MDN-0185, an Antiplasmodial Polycyclic Xanthone Isolated from

Note Cite This: J. Nat. Prod. 2018, 81, 1687−1691

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MDN-0185, an Antiplasmodial Polycyclic Xanthone Isolated from Micromonospora sp. CA-256353 Frederick Annang,†,§ Ignacio Peŕ ez-Victoria,†,§ Guiomar Peŕ ez-Moreno,‡ Elizabeth Domingo,† Ignacio Gonzaĺ ez,† Jose ́ Rubeń Tormo,† Jesús Martín,† Luis M. Ruiz-Peŕ ez,‡ Olga Genilloud,† Dolores Gonzaĺ ez-Pacanowska,‡ Francisca Vicente,† and Fernando Reyes*,† †

Fundación MEDINA, Avenida del Conocimiento 34, 18016, Armilla, Granada, Spain Instituto de Parasitología y Biomedicina “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avenida del Conocimiento s/n, 18016, Armilla, Granada, Spain

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‡

S Supporting Information *

ABSTRACT: A potent antiplasmodial polycyclic xanthone, MDN-0185 (1), was isolated from an unidentified species of the genus Micromonospora. The planar structure of 1 was established as a seven-ring polycyclic xanthone with partial structures very similar to two known natural products, namely, xantholipin and Sch 54445. Using ROESY correlations, the relative stereochemistry of the two independent stereoclusters of compound 1 could be determined. Mosher analysis and comparison of the specific rotation of compound 1 with that of xantholipin allowed the determination of its absolute configuration. Compound 1 exhibited an IC50 of 9 nM against Plasmodium falciparum 3D7 parasites.

M

(AB981051), using EzBiocloud and GenBank sequence similarity searches and homology analysis.7,8 The morphological, 16S rRNA gene sequence and phylogenetic data were indicative that this strain was representative of members of the genus Micromonospora, and the strain was referred to as Micromonospora sp. CA-256353. From bioassay-guided chromatography of the active crude extract obtained from a 3 L fermentation broth of this strain, a new polycyclic xanthone, dubbed MDN-0185 (1), was obtained.

alaria continues to plague about half of the world’s population, with the most vulnerable group being children under five years and pregnant women in poor African countries.1,2 Development of drug resistance in the parasites is a real problem in malaria control. With the current reports of delayed parasite clearance against artemisinin along the Thai− Cambodia boarder, any gains made in malaria control will be short-lived if this delayed clearance develops into a full artemisinin resistance and spreads to other parts of the world.3 Although the past decade has seen an upsurge in international research collaborations toward finding the next generation of antimalarial drugs, there is still a significant lack in novel compound scaffolds in the current antimalarial drug portfolios. Natural products, however, have continued to serve as a reliable source of novel chemistry based on which potent antimalarial drugs are developed.4,5 In a recent screening campaign, the bioactivity of 22 000 crude microbial extracts from the Fundación MEDINA’s extracts collection was evaluated in a Plasmodium falciparum lactate dehydrogenase whole cell assay.6 Herein we report the isolation of a new potent antiplasmodial polycyclic xanthone, MDN-0185 (1), from one of the microbial extracts identified as active. The extract-producing actinomycete strain was obtained from a mud sample collected in the riverbed of Torrent de la Mola (Formentera, Spain). The almost-complete 16S rRNA gene sequence (1401 nucleotides) of strain CA-256353 was compared with those deposited in public databases and the EzBiocloud server.7,8 This newly identified strain exhibited the highest similarity (99.42%) with Micromonospora soli SL3-70T © 2018 American Chemical Society and American Society of Pharmacognosy

Compound 1 was isolated as a yellowish powdery solid with IR absorptions at 3403, 1704, and 1635 cm−1 indicative of the presence of hydroxy, carbonyl, and conjugated carbonyl functional groups. ESI-TOF mass spectrometry of 1 showed a protonated molecular ion [M + H]+ at m/z 508.1243, in agreement with a molecular formula of C26H21NO10, indicating 17 degrees of unsaturation in the molecule. LC-ESI-TOF Received: April 24, 2018 Published: June 20, 2018 1687

DOI: 10.1021/acs.jnatprod.8b00323 J. Nat. Prod. 2018, 81, 1687−1691

Journal of Natural Products

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accounted for only 10 of these degrees, namely, four carbonyl carbons at δC 160.2 (C-1), 195.2 (C-6), 193.1 (C-17), 201.1 (C-29) and 12 olefinic carbons at δC 153.1 (C-3), 99.3 (C-4), 145.2 (C-5), 132.9 (C-13), 133.1 (C-14), 113.8 (C-15), 121.0 (C-18), 149.2 (C-19), 105.6 (C-20), 148.9 (C-21), 127.0 (C25), and 128.4 (C-26), thus indicating that compound 1 had a heptacyclic ring structure. The NMR data (Table 1) showed 21 protons, including one sp3 singlet methyl at δH 2.22 (CH330, δC 19.5), two sp3 methylenes at δH 2.62, 2.48 (CH2-8, δC 22.5) and 2.53, 2.11 (CH2-27, δC 25.0), a dioxygenated sp3 methylene at δH 5.36, 5.32 (CH2-11, δC 91.1), two sp3 methines at δH 3.59 (CH-7, δC 54.2) and 3.22 (CH-28, δC 38.4), three oxygenated sp3methines at δH 5.21 (CH-9, δC 69.1), 4.51 (CH-23, δC 79.9), and 4.24 (CH-24, δC 63.2), and three sp2 olefinic methines at δH 6.16 (CH-4, δC 99.3), 5.73 (CH-25, δC 127.0), and 5.76 (CH-26, δC 128.4). Additionally, four protons attached to heteroatoms at δH 12.31, 6.19, 11.70 and 5.22, could also be observed according to the absence of HSQC correlations. HMBC correlations were used to establish the attachment of the three hydroxy groups at δH 6.19, 11.70, and 5.22 to carbons C-16 (δC 76.1), C-19 (δC 149.2), and C24 (δC 63.2), respectively. The low-field chemical shift of the 19-OH was due to the possible formation of a hydrogen bond between this group and the oxygen of the neighboring ketone group at C-29 (δC 201.1). The low-field proton at δH 12.31 was identified as an NH group at position 2 of the molecule. HMBC correlations between H3-30 and C-4; H-4 and C-3/C6/C-18/C-30; H-2 and C-4/C-18; H-7 and C-6/C-8/C-9/C15/C-16; H-8a and C-6/C-7/C-9/C-16; H-8b and C-6/C-14; H-9 and C-8/C-13/C-14; H-11a/b and C-9/C-13/C-14; and 16-OH and C-7/C-15/C-16/C-17 led to the proposal of substructure X as part of compound 1. Substructure X was very similar to the ABCD substructural ring motif of xantholipin (Figure 1). Additional HMBC correlations between H-24 and C-23/C-25/C-26; H-25/H-26 and C-23/C-24/C-27/C-28; H27a and C-23/C-25/C-28; H-27b and C-25/C-28/C-29; H-28 and C-23/C-24/C-27/C-29; H-23 and C-27/C-29; and 19-

dereplication using the strategies implemented at Fundación MEDINA9 matched the molecular formula C26H21NO10 to a known polycyclic xanthone (antibiotic SF 2446B3). However, comparing the 1H NMR data of compound 1 to those of antibiotic SF 2446B310 showed significant differences between the two. Among others, signals for the two methoxy groups present in the structure of SF 2446B3 were not observed in the 1 H NMR spectrum of 1, confirming their structural difference. The IR, molecular formula, and dereplication hit (antibiotic SF 2446B3) obtained for compound 1 were suggestive that 1 might be a polycyclic xanthone; hence, its 13C and 2D NMR data (HSQC, HMBC, COSY, and ROESY) were acquired (Table 1) and compared to the NMR data of xantholipin11 and Sch 54445,12 two known polycyclic xanthones that seemed to share common structural features with the new compound. Although the molecular formula of compound 1 indicated 17 degrees of unsaturation, signals in the 13C NMR spectrum Table 1. NMR Spectroscopic Data (500 MHz, DMSO-d6 at 24 °C) of Compound 1 position

δC, type

1 2-NH 3 4 5 6 7

160.2, C

8

22.5, CH2

9

69.1, CH

11

91.1, CH2

13 14 15 16 16-OH 17 18 19 19-OH 20 21 23 24

132.9, C 133.1, C 113.8, C 76.1, C

24-OH 25 26 27

28 29 30

153.1, C 99.3, CH 145.2, C 195.2, C 54.2, CH

δH (J in Hz)

HMBC (H to C)

ROESY

12.31, br s

4, 18

6.16, br s

3, 6, 18, 30

3.59, br d (7.9)

6, 8, 9, 15, 16, 8b, 16-OH 17 6, 7, 9, 16 7, 9 6, 7, 9, 14

a 2.62, m b 2.48 ddd (13.5, 10.2, 8.5)a 5.21, dd (9.9, 7.0)

8, 13, 14

30

a 5.36 d (5.8) b 5.32 d (5.8)

9, 13 9, 13

8b, 11b, 16OH 11b 9, 11a

6.19, br s

7, 15, 16, 17

7, 9

11.7, s

15, 19, 20

193.1. C 121.0, C 149.2, C 105.6, C 148.9, C 79.9, CH 63.2, CH

4.51, dd (14.1, 3.5) 4.24, br ddd (7.0, 6.0, 3.5) 5.22, d (6.1) 127.0, CH 5.73, br d (11.5) 128.4, CH 5.76, br d (11.5) 25.0, CH2 a 2.53, ddd (18.2, 7.0, 1.2)a b 2.11, dd (18.2, 10.2) 38.4, CH 3.22, ddd (14.0, 10.5, 6.4) 201.1, C 19.5, CH3 2.22, br s

27, 29 23, 25, 26, 28 23, 23, 24, 23,

24, 25 24, 27 27, 28 25, 26, 28

24, 27b 23, 24-OH, 25 24, 28 24 27a, 27b 26, 28

25, 26, 28, 29

26

23, 24, 27, 29

24-OH, 27a

3, 4

4

Figure 1. HMBC correlations leading to substructures X and Y of compound 1. Subtructures X and Y were respectively found to be identical to the ABCD ring system of xantholipin and the EFG ring system of Sch 54445.

a

Half of the multiplet overlaps with the residual solvent signal. 1688



Note

OH and C-15/C-19/C-20 led to the proposal of the complementary substructure Y for the compound. Substructure Y was also very similar to the EFG ring system of Sch 54445 (Figure 1), except that substructure Y has a hydroxy group at C-24, as confirmed by HMBC correlations between the 24-OH and C-23/C-25, whereas the EFG substructural ring motif of Sch 54445 has a hydroxy group at C-27 in addition to a methoxy group at C-24. From Figure 1, it could clearly be seen that the fully substituted benzene ring E is the part that links the two substructures X and Y, hence completing the planar structure of compound 1. The relative configuration of the independent stereoclusters in rings C and G (Figure 2) was established by analysis of

Figure 3. ΔδSR values (in Hz) measured for the MTPA esters of compound 1.

stereoclusters. Theoretical calculations of electronic circular dichroism (ECD) spectra using the time-dependent density functional theory methodology and comparison with the experimental spectrum did not lead to conclusive results. However, the specific rotation measured for compound 1 ([α]D −432 (c 0.28, DMSO) immediately indicated that the stereocluster in ring C shares the same absolute configuration found in xantholipin (determined by the modified Mosher’s method after selective reduction of the C-6 carbonyl), which also displays a large negative specific rotation ([α]D −304 (c 0.53, dioxane)) and lacks any chiral center at ring G.11 Polycyclic xanthone natural products such as xantholipin,11 Sch 54445,12 and chrestoxanthone B14 feature an angular fused heptacyclic skeleton in which the helicity of the BCE ring system rotates strongly the plane of polarization of linearly polarized light and dominates the absolute value of the determined specific rotation. Clear evidence for that is provided by comparing chrestoxanthone B ([α]D −411 c 0.02, DMSO) with chrestoxanthone C ([α]D +70.5 c 0.06, DMF)14 (see Figure S10). Chrestoxanthone B is a rigid molecule with a large (in absolute value) specific rotation because it displays a helical twist for the BCE ring system due to the presence of ring D. The absolute chirality at C-9 determines the helicity sense and the sign of the specific rotation (see Figure S10). However, chrestoxanthone C lacks ring D, and thus the middle ring C has conformational freedom. This structural feature translates to the presence in an equimolar ratio of the two possible helicities of the BCE ring system (see Figure S10), hence behaving as a racemic helical system not contributing to the specific rotation, which for this compound is determined by the two chiral centers in ring G resulting in the much smaller (in absolute value) specific rotation of chrestoxanthone C compared to chrestoxanthone B. In the same manner, for compound 1 the contribution of the chiral centers at ring G to the specific rotation is much smaller than the contribution of the helicity of the molecule. Having the same large negative value of specific rotation as xantholipin clearly indicates the same helicity and thus the same absolute configuration 7S, 9R, 16R for the stereocluster in ring C for both molecules. This result is not surprising since compound 1 must be produced by a biosynthetic route analogous to the pathway already reported for xantholipin.15 Polycyclic xanthones belong to a broad polyketide family of natural products characterized by highly oxygenated, angular hexacyclic frameworks.16 Central to this framework is the xanthone moiety, which may be fully aromatic or tetrahydro or hexahydro derivatives of the original xanthone (xanthene-9one).16 Various classes of naturally occurring compounds that contain the xanthone moiety have been isolated from both terrestrial and marine organisms including higher plants, ferns, fungi, and actinobacteria.16 Initial interest in this class of

Figure 2. Key ROESY correlations (blue arrows) employed to determine the relative configuration of stereoclusters in rings C and G in compound 1.

coupling constants and ROESY correlations. In the case of ring C, the through-space correlations H-9/H-7, H-9/16-OH, and H-7/16-OH were identical to those observed in xantholipin for the same protons11 and indicate that H-7, H-9, and the hydroxy 16-OH are all cis oriented on the same face of ring C, thus displaying the same relative configuration found in xantholipin.11 Likewise, chemical shifts and coupling constants observed for H-7 and H-9 in compound 1 (Table 1) also match those observed for xantholipin, providing additional evidence of the same relative configuration of ring C in both compound 1 and xantholipin. Regarding ring G, the ROESY correlations observed for the pairs 24-OH/H-28 and H-23/H-24 alongside the absence of any correlation between 24-OH and H-23 immediately established the relative configuration for ring G (Figure 2). The stereochemistry of the fusion of rings F and G is trans, as is the configuration between H-23 and 24-OH. The absolute configuration of the stereocluster in ring G was determined based on the absolute configuration obtained for C-24 after Mosher ester analysis.13 Reaction of compound 1 with both enantiomers of α-methoxy-α-trifluoromethyl-αphenylacetyl chloride (MTPA-Cl) in dry pyridine yielded the desired monoester derivative at 24-OH as the main product (probably due to steric hindrance of the phenol at C-19). Direct NMR analysis of the derivatization reaction mixture clearly showed the induced shifts in resonance frequencies due to the esterification. The arrangement of ΔδSR values around C-24 (Figure 3 and Table S1) allowed us to propose an R absolute configuration for this chiral center, and hence the absolute configuration for the stereocluster in ring G turned out to be 23S, 24R, 28R according to the relative configuration previously determined by analysis of the ROESY correlations. The configuration relationship between stereoclusters in rings C and G (which would provide the absolute configuration of stereocluster in ring C) cannot be derived by NMR due to the large distance between these independent 1689



Note

Bioassay-Guided Isolation of Metabolites. A 3 L amount of fermentation broth of Micromonospora sp. CA-256353 was produced using the conditions described above. The broth was then extracted with acetone (1:1) by agitation in a Kuhner shaker at 200 rpm, 24 °C, for 1 h, after which the solid biomass was homogenized into the extraction solvent with a hand-held blender. The mixture was then filtered and all the acetone evaporated under a stream of nitrogen gas, leaving an aqueous residue of about 3 L, which was loaded onto an SP207ss resin column (65 g, 32 × 100 mm) that was washed with water and eluted at 20 mL/min with a stepped gradient of acetone in H2O at 10%, 20%, 40%, 60%, 80%, and finally 100% acetone. Each step of the gradient was maintained for 6 min, and three fractions were collected, except the final 100% step, which was maintained for 12 min and six fractions were collected. The fractions together with an aliquot of the crude were subjected to the P. falciparum 3D7 LDH bioassay as described.6 From this assay, six fractions (F8 to F13) were identified to be active against the P. faliciparum 3D7 parasites. Analytical HPLC of these active fractions showed them to have very similar chemical profiles; hence, they were pooled, filtered, dried, redissolved in 2 mL of DMSO, and used to run a preparative reversedphase HPLC (Agilent Zorbax SB-C8, 7 μm, 21.2 × 250 mm, 20 mL/ min, UV detection at 210 and 280 nm) using a linear gradient of CH3CN in H2O from 5% to 50% CH3CN in 45 min. The HPLC fractions generated were tested in the P. falciparum LDH whole parasite assay, and the fraction displaying antiplasmodial activity was subjected to two additional steps of semipreparative HPLC purification (Agilent Zorbax RX-C8 column, 5 μm, 9.4 × 250 mm, 3.6 mL/min, UV detection at 210 and 280) with a 45 min linear gradient from 5% to 100% of CH3CN in H2O, which finally yielded 0.8 mg of pure compound 1 (tR 19.5 min). MDN-0185 (1): yellowish powdery solid with [α]25D −432 (c 0.28, DMSO); IR (ATR) νmax (cm−1) 3403, 1704, 1635, 1600, 1554, 1459, 1410, 1371, 1260, 1148, 1078, 1027; 1H and 13C NMR data see Table 1; (+)-ESI-TOF MS m/z 508.1243 [M + H]+ (calcd for C26H22NO10, 508.1242); 1015.2408 [2M + H] + (calcd for C 52H 45 NO10, 1015.2407). Preparation of the (R)- and (S)-MTPA Ester Derivatives of 1. To a solution of compound 1 (650 μg, 1.28 μmol) in 300 μL of dry pyridine at room temperature was added (R)- or (S)-MTPA-Cl (1.9 μL, 10.15 μmol, 8 equiv). After 24 h analytical HPLC revealed the complete consumption of 1. The reaction solutions were evaporated to dryness, and the resulting crudes were dissolved in DMSO-d6 for direct analysis by NMR. The HSQC spectra of such reaction crudes clearly showed the shifts in the resonance frequency of protons in ring G of compound 1 due to the esterification of 24-OH (see Figure S9). Biological Activity. The IC50 of compound 1 was determined using the P. falciparum 3D7 lactate dehydrogenase assay. This is a whole parasite assay in which the late-ring/early trophozoite intraerythrocytic stage of synchronized P. falciparum 3D7 parasite culture is used. After 72 h of incubation of the parasites with the test compound, the synthetic cofactor APAD+, which is specific to the parasite LDH enzyme,20 is utilized to quantify the proportions of parasite viability by measuring the activity of this intracellular enzyme that is released upon lysis of the parasites. The compound was tested in triplicate using a 16-point dose−response curve of 1/2 serial dilutions with starting and final test compound concentrations of 50 μM and 1.5 nM, respectively, following methodology previously described.6

natural products originally stemmed from their antimicrobial activities; however this interest has expanded over the years to include antiproliferative properties as well as antidepressant, antiviral, antitubercular, cardiotonic, diuretic, choleretic, and cytotoxic activities.16,17 The broad range of potent activities reported for this large natural product family has further fueled pharmacological, biosynthetic, and synthetic chemical studies.16,17 Investigating the biosynthetic pathway for the production of the antitumor agent xantholipin, isolated from Streptomyces f lavogriseus, Zhang et al. identified a 52 kb xantholipin biosynthetic gene cluster with open reading frames that encode polyketide synthase II (PKS II) enzymes, regulators, and polyketide tailoring enzymes.15 They were able to produce nine different xantholipin analogues by inframe mutagenesis of five tailoring enzymes, thus shedding some light on the general biosynthetic pathways for xantholipin-related compounds such as 1.15 Work by the same group also showed that post-PKS B/C-ring stereogenic center and A-ring amide modifications are key structural features for the antitumoral bioactivity of xantholipin, thus giving some insight into the possible structure−activity relationships of closely related compounds of this family. Compound 1 exhibited a potent IC50 of 9 nM against P. falciparum 3D7 parasites. Interestingly, although the literature reports various classes of polycyclic xanthones with broadspectrum activities, only one member of this family, simaomicin α, has been reported to have an antiplasmodial activity (against P. falciparum K1 strain) with potency comparable to compound 1.18 Due to significant structural differences between the two compounds, MDN-0185 provides an alternative starting point for further development and application in antiplasmodial chemotherapy.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured using a JASCO P-2000 polarimeter. UV spectra were obtained with an Agilent 1100 DAD. IR spectra were recorded on a JASCO FT/IR-4100 spectrometer equipped with a PIKE MIRacle single reflection ATR accessory. NMR spectra were recorded in DMSO-d6 on a Bruker Avance III spectrometer (500 and 125 MHz for 1H and 13C NMR, respectively) equipped with a 1.7 mm TCI MicroCryoProbe (Bruker Biospin). Chemical shifts were reported in ppm using the signals of the residual solvent as internal reference (δH 2.51 ppm and δC 39.5 ppm). ESI-TOF mass spectra were acquired using a Bruker maXis QTOF mass spectrometer, and dereplication was performed as described previously.9,19 Medium-pressure fractionation of crude extracts were performed on a SP207ss resin column using a CombiFlash Rf system. Semipreparative and preparative HPLC separations were performed on Gilson HPLC systems with UV detection at 210 and 280 nm. Culturing Conditions of Micromonospora sp. CA-256353. The first seed culture of the Micromonospora sp. CA-256353 was prepared by inoculating 10 mL of seed medium, which consists of soluble starch (20 g/L), dextrose (10 g/L), NZ amine EKC (Sigma) (5 g/L), Difco beef extract (3 g/L), Bacto peptone (5 g/L), yeast extract (5 g/L), and CaCO3 (1 g/L), adjusted to pH 7.0 with NaOH before addition of CaCO3, in a 40 mL tube with 0.5 mL of a frozen inoculum stock of the producing strain and incubating the tube at 28 °C with shaking at 220 rpm for about 48 h. A second seed culture was prepared by inoculating 50 mL of seed medium in two 250 mL flasks with 2.5 mL of the first seed. A 5% aliquot of the second seed culture was transferred to each of the 20 × 500 mL flasks containing 150 mL of the production medium consisting of dextrin from corn (20 g/L), fructose (5 g/L), peptonized milk (10 g/L), and yeast autolysate (1.5 g/L), pH 7.0. The flasks were incubated at 28 °C for 14 days in a rotary shaker at 220 rpm and 70% humidity before harvesting.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00323. 1D and 2D NMR, HRMS, and UV(DAD) spectra of compound 1, HSQC spectra and 1H NMR data of Mosher ester derivatives of 1, energy-minimized molecular models of chrestoxanthones B and C (PDF) 1690



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Auncharoen, P.; Chutrakul, C.; Vichai, V. Tetrahedron 2016, 72, 775−778. (15) Zhang, W.; Wang, L.; Kong, L.; Wang, T.; Chu, Y.; Deng, Z.; You, D. Chem. Biol. 2012, 19, 422−432. (16) Winter, D. K.; Sloman, D. L.; Porco, J. A., Jr. Nat. Prod. Rep. 2013, 30, 382−391. (17) Peres, V.; Nagem, T. J. Quim. Nova 1997, 20, 388−397. (18) Ui, H.; Ishiyama, A.; Sekiguchi, H.; Namatame, M.; Nishihara, A.; Takahashi, Y.; Shiomi, K.; Otoguro, K.; Omura, S. J. Antibiot. 2007, 60, 220−222. (19) Martín, J.; Crespo, G.; González-Menéndez, V.; Pérez-Moreno, G.; Sánchez-Carrasco, P.; Pérez-Victoria, I.; Ruiz-Pérez, L. M.; González-Pacanowska, D.; Vicente, F.; Genilloud, O.; Bills, G. F.; Reyes, F. J. Nat. Prod. 2014, 77, 2118−2123. (20) Makler, M. T.; Hinrichs, D. J. Am. J. Trop. Med. Hyg. 1993, 48, 205−210.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +34 958 993965. Fax: +34 958 846710. ORCID

Ignacio Pérez-Victoria: 0000-0002-4556-688X Fernando Reyes: 0000-0003-1607-5106 Author Contributions §

F. Annang and I. Pérez-Victoria contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the European Commission FP7 Marie Curie Initial Training Network “ParaMet” (FP7PEOPLE-2011-ITN, GA290080), the Junta de Andalucı ́a (BIO-199, P12-BIO-2059), the Plan Nacional de Investigación Cientı ́fica, Instituto de Salud Carlos III-Subdirección General de Redes y Centros de Investigación Cooperativa-Red de Investigación Cooperativa en Enfermedades Tropicales (RICET: RD16/0027/0014 and RD16/0027/0015), and the Plan Nacional (SAF2016-79957-R). The polarimeter, HPLC, IR, NMR equipment, and plate reader used in this work were purchased via grants for scientific and technological infrastructures from the Ministerio de Ciencia e Innovación [Grant Nos. PCT-010000-2010-4 (NMR), INP-2011-0016-PCT010000 ACT6 (polarimeter, HPLC, and IR), and PCT01000-ACT7, 2011-13 (plate reader)].

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REFERENCES

(1) Guantai, E.; Chibale, K. Malar. J. 2011, 10, S2. (2) Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A. Nat. Rev. Microbiol. 2013, 11, 849−862. (3) World Health Organization Home Page. http://www.who.int/ mediacentre/factsheets/fs375/en (accessed March 5, 2018). (4) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629−661. (5) Beghyn, T.; Deprez-Poulain, R.; Willand, N.; Folleas, B.; Deprez, B. Chem. Biol. Drug Des. 2008, 72, 3−15. (6) Pérez-Moreno, G.; Cantizani, J.; Sánchez-Carrasco, P.; RuizPérez, L. M.; Martín, J.; El Aouad, N.; Pérez-Victoria, I.; Tormo, J. R.; González-Menendez, V.; González, I.; de Pedro, N.; Reyes, F.; Genilloud, O.; Vicente, F.; González-Pacanowska, D. PLoS One 2016, 11, e0145812. (7) EzBiocloud Home Page. https://www.ezbiocloud.net/ (accessed August 23, 2017). (8) Yoon, S. H.; Ha, S. M.; Kwon, S.; Lim, J.; Kim, Y.; Seo, H.; Chun, J. Int. J. Syst. Evol. Microbiol. 2017, 67, 1613−1617. (9) Pérez-Victoria, I.; Martín, J.; Reyes, F. Planta Med. 2016, 82, 857−871. (10) Takeda, U.; Okada, T.; Takagi, M.; Gomi, S.; Itoh, J.; Sezaki, M.; Ito, M.; Miyadoh, S.; Shomura, T. J. Antibiot. 1988, 41, 417−424. (11) Terui, Y.; Yiwen, C.; Jun-ying, L.; Ando, T.; Yamamoto, H.; Kawamura, Y.; Tomishima, Y.; Uchida, S.; Okazaki, T.; Munetomo, E.; Seki, T.; Yamamoto, K.; Murakamia, S.; Kawashima, A. Tetrahedron Lett. 2003, 44, 5427−5430. (12) Chu, M.; Truumees, I.; Mierzwa, R.; Terracciano, J.; Patel, M.; Loebenberg, D.; Kaminski, J. J.; Das, P.; Puar, M. S. J. Nat. Prod. 1997, 60, 525−528. (13) Su, B. N.; Park, E. J.; Mbwambo, Z. H.; Santarsiero, B. D.; Mesecar, A. D.; Fong, H. H.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2002, 65, 1278−1282. (14) Bunyapaiboonsri, T.; Lapanun, S.; Supothina, S.; Rachtawee, P.; Chunhametha, S.; Suriyachadkun, C.; Boonruangprapa, T.; 1691


MDN-0185, an Antiplasmodial Polycyclic Xanthone Isolated from

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