Synthesis, structural assignments and antiinfective activities of 3-O-benzyl-carvotacetone and 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone

Article abstract of DOI:10.1080/14786419.2020.1716346

In an attempt to synthesize carvotacetone analogues, new 3-O-benzyl-carvotacetone (10) and previously reported 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone (11) were synthesized from piperitone (7). In this work, we describe the synthesis of 10 and other

Full text of DOI:10.1080/14786419.2020.1716346

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Synthesis, structural assignments and
antiinfective activities of 3-O-benzyl-carvotacetone
and 3-hydroxy-2-isopropyl-5-methyl-p-
benzoquinone
Veronica M. Masila, Albert J. Ndakala, Robert Byamukama, Jacob O. Midiwo,
Rahab W. Kamau, Mei Wang, Mallika Kumarihamy, Jianping Zhao, Matthias
Heydreich & Ilias Muhammad
To cite this article: Veronica M. Masila, Albert J. Ndakala, Robert Byamukama, Jacob O. Midiwo,
Rahab W. Kamau, Mei Wang, Mallika Kumarihamy, Jianping Zhao, Matthias Heydreich & Ilias
Muhammad (2020): Synthesis, structural assignments and antiinfective activities of 3-O-benzyl-
carvotacetone and 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone, Natural Product Research,
DOI: 10.1080/14786419.2020.1716346
To link to this article: https://doi.org/10.1080/14786419.2020.1716346
Published online: 30 Jan 2020.
Article views: 21
View supplementary material
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gnpl20

NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1716346
Synthesis, structural assignments and antiinfective
activities of 3-O-benzyl-carvotacetone and 3-hydroxy-2-
isopropyl-5-methyl-p-benzoquinone
Veronica M. Masilaa, Albert J. Ndakalab, Robert Byamukamaa, Jacob O. Midiwob,
Rahab W. Kamauc, Mei Wangd, Mallika Kumarihamyd, Jianping Zhaod,
Matthias Heydreiche and Ilias Muhammadd
aDepartment of Chemistry, College of Natural and Applied Sciences, Makerere University, Kampala,
b
Uganda; Department of Chemistry, School of Physical Sciences, University of Nairobi, Nairobi,
c
Kenya; Department of Chemistry, College of Natural and Applied Sciences, University of Dar es
d
Salaam, Dar es Salaam, Tanzania; National Centre for Natural Products Research, Research Institute
e
of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi, USA; Institut
€
€
fur Chemie, Universitat Potsdam, Potsdam, Germany
ABSTRACT
ARTICLE HISTORY
Received 22 October 2019
Accepted 9 January 2020
In an attempt to synthesize carvotacetone analogues, new 3-O-
benzyl-carvotacetone (10) and previously reported 3-hydroxy-2-
isopropyl-5-methyl-p-benzoquinone (11) were synthesized from
piperitone (7). In this work, we describe the synthesis of 10 and
other analogues from 7. Luche reduction of 7 to cis-piperitol (8),
followed by benzylation yielded 3-O-benzyl-piperitol (9). Riley oxi-
dation of 9 afforded corresponding ketone 10, 11 and 3-benzy-
loxy-4-isopropylcyclohex-1-enecarbaldehyde (12). Structures of
these compounds were determined based on NMR, IR and LC-MS
spectral data. Compound 11, exhibited antiplasmodial activities
against chloroquine-sensitive (D6) and resistant (W2) strains of
Plasmodium falciparum with IC50 values of 0.697 and 0.653 mg/mL,
respectively. In addition, compound 11 was active against
Cryptococcus neoformans with an IC50 value of 3.11 mg/mL,
compared to reference standard fluconazole (IC50 value of
1.87 mg/mL), while 10 and 12 were inactive against both organ-
isms. This is the first report of the antiplasmodial and anticrypto-
coccal activity of compound 11.
KEYWORDS
Piperitone; Riley oxidation;
3-hydroxy-2-isopropyl-5-
methyl-p-benzoquinone;
3-O-benzyl-carvotacetone;
anti-plasmodial;
Cryptococcosis
CONTACT Veronica Masila
masilaveronica@gmail.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1716346.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
V. M. MASILA ET AL.
1. Introduction
Malaria is a parasitic disease that affects approximately 219 million and kills 435,000
people each year world wide, majority being children under the age of 5 years and
pregnant women (WHO 2018). The disease is life-threatening and is currently managed
by several drugs of plant origin or their derivatives such as quinine, mefloquine,
chloroquine and artemisinin (White 2007). The P. falciparum parasites are reported to
have developed resistance against some of these drugs (Price et al. 2004). Also, the
quinolines (quinine, chloroquine and mefloquine) have been reported to cause cardio-
toxicity (White 2007), hence the need to identify or develop new antimalarial drugs
which are affordable, less toxic and with different mechanism of action towards the P.
falciparum parasites.
Cryptococcosis, on the other hand, results from a fungal infection of the central
nervous system in immunocompromised and immunocompetent people by
Cryptococcus neoformans (Idnurm et al. 2005). One million cases of Cryptococcal men-
ingitis have been reported annually worldwide with over half a million deaths esti-
mated in endemic areas of sub-Saharan Africa (Park et al. 2009). Commonly used
treatments include the use of amphotericin B and fluconazole as the key antifungal
agents for inductive treatment with the former considered toxic and the latter more
effective but with severe side effects (Mitchell and Perfect 1995; Sar 2004). Other anti-
fungal agents such as allylamines and nystatin are reported to be insufficiently
absorbed and too toxic (Sar 2004), hence the search for new antifungal agents which
are less toxic is highly desirable.
Carvotacetones are monoterpene cyclohexanone derivatives mainly isolated from
fungi, mushrooms, bacteria and worms (Collu et al. 2008). Plants mainly from the
genus Sphaeranthus, have also been reported to contain carvotacetone derivatives
(Figure 1) (Jakupovic et al. 1990; Zdero et al. 1991; Machumi et al. 2012; Tran et al.
2019). Some of these cyclic unsaturated monoterpenes exhibit antimicrobial, antiplas-
modial, antiproliferative and antitumor activities (Marco-Contelles et al. 2004; Machumi
et al. 2012; Tran et al. 2019). They have been reported to be cytotoxic against human
solid tumor cells (Machumi et al. 2012) and other human cancer cell lines (Tran et al.
2018). The cyclohexenone core of these compounds is considered a potential new
class of small molecule “pharmacophore” for antitumor drug leads which targets
multi-drug resistant (MDR) tumours (Collu et al. 2008).
3-Acetoxy-5,7-dihydroxycarvotacetone (4) has been reported to possess anti-plas-
modial activity with IC50 values of 0.60 and 0.68 mg/mL against chloroquine sensitive
(D6) and chloroquine resistant (W2) strains of P. falciparum, respectively (Machumi
et al. 2012). In addition, compound 4 and its analog 3 also displayed cytotoxicity to
various human solid tumor cells (Machumi et al. 2012). 3-Angeloyloxy-5-[3-chloro-2-
hydroxy-2-methylbutanoxy]-7-hydroxycarvotacetone (5) and 5-angeloyloxy-7-hydroxy-
3-tigloyloxycarvotacetone (6) displayed activities against four human cancer cell lines
(acute lymphoblastic leukemia (CCRF-CEM), breast adenocarcinoma (MDA-MB-231),
glioblastoma astrocytoma (U-251) and colon carcinoma (HCT-116)) with IC50 values
between 1.44-6.97 and 3.57-6.86 mg/mL, respectively (Tran et al. 2018). The synthetic
carvotacetone analogue (1) had an IC50 value of 3.52 mg/mL towards non-small cell
lung cancer cell lines (Christou et al. 2013).

NATURAL PRODUCT RESEARCH
3
In continuation of our previous report on carvotacetones from S. bullatus (Machumi
et al. 2012), the anti-plasmodial and cytotoxic activities of these small molecules had
prompted us to synthesise previously unreported benzylated carvotacetone analogues
in order to evaluate their bioactivities.
In this paper, we describe a short strategy to prepare 3-hydroxy-2-isopropyl-5-
methyl-p-benzoquinone (11) and the 3-O-benzyl-carvotacetone (10) together with
other analogues from piperitone (7), predominantly (R) (-) form. The spectroscopic
characterization, using full NMR and MS data of the synthetic compounds and their
intermediates are also discussed. In addition, the anti-plasmodial and the antifungal
activities for these compounds are also reported here.
2. Results and discussion
2.1. Synthesised compounds
The synthesis began from piperitone (7), predominantly (R) (-) form, which was sub-
jected to Luche reduction (Fruhmann et al. 2014) to form cis-piperitol (8) in 78% yield.
1
The identity of 8 was readily confirmed on the basis of its H and 13C NMR spectral
data. Both the 1H and 13C were consistent with literature values for cis piperitol
ꢀ
(Winska et al. 2010).
Cis-piperitol was then protected as the benzyl ether. Benzylation of 8 was carried
out with benzyl bromide using NaH as a base. Chromatographic purification yielded a
pale-yellow oil of 3-O-benzyl-piperitol (9), 5.2 g (58%). The success of the reaction was
confirmed by NMR spectral data. The 1H NMR spectrum showed close similarity to
compound 8, presence of an isopropyl unit (CH3)2CH-, d 0.98 (d, J ¼ 6.5 Hz) and d 1.0
(d, J ¼ 6.5 Hz) , methine proton at d 1.86 (m), another methine proton at d 1.09 (m),
two sets of methylene protons at d 2.02/2.07 (dd), d 1.63 (m) and a methyl attached to
an olefinic carbon was observed at d 1.77 (s). The major difference was the presence
of an additional set of oxy-methylene protons at d 4.73 and d 4.49 integrating for one
proton each appearing as a doublet with a J value of 11.7 Hz and three sets of aro-
matic protons observed at d 7.39 (m), d 7.36 (m) and d 7.28 (m).
Most of the 13C NMR data resembled that of compound 8 with the characteristic
peaks of the isopropyl moiety present. An additional deshielded oxymethylene carbon
appearing at d 70.1, a quaternary carbon at d 139.6 and three sets of aromatic carbons
at d 128.2, 127.5 and d 127.2 were notable. In the HMBC spectrum, the oxymethine
proton at d 3.89 (H-3), correlated well with the oxy-methylene carbon at position 70,
methylene carbon at position five, olefinic carbons at position two and one, (H-3 ! C-
70, C-5, C-2, C-1), with proton H-70 showing strong correlations with oxymethine car-
bon at position three and aromatic carbons, (H-70 ! C-3, C-10, C-20/C-60). This was a
very clear indication that the benzyl ether group had been introduced to the cis-piper-
itol to form 3-O-benzyl-piperitol (9).
Allylic oxidation of 9 proceeded under Riley oxidation conditions using SeO2 in
dioxane/formic acid (Nakamura and Nakada 2013) to provide the corresponding allylic
ketone 10 as a reddish-brown oil in 50% yield, a benzoquinone 11 (36%), previously
synthesised (Kende et al. 1974; Santos et al. 2003) and isolated from Antiphiona pinna-
tisecta (Zdero and Bohlmann 1989), and an aldehyde 12 (10%). The IR spectrum

4
V. M. MASILA ET AL.
Figure 1. Synthetic carvotacetone (1) (Christou et al. 2013) and isolated carvotacetones from S. bul-
latus (2–4) (Machumi et al. 2012) and S. africanus (5–6) (Tran et al. 2018).
showed characteristic absorption bands of an ether, C-O-C at 1039.63 cmꢀ1 and a car-
1
bonyl at 1658.78 cmꢀ1.The H-NMR and 13C NMR spectra were similar to that of com-
pound 9. However, the methylene proton signal appearing at d 2.02/2.07 disappeared
together with the peak for the carbon correlating to it at d 31.7 at position six. This
methylene carbon had been replaced with a signal appearing at d 198.1 ppm for the
carbonyl group. The methyl protons at position seven d 1.83 showed strong correla-
tions with the keto group at position six, and two olefinic carbons at position one and
two, (H-7 ! C-1, C-2 and C-6), with the proton at position two correlating with H-2 !
C-4 and C-6. The compound was therefore identified as a ketone, 3-O-benzyl-carvota-
cetone (10).
Compound 12 was synthesised as a reddish-brown paste having a molecular for-
1
mula of C17H22O2 and a molecular ion peak at m/z 259.2. The H and 13C NMR bore a
resemblance to those of compound 9 except for an additional characteristic peak of
an aldehydic proton appearing at d 9.54, (s) with a HSQC correlation to the peak at d
194.7. It was also noted that the peak for the methyl at d 1.77 (s) and its correspond-
ing carbon at d 23.7 disappeared. The position of the carbonyl group of the aldehyde
was confirmed based on HMBC correlation of the de-shielded aldehydic proton d 9.54
with C-6, C-2 and C-1. In addition, H-6 and H-2 strongly correlated with the carbonyl

NATURAL PRODUCT RESEARCH
5
group at position seven. Hence, the compound was deduced to be an aldehyde,
3-benzyloxy-4-isopropylcyclohex-1-enecarbaldehyde (12).
2.2. Anti-plasmodial and antifungal activities
Compound 11 displayed good activity against P. falciparum parasites with IC50 values
of 0.697 and 0.653 mg/mL against chloroquine sensitive (D6) and chloroquine resistant
(W2) strains, respectively. Chloroquine which was used as the standard drug had IC50
values of 0.01 and 0.14 mg/mL against D6 and W2, respectively. However, all the other
compounds were found to have IC50 > 4.76 mg/mL against P. falciparum. In addition,
compound 11 was found to be selectively active against C. neoformans with an IC50
value of 3.11 mg/mL, compared to fluconazole (IC50 value of 1.87 mg/mL), a reference
standard, while compounds 8, 10 and 12 were inactive against C. neoformans (IC50
value of >20, >20 and 15.77 mg/mL), respectively. This appears to be the first report
of the antiplasmodial and anticryptococcal activity of compound 11.
3. Experimental
3.1. Instruments and chemicals
All reagents and other chemicals were purchased from Merck, Loba Chemie and Santa
Cruz and used without further purification. Reactions requiring anhydrous conditions
were performed under nitrogen. The reactions were done in glassware that were dried
in an oven (110 ꢁC) for at least 2 hours and allowed to cool under nitrogen. Solvents
for column chromatography were distilled in the laboratory in glass apparatus.
Chromatographic separation was done on silica gel 60-120 mesh. Thin layer chroma-
tography was performed on Merck silica gel 60 F254 TLC plates and visualised under
254 nm UV lamp and 0.5% KMnO4 as a visualizing agent.
1H-NMR (500 MHz) and 13C-NMR (125 MHz) were recorded on an Agilent DD2-500
NMR spectrometer (Santa Clara, CA, USA) with tetramethyl silane as an internal stand-
ard. The high resolution mass spectrum was acquired via LCMS (Agilent).
3.2. Synthesis of compound 8, 9, 10, 11 and 12
All the compounds were synthesised as illustrated in Figure 2.
3.2.1. Luche reduction of piperitone (7)
Piperitone (17.50 g) and CeCl3.7H2O (21.44 g) in a 250 mL reaction flask were dissolved
in 100 mL of MeOH. NaBH4 (4.36 g) was added to the reaction mixture within five
minutes with constant stirring. The progress of the reaction was monitored using TLC
with 0.5% KMnO4 as a visualizing agent. TLC analysis (EtOAc:n-hexane ¼ 1:9) revealed
total conversion of the starting material after 24 hours. The reaction mixture was con-
centrated under reduced pressure on a rotary evaporator. Work up was done by parti-
tioning the concentrate in a mixture of 200 mL of ethyl acetate and 50 mL of H2O. The
organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure

6
V. M. MASILA ET AL.
Figure 2. Synthetic route to compounds 8, 9, 10, 11 and 12.
and subjected to gradient column chromatography to provide a pale-yellow oil (8),
(13.6 g, 78%).
3.2.2. Benzylation of (8)
Cis-piperitol 8, (9.0 g) was dissolved in 30 mL of anhydrous THF under N2 in a 100 mL
round bottomed flask. Sodium hydride (14.29 g, 60% dispersion in mineral oil) , was
added and stirred at room temperature for 30 minutes. Benzyl bromide (9 mL) was
added dropwise to the reaction mixture and left to stir at room temperature for
36 hours. Methanol (5 mL) was used to quench the reaction. Work up was done by
concentrating the mixture on a rotary evaporator, dissolving it in 100 mL of CH2Cl2
and washing with 30 mL of H2O twice. The organic phase was dried over Na2SO4, fil-
tered, concentrated under reduced pressure and purified by column chromatography
using (CH2Cl2/n-hexane 0.5:9.5) to provide a colourless oil of 9 (5.2 g, 58%).
3.2.3. Riley oxidation of 9 to 10, 11 and 12
3-O-benzyl-piperitol 9, (2.0 g) in 1,4 dioxane/HCOOH (25/1) was placed in a 100 mL
round bottomed flask. Selenium dioxide (1.2 g) was added at room temperature and
j
stirred at 80 C for 3 days. The mixture was then concentrated on a rotary evaporator.
The concentrate was partitioned in a mixture of water (20 mL) and CH2Cl2 (100 mL)
using separatory funnel. The aqueous layer was extracted twice with 200 mL of CH2Cl2.
The combined organic extract was dried over Na2SO4, filtered, concentrated under
reduced pressure and purified by column chromatography using (EtOAc/n-hexane ¼
1:9) to provide 1000 mg (50%) of 10, 700 mg (35.5%) of 11 and 200 mg (10%) of 12.

NATURAL PRODUCT RESEARCH
7
4. Spectroscopic Data
1
3-O-benzyl-piperitol (9): Pale yellow oil. H and 13C NMR (CDCl3, 500 and 125 MHz): see
Table S1. IR: 1062.78 cmꢀ1, MS: m/z 243.4.
1
3-O-benzyl-carvotacetone (10): Reddish brown paste. H and 13C NMR (CDCl3, 500
and 125 MHz): see Table S9. IR: 1658.78 cmꢀ1, 1039.63 cmꢀ1, m/z 259.2.
3-Benzyloxy-4-isopropylcyclohex-1-enecarbaldehyde (12): Reddish brown paste. 1H
1
NMR (CDCl3, 600 MHz, ppm): H and 13C NMR (CDCl3, 500 and 125 MHz): see Table
S17. IR:1681.93 cmꢀ1, 1056.99 cmꢀ1, m/z 259.2.
4.1. Antiplasmodial and antifungal activities
The antiplasmodial assay was assessed in vitro by a colorimetric method that deter-
mines the parasitic lactate dehydrogenase (pLDH) activity (Makler and Hinriches 1993;
Makler et al. 1993), in accordance with those reported previously (Samoylenko
et al. 2009).
All the organisms in the antimicrobial assay were obtained from the American Type
Culture Collection (Manassas, VA). Susceptibility testing was performed using a modi-
fied version of the CLSI methods (NCCLS 1998, 2000a, 2000b). Drug controls cipro-
floxacin, methicillin and vancomycin for bacteria and amphotericin B for yeasts and
fungi were included in each assay. Susceptibility testing was performed at the
National Center for Natural Products Research, University of Mississippi, as described
(Samoylenko et al. 2009).
Acknowledgements
The authors sincerely thank Dr. Siddharth K. Tripathi, Dr. Shabana Khan and Mr. John Trott for
assistance in antifungal and antiplasmodial assays, and Angela Kritschka for NMR.
Disclosure statement
Authors declare no conflict of interest.
Funding
This work was financially supported by International Science Programme, Uppsala University,
Sweden through (ISP)-KEN-02 project, Department of Chemistry, University of Nairobi, and par-
tially by the USDA ARS Specific Cooperative Agreement No. 58-6408-1-603. Veronica Masila is
thankful to the DAAD-NAPRECA for the Ph.D. scholarship.
References
Christou S, Ozturk E, Pritchard RG, Quayle P, Stratford IJ, Whitehead RC, Williams KF. 2013. A syn-
thetic approach to novel carvotacetone and antheminone analogues with anti-tumour activ-
ity. Bioorg Med Chem Lett. 23(18):5066–5069.

8
V. M. MASILA ET AL.
Collu F, Bonsignore L, Casu M, Floris C, Gertsch J, Cottiglia F. 2008. New cytotoxic saturated and
unsaturated cyclohexanones from Anthemis maritima. Bioorg Med Chem Lett. 18(5):
1559–1562.
€
Fruhmann P, Hametner C, Mikula H, Adam G, Krska R, Frohlich J. 2014. Stereoselective Luche
reduction of deoxynivalenol and three of its acetylated derivatives at C8. Toxins. 6(1):325–336.
Idnurm A, Bahn YS, Nielsen K, Lin X, Fraser JA, Heitman J. 2005. Deciphering the model patho-
genic fungus Cryptococcus neoformans. Nat Rev Microbiol. 3(10):753–764.
Jakupovic J, Grenz M, Bohlmann F, Mungai GM. 1990. Carvotacetone derivatives and eudesman-
12, 6b-olides from Sphaeranthus species. Phytochemistry. 29(4):1213–1217.
Kende AS, Bentley TJ, Mader RA, Ridge D. 1974. Simple total synthesis of (þ)-dendrobine. J Am
Chem Soc. 96(13):4332–4334.
Machumi F, Yenesew A, Midiwo J, Heydenreich M, Kleinpeter E, Khan S, Muhammad I. 2012.
Antiparasitic and anticancer carvotacetone derivatives from Sphaeranthus bullatus. Planta
Med. 7(9):1123–1126.
Makler MT, Hinriches DJ. 1993. Measurement of the lactate dehydrogenase activity of
Plasmodium falciparum as an assessment of parasitemia. Am J Trop Med Hyg. 48(2):205–210.
Makler MT, Ries JM, Williams JA, Bancroft JE, Piper RC, Gibbins BL, Hinriches DJ. 1993. Parasite
lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. Am J Trop
Med Hyg. 48(6):739–741.
Marco-Contelles J, Molina MT, Anjum S. 2004. Naturally occurring cyclohexane epoxides:
Sources, biological activities, and synthesis. Chem Rev. 104(6):2857–2900.
Mitchell TG, Perfect JR. 1995. Cryptococcosis in the Era of AIDS—100 Years after the Discovery
of Cryptococcus neoformans. Clin Microbiol Rev. 8(4):515–548.
Nakamura A, Nakada M. 2013. Allylic oxidations in natural product synthesis. Synthesis. 45(11):
1421–1451.
NCCLS. 1998. Reference method for broth dilution antifungal susceptibility testing of conidium-
forming filamentous fungi; proposed standard, M38-P. National Committee on Clinical
Laboratory Standards. 18 (13).
NCCLS. 2000a. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aer-
obically M7-A5. National Committee on Clinical Laboratory Standards. 20 (2).
NCCLS 2000b. Susceptibility testing of mycobacteria, nocardia, and other aerobicactinomycetes;
tentative standard. M24-T2. National Committee on Clinical Laboratory Standards. 20(26),
second edition.
World malaria report 2018World Malaria Report. Geneva: World Health Organization.
Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. 2009. Estimation of
the current global burden of cryptococcal meningitis among persons living with HIV/AIDS.
Concise Communication. 23:525–530.
Price RN, Uhlemann A-C, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K,
Looareesuwan S, White NJ, et al. 2004. Mefloquine resistance in Plasmodium falciparum and
increased pfmdr1 gene copy number. Lancet. 364(9432):438–447.
Samoylenko V, Jacob MR, Khan SI, Zhao J, Tekwani BL, Midiwo JO, Walker LA, Muhammad I.
2009. Antimicrobial, antiparasitic and cytotoxic spermine alkaloids from Albizia schimperiana.
Nat Prod Commun. 4(6):791–796.
~
Santos I, Simoes MM, Pereira M, Martins RRL, Neves M, Cavaleiro JAS, Cavaleiro A. 2003.
Oxidation of monoterpenes with hydrogen peroxide catalysed by Keggin-type tungstoborates.
J Mol Catal A: Chem. 195(1-2):253–262.
Sar B. 2004. Increasing in vitro resistance to fluconazole in Cryptococcus neoformans Cambodian
isolates: April 2000 to March 2002. J Antimicrob Chemother. 54(2):63–565.
Tran HT, Gao X, Kretschmer N, Pferschy-Wenzig EM, Raab P, Pirker T, Temml V, Schuster D,
Kunert O, Huynh L, et al. 2019. Anti-inflammatory and antiproliferative compounds from
Sphaeranthus africanus. Phytomedicine. 62:152951.
Tran HT, Pferschy-Wenzig EM, Kretschmer N, Kunert O, Huynh L, Bauer R. 2018. Antiproliferative
carvotacetones from Sphaeranthus africanus. J Nat Prod. 81(8):1829–1834.
White NJ. 2007. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 7:549–558.

NATURAL PRODUCT RESEARCH
9
ꢀ
ꢀ
ꢀ
Winska K, Grudniewska A, Chojnacka A, Białonska A, Wawrzenczyk C. 2010. Enzymatic resolution
of racemic secondary cyclic allylic alcohols. Tetrahedron: Asymmetry. 21(6):670–678.
Zdero C, Bohlmann F. 1989. Pseudoguaianolides and constituents from Ianisopappus pinnatifidus
and Antiphiona species. Phytochemistry. 28(4):1155–1161.
Zdero C, Bohlmann F, Mungai GM. 1991. Carvotacetone derivatives and other constituents from
representatives of the Sphaeranthus group. Phytochemistry. 30(10):3297–3303.