.4 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 171.7, 137.9, 128.6, 127.9, 127.8, 84.7, 74.1, 73.7, 39.3, 38.4, 37.2, 32.0, 30.0, 29.7, 29.5, 23.9, 22.8, 22.8, 21.7, 14.3 ppm; HRMS (ESI-TOF): calcd. for C23H36O3Na [M + Na]+ 383.2562; found 383.2558.

4.12. (4. R,6S)-4-Methylmalyngolide (8)

In a 10mL conical flask containing a magnetic stirrer bar, protected lactone 25 (0.045 g, 0.125 mmol) was dissolved in ethyl acetate (2 mL) and Pd(OH)2/C (20 wt.%) (0.0018 g, 0.0125 mmol) was added. The reaction vessel was placed in a Parr reactor under 25 bar H2 pressure for 72 h. The reaction was monitored by TLC (pentane/diethyl ether, 1:1). Upon reaction completion, the crude product was run through a small silica gel column (ethyl acetate) to yield (4R, 6S)-4-methylmalyngolide 8 as a colourless oil (0.022 mg, 65%). (see Figure S14 for 1H and 13C NMR spectra).
Spectroscopic analysis of 8: Rf = 0.08 (pentane/diethyl ether, 1:1); [α]D20 = −14.8 (c = 0.7, CHCl3); IR (neat): νmax = 3423, 2924, 2854, 1722, 1458, 1377, 1246, 1088 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.68 (d, J = 12.0 Hz, 1H), 3.50–3.41 (m, 1H), 2.60 (ddd, J = 17.2, 4.4, 2.2 Hz, 1H), 2.16–2.03 (m, 1H), 1.97 (dd, J = 17.2, 12.0 Hz, 1H), 1.79–1.67 (m, 2H), 1.64–1.51 (m, 2H), 1.42 (s, 1H), 1.37–1.19 (m, 14H), 1.03 (d, J = 6.3 Hz, 3H), 0.87 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 171.6, 86.6, 67.7, 38.1, 36.5, 34.6, 31.8, 30.0, 29.5, 29.4, 29.2, 23.8, 23.5, 22.6, 21.4, 14.1 ppm; HRMS (ESI-TOF): calcd. for C16H30O3Na [M + Na]+ 293.2093; found 293.2088.

4.13. (4S,6S)-4-Methylmalyngolide (7)

Protected lactone 21 (0.075 g, 0.208 mmol) was subjected to the same procedure as 25. Upon reaction completion, the crude product was run through a small silica gel column (ethyl acetate) to yield (4S,6S)-4-methylmalyngolide 7 as a colourless oil (0.053 mg, 94%). (see Figure S15 for 1H and 13C NMR spectra).
Spectroscopic analysis of 7: Rf = 0.10 (pentane/diethyl ether, 1:1); [α]D20 = + 45.3 (c = 0.35, CHCl3); IR (neat): νmax = 3018, 2928, 1711, 1215 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.64 (d, J = 11.7 Hz, 1 H), 3.58 (d, J = 11.7 Hz, 1 H), 2.59 (ddd, J = 17.4, 4.5, 2.3 Hz, 1 H), 2.29–2.17 (m, 1 H), 1.95–1.84 (m, 2 H), 1.69–1.57 (m, 2 H), 1.43–1.18 (m, 16 H), 0.99 (d, J = 6.3 Hz, 3 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm; 13C NMR (101 MHz, CDCl3) δ 172.1, 86.1, 68.0, 38.4, 38.4, 37.1, 32.0, 30.0, 29.6, 29.4, 24.4, 23.1, 22.8, 21.6, 14.2 ppm; HRMS (ESI-TOF): calcd. for C16H30O3Na [M + Na]+ 293.2093; found 293.2080.

5. Materials and Methods—Biological Testing

5.1. Preparation of Compounds

Samples were reconstituted into an appropriate volume of DMSO to achieve a final concentration of 10 mg/mL.

5.2. Antibacterial Activity Testing—Determination of Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC)

Samples of each of these chemical compounds were reconstituted into an appropriate volume of DMSO to achieve a final concentration of 10 mg/mL. MIC values for these compounds was determined by two-fold broth microdilution in 96-well microtiter plates. Briefly, overnight cultures of Escherichia coli ATCC 25922, Escherichia coli 4, MRSA ATCC 43300 and MRSA 06/04 (see Table S1 for further information about the isolates) were diluted in sterilised PBS to approximately 105 CFU/mL. Aliquots of 5 µL were then transferred to separate wells in a 96-well plate that contained 100 µL of each compound at varying concentrations (ranging from 100–0.195 μg/mL) prepared from two-fold serial dilutions in Mueller-Hinton (MH) broth. Plates were incubated at 37 °C for 18 h using an Omnilog® automated incubator (Biolog Inc.;21124 Cabot Boulevard, Hayward, CA 94545, USA) and MIC values recorded.
Determination of the MBC values for all compounds tested above was performed in MH broth media. Again, 5µL were collected from the MICs 96-well plates (above) and re-inoculated into fresh sterile 96-well plates containing fresh MH. Plates were incubated under the same conditions mentioned above. The assay was performed in triplicate for each compound. (see Table S1 for UCD Centre for Food Safety strains used for determination of antibacterial activity and Table S2 for Antibacterial activity of compounds tested – MIC and MBC results (triplicates)).

Supplementary Materials

The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/ijms22126400/s1. Figure S1: SFC Chromatograms of Reference and Intermediate 14; Figure S2: 1H NMR and 13C NMR Spectra of Compound 10; Figure S3: 1H NMR and 13C NMR Spectra of Compound 11; Figure S4: 1H NMR and 13C NMR Spectra of Compound 12; Figure S5: 1H NMR and 13C NMR Spectra of Compound 13; Figure S6: 1H NMR and 13C NMR Spectra of Compound 14; Figure S7: 1H NMR and 13C NMR Spectra of Compound 15; Figure S8: 1H NMR and 13C NMR Spectra of Compound 18; Figure S9: 1H NMR and 13C NMR Spectra of Compound 22; Figure S10: 1H NMR and 13C NMR Spectra of Compounds 23/24; Figure S11: 1H NMR and 13C NMR Spectra of Compounds 19/20; Figure S12: 1H NMR and 13C NMR Spectra of Compound 25; Figure S13: 1H NMR and 13C NMR Spectra of Compound 21; Figure S14: 1H NMR and 13C NMR Spectra of Compound 8; Figure S15: 1H NMR and 13C NMR Spectra of Compound 7.

Author Contributions

Conceptualisation, P.J.G.; synthetic methodology, J.B., C.K. and R.D.; biological testing J.A. and M.M.; writing—original draft preparation, C.K.; writing—review and editing, P.J.G.; supervision, P.J.G. and S.F.; project administration, P.J.G.; funding acquisition, P.J.G. All authors have read and agreed to the published version of the manuscript.

Funding

J.B. is grateful for the award of an IRCSET/LEO Pharma Enterprise Partnership Scheme Postgraduate Research Scholarship (EPSPG/2012/350). This publication has emanated from research conducted with the financial support of the Synthesis and Solid State Pharmaceutical Centre (SSPC), funded by Science Foundation Ireland (SFI) under grant numbers 12\RC\2275. C.K. is grateful for the award of a SSPC Ph.D. Scholarship. R.D. is grateful for the award of an Irish Research Council (IRC) EMBARK Initiative PhD Scholarship (RS/2010/2191).

Acknowledgments

Facilities were provided by the Centre for Synthesis and Chemical Biology (CSCB), funded by the Higher Education Authority’s PRTLI. The authors wish to thank Yannick Ortin of the UCD NMR Centre in the School of Chemistry/CSCB for help with NMR spectroscopic studies.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 22 06400 g001 550
Figure 1. (+)-Tanikolide and (−)-malyngolide.
Figure 1. (+)-Tanikolide and (−)-malyngolide.
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Ijms 22 06400 g002 550
Figure 2. β-Methyl-(+)-tanikolide based analogues 3–6.
Figure 2. β-Methyl-(+)-tanikolide based analogues 3–6.
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Ijms 22 06400 g003 550
Figure 3. Synthesis of malyngolide analogues 7 and 8.
Figure 3. Synthesis of malyngolide analogues 7 and 8.
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Table
Table 1. Antibacterial activity of 3–6—MIC and MBC results (triplicates) [a].
Table 1. Antibacterial activity of 3–6—MIC and MBC results (triplicates) [a].
CompoundE. coli 25922E. coli 4MRSA ATCC 43300MRSA 06/04
MIC [b]MBCMICMBCMICMBCMICMBC
3>100>100>100>100>100>100>100 *>100
4>100>100>100>100>100>100>100 *>100
5>100>100>100>10012.512.512.550
6>100>100>100>100>100>100>100 *>100
[a] * denotes a change in strain phenotype [b] MIC—minimum inhibitory concentration, MBC—minimum bactericidal concentration. Values are given in μg/mL. Bold-face values denote compounds that showed activity against the tested bacteria. The maximum concentration of compound tested in each case was 100 μg/mL.
Table
Table 2. The MIC and MBC measurements for compounds 7 and 8.
Table 2. The MIC and MBC measurements for compounds 7 and 8.
CompoundE. coli 25922E. coli 4MRSA ATCC 43300MRSA 06/04
MIC [a]MBCMICMBCMICMBCMICMBC
7>100>100>100>10050505050
8>100>100>100>100501005050
[a] MIC—minimum inhibitory concentration, MBC—minimum bactericidal concentration. Values are given in μg/mL. Bold-face values denote compounds that showed activity against the tested bacteria. The maximum concentration of compound tested in each case was 100 μg/mL.
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Breheny, J.; Kingston, C.; Doran, R.; Anes, J.; Martins, M.; Fanning, S.; Guiry, P.J. Investigation of the Anti-Methicillin-Resistant Staphylococcus aureus Activity of (+)-Tanikolide- and (+)-Malyngolide-Based Analogues Prepared by Asymmetric Synthesis. Int. J. Mol. Sci. 2021, 22, 6400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126400

AMA Style

Breheny J, Kingston C, Doran R, Anes J, Martins M, Fanning S, Guiry PJ. Investigation of the Anti-Methicillin-Resistant Staphylococcus aureus Activity of (+)-Tanikolide- and (+)-Malyngolide-Based Analogues Prepared by Asymmetric Synthesis. International Journal of Molecular Sciences. 2021; 22(12):6400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126400

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Breheny, Joseph, Cian Kingston, Robert Doran, Joao Anes, Marta Martins, Séamus Fanning, and Patrick J. Guiry. 2021. "Investigation of the Anti-Methicillin-Resistant Staphylococcus aureus Activity of (+)-Tanikolide- and (+)-Malyngolide-Based Analogues Prepared by Asymmetric Synthesis" International Journal of Molecular Sciences 22, no. 12: 6400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126400

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