Synthesis and antimalarial activity of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxanes

Article abstract of DOI:10.1021/ml300188t

Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, β-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug β-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.

Full text of DOI:10.1021/ml300188t

Letter
pubs.acs.org/acsmedchemlett
Synthesis and Antimalarial Activity of 3,3-Spiroanellated 5,6-
Disubstituted 1,2,4-Trioxanes
Ranjani Maurya,† Awakash Soni,‡ Devireddy Anand,† Makthala Ravi,† Kanumuri S. R. Raju,§ Isha Taneja,§
Niraj K. Naikade,† S. K. Puri,‡ Wahajuddin,§ Sanjeev Kanojiya,∥ and Prem P. Yadav*,†
‡
§
†Division of Medicinal & Process Chemistry, Division of Parasitology, Division of Pharmacokinetics and Metabolism, and
∥Sophisticated Analytical Instrument Facility, Central Drug Research Institute, Lucknow-226001, India
S
* Supporting Information
ABSTRACT: Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19−34 have been synthesized and appraised
for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging
from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100%
protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, β-
arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound
25 displayed a similar in vitro pharmacokinetic profile to that of reference drug β-arteether. The activity results demonstrated the
importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.
KEYWORDS: 1,2,4-trioxane, antimalarial, in vivo, orally active
ynthetic trioxanes containing a 1,2,4-trioxane pharmaco-
based on allylic alcohols derived from wittig/reformatsky
Sphore of artemisinin have been a key area of research since products of various phenyl methyl ketones. They have
experimental results to support the importance of an aryl
vinyl substitution at C-6 of the 1,2,4-trioxane moiety, along
with effects of different substituents in the aromatic ring. The
results from Singh et al. motivated us to keep the C-6 phenyl
vinyl part as such in our 1,2,4-trioxane (prototype III, Figure 1).
For prototype II, Griesbeck et al. utilized diastereoselective
photooxygenation to synthesize racemic threo-β-hydroperoxy
alcohols that were in turn used to synthesize diastereomerically
pure aliphatic C-5,6-substituted 1,2,4-trioxane and reported in
vitro antimalarial activities against the K1 strain of P.
falciparum.31−33 On the basis of the in vitro activity profile of
some of these Griesbeck's 1,2,4-trioxanes, O'Neill et al.
reported the synthesis of C-5,6-alkylsubstituted 1,2,4-trioxanes
by stereoselective photooxygenation of chiral allylic alcohols.34
From Figure 1, it is clear that approach I is attractive because of
promising in vivo activity results, while approach II is attractive
for in vitro activity results of C-5,6-dialkyl-substituted 1,2,4-
the discovery of the antimalarial lead molecule artemisinin from
Artemisia annua.1−5 Malaria is of serious concern in many
tropical areas of the world, and the situation has worsened due
to drug resistance to common chemotherapeutic agents.6
Artemisinin and its derivatives have been thoroughly
investigated for their efficacy against malaria parasite and also
their peroxide specific mode of action.7−17 Since identification
of the peroxide group-specific antimalarial activity of
artemisinin, many synthetic peroxides have been synthesized
and tested for their efficacy and were found to show promising
antimalarial activity as compared to artemisinin.18−24 For the
synthesis and assessment of the antimalarial activity of the
1,2,4-trioxane skeleton, two major prototypes are reported in
the literature (Figure 1): (I) aryl vinyl substitution at C-6
position25−30 and (II) alkyl vinyl substitution at C-6 and alkyl/
cycloalkyl substitution at C-5 position.31−33 So far, synthesized
trioxanes have a substitution at C-6 because of the ease of
synthesis via ene reaction of allylic alcohols with singlet oxygen.
A substitution corresponding to the phenyl vinyl part of the
molecule has been the subject of an extensive study by Singh et
al.,25−30 where they have synthesized a number of compounds
Received: July 9, 2012
Accepted: December 11, 2012
© XXXX American Chemical Society
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Figure 1. Basis for the synthesis of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxane.
Scheme 1. Synthesis of 3,3-Spiroanellated 5,6-Disubstituted 1,2,4-Trioxanes (19−34)
trioxanes. Taking in to consideration the importance of a
phenyl substituent on the synthetic 1,2,4-trioxanes evident from
work by Singh et al. and in vitro activity results of C-5,6-
disubstituted 1,2,4-trioxanes, we envisage a new route for aryl
substitution at C-5 and aryl vinyl substitution at C-6 positions
of the 1,2,4-trioxane moiety to assess their in vivo antimalarial
potential. (Figure 1, prototype III).
5,6-Disubstituted 1,2,4-trioxanes 19−34 were prepared by
the procedure given in Scheme 1 and starts with the formation
of homochalcones. The desired homochalcones 1−6 were
synthesized by the thionyl chloride-catalyzed self-condensation
of substituted acetophenones in ethanol in the temperature
range from −5 to 0 °C (21−42% yields), following the
reported procedure.35 Homochalcones 1−6 were reduced by
sodium borohydride (NaBH4) in a mixture of methanol and
tetrahydrofuran (THF) to give the corresponding allylic alcohol
736−12 (55−66%) yields. Allylic alcohols are a very useful
intermediates for the synthesis of 1,2,4-trioxanes via peroxyke-
talization of hydroperoxyalcohol. The synthesis of allylic
alcohol-derived hydroperoxides has been the key step toward
development of many synthetic 1,2,4-trioxanes. Photooxygena-
tion of allylic alcohols 7−12 in acetonitrile (CH3CN) and
chloroform (CHCl3) with methylene blue as a sensitizer
furnished a diasteromeric mixture of threo (major) and erythro
(minor) β-hydroperoxyalcohol 13−18 (44−66%). The threo-
selectivity is explained on the basis of a hydroxyl-directing effect
of allylic alcohol, which is in turn strongly affected by
competing hydrogen bond acceptors. Peroxyketalization of
hydroperoxyalcohol 13−15, 17, and 18 with cyclopentanone
and cyclohexanone was carried out in the presence of catalytic
acid to furnish exclusively the threo-1,2,4-trioxanes 19−23 (17−
26%) and 24−28 (15−28%), respectively. Similarly Peroxyke-
talization of hydroperoxyalcohol 13−18 with admantanone
were carried out in presence of p-toulene sulfonic acid (PTSA)
to furnish the threo-1,2,4-trioxanes 29−34 (14−28%). The
relative configuration of the product was determined to be threo
3
based on JH5−H6 observed in the proton spectrum of product
(3JH5−H6 = 9.6 Hz for compound 25).31,32 The corresponding
peroxyketalization product from erythro (minor) β-hydro-
peroxyalcohol could not be isolated in all cases. This is the first
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Table 1. In Vivo Antimalarial Activity of Compounds 19−34 against Multidrug-Resistant P. yoelii nigeriensis in Swiss Mice by
oral and im Routes
a
b
Percent suppression = [(c − t)/c] × 100, where c = parasitaemia in control group, and t = parasitaemia in treated group. 100% suppression of
parasitaemia means that the number of parasites, if present, is below the detection limit.
report for the synthesis of 5-aryl, 6-aryl vinyl-substituted 1,2,4-
trioxanes and their antimalarial activities.
doses of 48, 24, and 12 mg/kg × 4 days. The results are
summarized in Table 1.
Compounds 19−34 were screened for antimalarial activity
against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss
mice via oral route using Peter's procedure.37 In this model, β-
arteether (standard drug) showed 100% suppression of
parasitemia37 at 48 mg/kg × 4 days, and all of the treated
mice survived beyond day 28. At 24 mg/kg × 4 days, β-
arteether provides only 20% protection to the treated mice.
Therefore, all of the trioxanes were initially tested at 96 mg/kg
× 4 days orally, double the effective dose of β-arteether.
Compounds 22, 25, and 26 provided 100% protection38 at 96
mg/kg × 4 days dose and hence were further screened at lower
As evident from Table 1, some of the tested compounds
displayed activity comparable with or better than that of β-
arteether by oral route. Compound 25, the most active
compound of the series, showed 100% parasite suppression
on day 4 and 100% survival on day 28 of treatment at a dose of
24 mg/kg × 4 days, while at 12 mg/kg × 4 days, 100%
suppression of parasitaemia on day 4 was shown but provided
poor protection in terms of survival of the treated mice.
Compound 25 is twice as active as β-arteether by oral route.
Compound 22, the next best compound, showed 20%
protection at 48 mg/kg × 4 days, while at 24 mg/kg × 4 days,
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98.58% suppression of parasitaemia on day 4 was shown and
provided poor protection in terms of survival of the treated
mice. Compound 26 showed 80% protection at 96 mg/kg × 4
days dose, whereas only 89.43% suppression of parasitaemia on
day 4 was observed at 48 mg/kg × 4 days dose. Compound 27
showed 100% suppression of parasitaemia on day 4 at 96 mg/
kg and provided 40% protection in terms of survival of the
treated mice. The compounds 22, 26, 27, and 30 were inactive
at further lower doses. Activity results given in Table 1 and a
comparative study in Figure 133,39 clearly indicated that aryl
substitution at C-5 resulted in highly active 1,2,4-trioxanes
where the best active compound, that is, compound 25, was
twice as active as the reference drug β-arteether and 3.75 times
more active as compared to the compound A (Figure 1)
without C-5 aryl substitution. Biologically the most promising
molecule of this series, compound 25 was assessed for its
biopharmaceutical properties (Table 2). It could be categorized
AUTHOR INFORMATION
Corresponding Author
*Tel: +91-522-2612411-4496. Fax: +91-522-2623405,
2623938. E-mail: pp_yadav@cdri.res.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.M., D.A., M.R., N.K.N., and A.S. are thankful to CSIR, New
Delhi, for fellowship. We are thankful to the Anoop K.
Srivastava for providing technical support during the course of
work and SAIF-CDRI, Lucknow, for providing spectral data.
The manuscript bears CDRI communication no. 8341.
ABBREVIATIONS
NaBH4, sodium borohydride; THF, tetrahydrofuran; CH3CN,
acetonitrile; CHCl3, chloroform; PTSA, p-toulene sulfonic acid
■
Table 2. Biopharmaceutical Properties of Compound 25
REFERENCES
■
drug-likeness property
compound 25
13 μM
β-arteether43
(1) For reviews on artemisinin and its analogues, see the following:
Chaturvedi, D.; Goswami, A.; Pratim Saikia, P.; Barua, N. C.; Rao, P.
G. Artemisinin and its derivatives: A novel class of antimalarial and
anti-cancer agents. Chem. Soc. Rev. 2010, 39, 435−454.
(2) Muraleedharan, K. M.; Avery, M. A. Progress in the development
of peroxide-based antiparasitic agents. Drug Discovery Today 2009, 14,
793−803.
(3) Jefford, C. W. New developments in synthetic peroxidic drugs as
artemisinin mimics. Drug Discovery Today 2007, 12, 487−494.
(4) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Synthetic peroxides as
antimalarials. Med. Res. Rev. 2004, 24, 425−448.
(5) Klayman, D. L. Qinghaosu (artemisinin): An antimalarial drug
from China. Science 1985, 228, 1049−1055.
(6) WHO. 10 Facts on Malaria; www.who.int/features/factfiles/
malaria.
(7) Luo, X. D.; Shen, C. C. The chemistry, pharmacology, and
clinical applications of qinghaosu (artemisinin) and its derivatives.
Med. Res. Rev. 1987, 7, 29−52.
(8) Cumming, J. N.; Ploypradith, P.; Posner, G. H. Antimalarial
activity of artemisinin (qinghaosu) and related trioxanes: mecha-
nism(s) of action. Adv. Pharmacol. 1997, 37, 253−297.
(9) Bhattacharya, A. K.; Sharma, R. P. Recent developments on the
chemistry and biological activity of artemisinin and related
antimalarials−an update. Heterocycles 1999, 51, 1681−1745.
(10) Borstnik, K.; Paik, I. H.; Shapiro, T. A.; Posner, G. H.
Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A
and related compounds. Int. J. Parasitol. 2002, 32, 1661−1667.
(11) Ploypradith, P. Development of artemisinin and its structurally
simplified trioxane derivatives as antimalarial drugs. Acta Trop. 2004,
89, 329−342.
(12) O'Neill, P. M.; Posner, G. H. A medicinal chemistryperspective
on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47,
2945−2964.
(13) Asthana, O. P.; Srivastava, J. S.; Valecha, N. Current status of the
artemisinin derivatives in the treatment of malaria with focus on
arteether. J. Parasitic Dis. 1997, 211, 1−12.
(14) Jambou., R.; Legrand, E.; Niang, M.; Khim, N.; Lim, P.; Volney,
B.; Ekala, M. T.; Bouchier, C.; Esterre, P.; Fandeur, T.; Mercereau-
Puijalon, O. Resistance of Plasmodium falciparum field isolates to in
vitro artemether and point mutations of the SERCA-type PfATPase6.
Lancet 2005, 366, 1960−1963.
(15) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C.
W. The chemotherapy of rodent malaria. XLVIII. The activities of
some synthetic 1,2,4-trioxanes against chloroquine-sensitive and
chloroquine-resistant parasites. Part 1: Studies leading to the
development of novel cis-fused cyclopenteno derivatives. Ann. Trop.
Med. Parasitol. 1993, 87, 1−7.
solubility, distilled water (S)
practically
insoluble
distribution coefficient (Log D),
pH 7.4
4.23
3.6
in situ permeability (Peff, cm/s)
11.28 1.68 × 10−5 NA
plasma protein binding (% free) 0.8
metabolic stability,
1−2
half-life (T1/2, min)
23.00
60.26
47.36
36.58
clearance (CLint, μL/min/mg)
as a class II drug as per the Biopharmaceutical Classification
System based on its low solubility and high permeability.40 It
was found to be highly protein bound, 50% metabolically stable
after 30 min on incubation with rat liver microsomes, and was
not an inhibitor of rat CYPs 3A, 2D4, 1A2, or 2C11 (IC50
>
100 μM) (Supporting Information, Experimental Section).
When compared to the reference drug, β-arteether, compound
25 showed a similar in vitro pharmacokinetic profile; however,
it was found to be less metabolically stable. The biopharma-
ceutical properties obtained meet most of the criteria set by
MMV Compound Progression Criteria 2008; thus, it may be a
potential candidate for lead selection and optimization.41,42
In conclusion, the C-5 aryl and C-6 arylvinyl-substituted
1,2,4-trioxanes were synthesized using a simple methodology
starting from self-condensation products of acetophenones, that
is, homochalcones, in the least possible number of steps.
Compound 25 was identified as the most active compound of
the series, which is twice as active as β-arteether. The activity
results demonstrated the importance of an aryl moiety at the C-
5 position on the 1,2,4-trioxane pharmacophore. Further work
on C-5-substituted 1,2,4-trioxanes with better aqueous
solubility, oral bioavailability, and efficacy is under progress.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed spectroscopic data, 1H and 13C NMR and mass spectra
of synthesized compounds, and experimental procedures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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(16) Peters, W.; Robinson, B. L.; Rossier, J. C.; Misra, D.; Jefford, C.
W.; Rossiter, J. C. The chemotherapy of rodent malaria. XLIX. The
activities of some synthetic 1,2,4-trioxanes against chloroquine-
sensitive and chloroquine-resistant parasites. Part 2: Structure-activity
studies on cis-fused cyclopenteno-1,2,4-trioxanes (fenozans) against
drug-sensitive and drug-resistant lines of Plasmodium berghei and P.
yoelii ssp. NS in vivo. Ann. Trop. Med. Parasitol 1993, 87, 9−16.
(17) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C.
W. The chemotherapy of rodent malaria. L. The activities of some
synthetic 1,2,4-trioxanes against chloroquine- sensitive and chlor-
oquine-resistant parasites. Part 3: Observations on 'Fenozan-50F', a
difluorinated 3,3′-spirocyclopentane 1,2,4- trioxane. Ann. Trop. Med.
Parasitol. 1993, 87, 111−123.
(18) Kepler, J. A.; Philip, A.; Lee, Y. W.; Morey, M. C.; Carroll, F. I.
1,2,4-Trioxanes as potential antimalarial agents. J. Med. Chem. 1988,
31, 713−716.
(19) Posner, G. H.; Maxwell, J. P.; O'Dowd, H.; Krasavin, M.; Xie, S.;
Shapiro, T. A. Antimalarial sulfide, sulfone, and sulfonamide trioxanes.
Bioorg. Med. Chem. 2000, 8, 1361−1370.
(20) Posner, G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik, I.-
H.; Shapiro, T. A. Antimalarial simplified 3-aryltrioxanes: Synthesis
and preclinical efficacy/toxicity testing in rodents. J. Med. Chem. 2001,
44, 3054−3058.
(21) Posner, G. H.; Jeon, H. B.; Polypradith, P.; Paik, I.-H.; Borstnik,
K.; Xie, S.; Shapiro, T. A. Orally active, water-soluble antimalarial 3-
aryltrioxanes: Short synthesis and preclinical efficacy testing in rodents.
J. Med. Chem. 2002, 45, 3824−3828.
(22) O'Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.;
Bachi, M. D.; Stocks, P. A. Application of thiol-olefin cooxygenation
methodology to a new synthesis of the 1,2,4-trioxane pharmacophore.
Org. Lett. 2004, 6, 3035−3038.
(23) Cabaret, O. D.; Vical, F. B.; Loup, C.; Robert, A.; Gornitzka, H.;
bonhoure, A.; Vial, H.; Magnaval, J. F.; Seguela, J- P.; Meunier, B.
Synthesis and antimalarial activity of trioxaquines derivatives. Chem.
Eur. J. 2004, 10, 1625−1636.
(33) Griesbeck, A. G.; El-Idreesy, T. T.; Hoinck, L.-O.; Lex, J.; Brun,
̈
R. Novel spiroanellated 1,2,4-trioxanes with high in vitro antimalarial
activities. Bioorg. Med. Chem. Lett. 2005, 15, 595−597.
́
(34) Sabbani, S.; Pensee, L. L.; Bacsa, J.; Hedenstrom, E.; O'Neill, P.
̈
M. Diastereoselective schenck ene reaction of singlet oxygen with
chiral allylic alcohols; access to enantiomerically enriched 1,2,4-
trioxanes. Tetrahedron 2009, 65, 8531−8537.
(35) Hu, Z.; Liu, J.; Li, G.; Dong, Z.; Li, W. Synthesis of Asymmetric
Triarylbenzenes by Using SOCl2-C2H5OH Reagent. J. Chin. Chem. Soc.
2004, 51, 581−584.
(36) Arai, N.; Azuma, K.; Nii, N.; Ohkuma, T. Highly
Enantioselective Hydrogenation of Aryl Vinyl Ketones to Allylic
Alcohols Catalyzed by the Tol-Binap/Dmapen Ruthenium (II)
Complex. Angew. Chem., Int. Ed. 2008, 47, 7457−7460.
(37) Peter's procedure: 100% suppression of parasitaemia means that
the number of parasites, if at all present, is below the detection limit.
The parasites present below the detection limit can multiply and
eventually can be detected. In such cases, although the drug is
providing near 100% suppression of the parasitemia, it will not provide
full protection to the treated mice. Multidrug-resistant P. yoelii
nigeriensis used in this study is resistant to chloroquine, mefloquine,
and halofantrine.
(38) One hundred percent protection means that all of the treated
mice survive till day 28. Similarly, 60% protection means only 60% of
the treated survive till day 28.
(39) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. In vivo potent
antimalarial 1,2,4-trioxanes: synthesis and activity of 8-(α-arylvinyl)-
6,7,10-trioxaspiro[4,5]decanes and 3-(α-arylvinyl)-1,2,5-trioxaspiro-
[5,5]undecanes against Plasmodium berghei in mice. Bioorg. Med.
Chem. Lett. 1995, 5, 1913−1916.
(40) Ku, M. S. Use of the Biopharmaceutical Classification System in
Early Drug Development. AAPS J. 2008, 10, 208−212.
(41) Medicines For Malaria Venture (MMV). MMV Compound
Progression Criteria; August, 2008; 8 pp.
(42) Bosman, A.; Malaria, R. B. Review of Application for Inclusion of a
Drug in the WHO Essential Drugs List, 2002; http://archives.who.int/
eml/expcom/expcom12/arteether_review.doc.
(24) Slack, R. D.; Jacobine, A. M.; Gary, G. H. Antimalarial
peroxides: Advances in drug discovery and design. Med. Chem.
Commun. 2012, 3, 281−297.
(25) Singh, C.; Malik, H.; Puri, S. K. Orally Active 1, 2, 4-Trioxanes:
Synthesis and Antimalarial Assessment of a New Series of 9-
Functionalized 3-(1-Arylvinyl)-1,2,5-trioxaspiro[5.5]undecanes against
Multi-Drug-Resistant Plasmodium yoelii nigeriensis in Mice. J. Med.
Chem. 2006, 49, 2794−2803.
(43) Grace, J. M.; Aguilar, A. J.; Trotman, K. M.; Brewer, T. G.
Metabolism of β-arteether to dihydroqinghaosu by human liver
microsomes and recombinant cytochrome P450. Drug Metab. Dispos.
1998, 26 (4), 313−317.
(26) Singh, C.; Verma, V. P.; Naikade, N. K.; Singh, A. S.; Hassam,
M.; Puri, S. K. Novel Bis- and Tris-1,2,4-trioxanes: Synthesis and
Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii in
Swiss Mice. J. Med. Chem. 2008, 51, 7581−7592.
(27) Singh, C.; Gupta, N.; Puri, S. K. Synthesis of new 6-alkylvinyl/
arylalkylvinyl substituted 1,2,4-trioxanes active against multidrug-
resistant malaria in mice. Bioorg. Med. Chem. 2004, 12, 5553−5562.
(28) Singh, C.; Malik, H.; Puri, S. K. Orally active amino
functionalized antimalarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett.
2004, 14, 459−462.
(29) Singh, C.; Kanchan, R.; Srivastava, D.; Puri, S. K. 8-(1-
Naphthalen-2-yl-vinyl)-6,7,10-trioxaspiro (4.5) decane, a new 1,2,4-
trioxane effective against rodent and simian malaria. Bioorg. Med.
Chem. Lett. 2006, 16, 584−586.
(30) Singh, C.; Hassam, M.; Naikade, N. K.; Verma, V. P.; Singh, A.
S.; Puri, S. K. Synthesis and Antimalarial Assessment of a New Series
of Orally Active Amino-Functionalized Spiro 1,2,4-Trioxanes. J. Med.
Chem. 2010, 53, 7587−7598.
(31) Griesbeck, A. G.; El-Idreesy, T. T.; Fiege, M.; Brun, R. Synthesis
of Antimalarial 1,2,4-Trioxanes via Photooxygenation of a chiral allylic
alcohol. Org. Lett. 2002, 4, 4193−4195.
(32) Griesbeck, A. G.; El-Idreesy, T. T.; Lex, J. Singlet oxygen
addition to chiral allylic alcohols and subsequent peroxyacetalization
with β-naphthaldehyde: Synthesis of diastereomerically pure 3-β-
naphthyl-substituted 1,2,4-trioxanes. Tetrahedron 2006, 62, 10615−
10622.
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