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7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activity

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Igor Opsenica at University of Belgrade
Igor Opsenica
Natasa Terzić at University of Belgrade
Natasa Terzić
Dejan Opsenica at University of Belgrade
Dejan Opsenica
Wilbur K Milhous
Wilbur K Milhous
Wilbur K Milhous
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Abstract

Several C2 symmetrical mixed tetraoxanes were prepared starting from a gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced antimalarial activity against P. falciparum chloroquine resistant W2 and chloroquine susceptible D6 strains, with N-(2-dimethylamino)ethyl-7,8,15,16-tetraoxa-dispiro[5.2.5.2] hexadecane-3-carboxamide being as active as artemisinin.
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7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activi
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J. Serb. Chem. Soc. 69 (11) 919–922 (2004) UDC 547.461+547.218.1:615.28
JSCS – 3219 Preliminary communication
PRELIMINARY COMMUNICATION
7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid
derivatives and their antimalarial activity*
IGOR OPSENICA1#, NATA[A TERZI]1#, DEJAN OPSENICA1#, WILBUR K. MILHOUS2and
BOGDAN [OLAJA3,+#
1Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia and Montenegro, 2Devision
of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC
20307-5100, USA and 3Faculty of Chemistry, University of Belgrade, P.O. Box 158, 11001 Bel-
grade, Serbia and Montenegro (e-mail: bsolaja@chem.bg.ac.yu)
(Received 27 May 2004)
Abstract: Several C2 symmetrical mixed tetraoxanes were prepared starting from a
gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced
antimalarial activity against P. falciparum chloroquine resistant W2 and chloro-
quine susceptible D6 strains, with N-(2-dimethylamino)ethyl-7,8,15,16-tetraoxa-di-
spiro[5.2.5.2]hexadecane-3-carboxamide being as active as artemisinin.
Keywords: mixed tetraoxane, malaria, Plasmodium falciparum, gem-dihydroperoxide.
INTRODUCTION
Malaria is a serious infectious disease affecting 300–500 million people per
year.1The disease is caused by multiplication of the protozoan parasite Plasmo-
dium falciparum in erythrocytes. Increased resistance to standard, and affordable,
antimalarial drugs, such as chloroquine (CQ), further complicates the treatment of
infected individuals. The emergence of peroxide antimalarias of the 1,2,4-tri-
oxacyclohexane class (trioxanes), such as artemisinin and its derivatives, opened
new possibilities for treating the parasitemia. Another peroxide class of com-
pounds, 1,2,4,5-tetraoxacyclohexanes (tetraoxanes),2hasalsoprovedtobeeffec
-
tive antimalarials, although their pharmacological properties have been less ex-
plored than those of the trioxanes.
In addition to steroidal tetraoxanes, a significant number of dicyclohexylidene
tetraoxanes have been synthesised and their antimalarial activity evalueated in vi-
tro and in vivo.3However, the structure of the previously evaluated dicyclohexyli-
919
* Dedicated to Professor @ivorad ^ekovi} on the occasion of his 70th birthday.
+ Phone: +381-11-63-86-06. Fax: +381-11-63-60-61.
# Serbian Chemical Society active member.
dene tetraoxanes was limited by the mode of their synthesis: only bis compounds
could be obtained directly from the corresponding ketones.4Recent syntheses of
mixed tetraoxanes5,6 opened new possibilities for the controlled preparation of this
class of promising antimalarials.
In this paper, the synthesis and initial results of biological evaluation of mixed
tetraoxanes, derivatives of 7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-car-
boxylic acid are reported. The present class of compounds was designed with the
aim of obtaining the simplest amphiphilic structures of C2 symmetry in an effort to
minimise the influence of steric effects of the tetraoxane antimalarials on their ac-
tivity, and to investigate the direct influence of various functionalities.
CHEMISTRY
Gem-dihydroperoxide 1was obtained in 50 % yield from cyclohexanone us-
ing 30 % hydrogen peroxide and HCl as a catalyst. Compound 1was identified by
comparison of its IR, 1H-NMR and 13C-NMR data7to those of previously synthe-
sised gem-dihydroperoxides.5a The obtained gem-dihydroperoxide was coupled to
ketone 2according to a recently developed procedure5a to yield the parent mixed
tetraoxane, methyl 7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylate
(3) in 28 % yield. The identity of 3was established from its spectral data.8Using
the ester®acid®amide sequence (Scheme 1) desired amides were obtained in
68–80 % overall yield.
ANTIMALARIAL ACTIVITY
The tetraoxanes were screened against Plasmodium falciparum CQ resistant
W2 and CQ susceptible D6 strains following the protocol given in Ref. 2c. All the
synthesised tetraoxanes exhibited pronounced antimalarial activity. In accordance
with previous findings,2c the acid 4was less active than the methyl ester 3,andsig
-
nificantly less active than the corresponding amides 5–7 against both clones. Ac-
cording to a current hypothesis suggesting that peroxides exert their antimalarial
activity in the food-vacuole (FV) of P. falciparum at pH »5.5, amide 7, possessing
920 OPSENICA et al.
Scheme 1.
an N,N-dimethylamino group, was designed in the expectation that protonation of
the basic nitrogen would mediate the efflux through the FV membranes, hence in-
creasing its concentration at the site of action. The in vitro antimalarial activity of
tetraoxane 7(Table I) confirms our expectations, and the results of further in vitro
and in vivo screening will be reported in due time elsewhere.
Acknowledgements: This work was supported by the Ministry of Science, Technologies and
Development of Serbia (Grant no. 1579).
IZVOD
ANTIMALARIJSKA AKTIVNOST DERIVATA
7,8,15,16-TETRAOKSA-DISPIRO[5.2.5.2]HEKSADEKAN-3-KARBOKSILNE
KISELINE
IGOR OPSENICA1, NATA[A TERZI]1, DEJAN OPSENICA1,WILBUR K. MILHOUS2iBOGDAN
[OLAJA3
1Insitut za hemiju, tehnologiju i metalurgiju, Beograd, 2Division of Experimental Therapeutics, Walter Reed
Army Institute of Research, Washington, DC 20307-5100 i3Hemijski fakultet Univerziteta u Beogradu, p. pr.
158, Beograd
U ovom radu prikazana je sinteza serije C2 me{ovitih tetraoksana polaze}i od
gem-dihidroperoksida cikloheksanona. Dobijenim derivatima ispitana je in vitro aktiv-
nost prema W2 iD6 sojevima P. falciparum. Utvr|eno je da derivat N-(2-dimetilamino)e-
til-7,8,15,16-tetraoksa-dispiro[5.2.5.2]heksadekan-3-karboksamid pokazuje aktivnost vrlo
blisku aktivnosti poznatog antimalarika artemizinina.
(Primqeno 27. maja 2004)
REFERENCES
1. Malaria Foundation International, http://www.malaria.org/, and the sites given therein
2. (a) J. L. Vennerstrom, H.-N. Fu, W. Y. Ellis, A. L. Ager, Jr., J. K. Wood, S. L. Andersen, L.
Gerena, W. K. Milhous, J. Med. Chem. 35 (1992) 3023; (b) N. M. Todorovi}, M. Stefanovi}, B.
Tinant,J.-P.Declercq,M.T.Makler,B.A.[olaja,Steroids 61 (1996) 688; (c) D. Opsenica, G.
Pocsfalvi, Z. Jurani}, B. Tinant, J. -P. Declercq, D. E. Kyle, W. K. Milhous, B. A. [olaja, J. Med.
Chem. 43 (2000) 3274; (d) D. Opsenica, D. E. Kyle, W. K. Milhous, B. A. [olaja, J. Serb. Chem.
Soc. 68 (2003) 291, (d) D. Opsenica, G. Angelovski, G. Pocsfalvi, Z. Jurani}, @. @i`ak, D. Kyle,
W. K. Milhous, B. A. [olaja, Bioorganic & Medicinal Chemistry 11 (2003) 2761
MIXED TETRAOXANES 921
TAB L E I . In vitro antimalarial activity of the synthesised tetraoxanes
Compound W2 (IC50)/(ng/mL) D6 (IC50)/(ng/mL)
311.57 8.36
4112.51 116.89
55.47 6.5
66.89 6.04
73.33 3.85
CQ 111.75 4.39
Artemisinin 2.2a4.7a
aData taken from Ref. 2a
3. J. L. Vennerstrom, A. L. Ager, S. L. Andersen, J. M. Grace, V. Wongpanich, C. K. Angerhofer, J.
K.Hu,D.L.Wesche,Am. J. Trop. Med. Hyg. 62 (2000) 573
4. J. L. Vennerstrom, Y. Dong, S. L. Andersen, A. L. Ager Jr., H. -N. Fu, R. E. Miller, D. L. Wesche,
D. E. Kyle, L. Gerena, S. M. Walters, J. K. Wood, G. Edwards, A. D. Holme, W. G. McLean, W.
K. Milhous, J. Med. Chem. 43 (2000) 2753, and references cited therein
5. B. A. [olaja, N. Terzi}, G. Pocsfalvi, L. Gerena, B. Tinant, D. Opsenica, W. K. Milhous, J. Med.
Chem. 45 (2002) 3331
6. (a) H. -S. Kim, K. Tsuchiya, Y. Shibata, Y. Wataya, Y. Ushigoe, A. Masuyama, M. Nojima, K. J.
McCullough, J. Chem. Soc., Perkin Trans 1(1999) 1867; (b) J. Iskra, D. Bonnet-Delponb, J. -P.
Be’gue, Tetrahedron Lett. 44 (2003) 6309
7. IR: Characteristic intramolecular OH bonding at 3419 cm-1 (film) and 3424 cm-1 (CCl4);
1H-NMR (CDCl3): 9.60 ppm, (2H, HOO–C(1), exhangeable with D2O); 13C-NMR (CDCl3):
110.94 ppm (C(1))
8. Spectral data for 3: colourles foam, softenes at 75–80 ºC. IR (KBr): 3444w, 3007w, 2938s,
2865m, 1736s, 1452s, 1329m, 1270m, 1201s, 1074s, 1010w, 931m, 838mcm-1.1H-NMR (200
MHz, CDCl3): 3.67 (s,CH
3O2C–C(3)), 2.87 (bs, H–C(3)), 2.5–2.1 (m, 3H), 2.0–1.4 (m, 15H).
13C-NMR (50 MHz, CDCl3): 174.82, 108.15, 107.04, 51.47, 41.24, 31.50, 30.06, 29.37, 27.90,
25.15, 24.40, 23.67, 21.80. ESI-MS (m/z(%)): 339.36 (100), 327.35 ([M+Na+H2O]+, 50),
313.40 ([M+CH+H]+, 35) 304.37 ([M+H2O]+, 35), 288.34 (55), 285.37 ([M]+, 95), 257.25 (45),
244.31 (85), 142.26 (65), 209.23 (10), 187.19 (10), 155.20 (45), 141.20 (25), 118.24 (15),
100.32 (10), 68.41 (30).
922 OPSENICA et al.
... New class of mixed steroidal tetraoxanes 1 obtained from cholic [9e11] and deoxycholic [12] acids are much more potent as antimalarials both in vitro and in vivo, in respect to bis-steroidal analogues. Along with steroid-based, the tetraoxanes derived from cyclohexane were also tested as antimalarials and showed significant in vitro and in vivo potencies [11,13]. Many tetraoxane derivatives also exhibited antiproliferative activity against various human cancer cell lines, with morphological appearance reminiscent for apoptosis [7,14], and showed very low cytotoxicity toward healthy human cells. ...
... Synthesis, antimalarial and antiproliferative activity of compounds 1e33 were reported previously. Detail description of all experimental procedures can be found in the following references (see also Table 1): For the compounds 1e5, references [11,13]; for the compounds 6e11 [12]; 12e16 [9]; 19, 20, 21, 24e27 [7]; 17, 18, 22, 23, also 19 and 24 [8]; and for the compounds 28e33 reference [9]. Description of computational procedures and GRIND [15,16] methodology are given in Supplementary material. ...
An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes
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  • Oct 2010
  • EUR J MED CHEM
An alignment-free 3D QSAR study on antiproliferative activity of the thirty-three 1,2,4,5-tetraoxane derivatives toward two human dedifferentiated cell lines was reported. GRIND methodology, where descriptors are derived from GRID molecular interaction fields (MIF), were used. It was found that pharmacophoric pattern attributed to the most potent derivatives include amido NH of the primary or secondary amide, and the acetoxy fragments at positions 7 and 12 of steroid core which are, along with the tetraoxane ring, common for all studied compounds. Independently, simple multiple regression model obtained by using the whole-molecular properties, confirmed that the hydrophobicity and the H-bond donor properties are the main parameters influencing potency of compounds toward human cervix carcinoma (HeLa) and human malignant melanoma (FemX) cell lines. Corollary, similar structural motifs are found to be important for the potency toward both examined cell lines.
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... Tetraoxanes evaluated here have proven to be excellent intra-erythrocytic antimalarials without any observed toxicity ( Figure S1, Table S2). 44,45,46,47,48,49 The structures of the two most LS-active steroidal tetraoxanes are given in Figure 3, ...
Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
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The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro, and in vivo activity against P. berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intra-hepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 µM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50= 0.33 µM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V P. falciparum gametocytes (IC50 = 1.16  0.37 µM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
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... A solution of 1 16 (100 mg, 0.37 mmol), Et 3 N (52 µL, 0.37 mmol), and ClCO 2 Et (34.8 µL, 0.37 mmol) in dry CH 2 Cl 2 (10 mL), was stirred for 90 min at 0°C. Then, the amine AQ 17 (163 mg, 0.73 mmol) was added, and after 30 min of stirring, the reaction mixture was warmed to rt. ...
New Chimeric Antimalarials with 4-Aminoquinoline Moiety Linked to a Tetraoxane Skeleton
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  • Sep 2008
  • J MED CHEM
The synthesis of the chimeric molecules consisting of two pharmacophores, tetraoxane and 7-chloro-4-aminoquinoline, is reported. The tetraoxanes 2, 4, and 8 show relatively potent in vitro antimalarial activities, with IC90 values for the Plasmodium falciparum strain W2 of 2.26, 12.44, and 10.74 nM, respectively. In addition, two compounds, 2 and 4, cured mice in a modified Thompson test for antimalarial blood stage activity, with a minimum curative dose of 80 mg/kg, a minimum active dose of 20 mg/kg/day, and a maximum tolerated dose of >960 mg/kg.
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Artemisinins and synthetic peroxides as highly efficient antimalarials
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Malaria is devastating disease and global public health problem, with nearly half world population exposed to risk. Illness is caused by five Plasmodium species, P. falciparum, P. ovale, P. vivax, P. malaria and P. knowlesi, from which P. falciparum is the most serious one causing cerebral malaria and is the major reason for malaria mortality. Vaccine against malaria is not expected in the near future and chemotherapy remains as most feasible alternative for treatment of the disease. The development of widespread drugresistance to chloroquine (CQ), the most successful antimalarial drug up to date, has resulted in severe health issues for countries in malaria endemic regions. Organic peroxides, like artemisinins, 1,2,4-trioxanes, 1,2,4-trioxolanes, 1,2,4,5-tetraoxanes and their chimeras, are the best choice for malaria treatment nowadays. These therapeutics are fast acting, non-toxic, low costing and without reported data of parasite resistance. Stability of peroxide bonds enables synthetic comfort and resulting in diversity of synthesized structures. The most important classes of peroxide antimalarials with promising representatives are reviewed and possible mechanisms of action were presented in details.
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Tetraoxane Antimalarials and Their Reaction with Fe(II)
Article
  • Jul 2006
Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.
View
  • Jan 1992
  • 61-688
  • J L Vennerstrom
  • H.-N Fu
  • W Y Ellis
  • A L Ager
  • J K Jr
  • S L Wood
  • L Andersen
  • W K Gerena
  • Milhous
Malaria Foundation International, http://www.malaria.org/, and the sites given therein 2. (a) J. L. Vennerstrom, H.-N. Fu, W. Y. Ellis, A. L. Ager, Jr., J. K. Wood, S. L. Andersen, L. Gerena, W. K. Milhous, J. Med. Chem. 35 (1992) 3023; (b) N. M. Todorovi}, M. Stefanovi}, B. Tinant, J. -P. Declercq, M. T. Makler, B. A. [olaja, Steroids 61 (1996) 688; (c) D. Opsenica, G.
  • Jan 2000
  • 62-573
  • J L Vennerstrom
  • A L Ager
  • S L Andersen
  • J M Grace
  • V Wongpanich
  • C K Angerhofer
  • J K Hu
  • D L Wesche
J. L. Vennerstrom, A. L. Ager, S. L. Andersen, J. M. Grace, V. Wongpanich, C. K. Angerhofer, J. K. Hu, D. L. Wesche, Am. J. Trop. Med. Hyg. 62 (2000) 573
  • Jan 2000
  • 43-2753
  • J L Vennerstrom
  • Y Dong
  • S L Andersen
  • A L Ager Jr
  • H.-N Fu
  • R E Miller
  • D L Wesche
  • D E Kyle
  • L Gerena
  • S M Walters
  • J K Wood
  • G Edwards
  • A D Holme
  • W G Mclean
  • W K Milhous
J. L. Vennerstrom, Y. Dong, S. L. Andersen, A. L. Ager Jr., H. -N. Fu, R. E. Miller, D. L. Wesche, D. E. Kyle, L. Gerena, S. M. Walters, J. K. Wood, G. Edwards, A. D. Holme, W. G. McLean, W. K. Milhous, J. Med. Chem. 43 (2000) 2753, and references cited therein
  • Jan 1867
  • H.-S Kim
  • K Tsuchiya
  • Y Shibata
  • Y Wataya
  • Y Ushigoe
  • A Masuyama
  • M Nojima
  • K J Mccullough
(a) H. -S. Kim, K. Tsuchiya, Y. Shibata, Y. Wataya, Y. Ushigoe, A. Masuyama, M. Nojima, K. J. McCullough, J. Chem. Soc., Perkin Trans 1 (1999) 1867; (b) J. Iskra, D. Bonnet-Delponb, J. -P.
13 C-NMR (50 MHz, CDCl 3 ): 174
  • 3-67
  • Mhz
MHz, CDCl 3 ): 3.67 (s, CH 3 O 2 C–C(3)), 2.87 (bs, H–C(3)), 2.5–2.1 (m, 3H), 2.0–1.4 (m, 15H). 13 C-NMR (50 MHz, CDCl 3 ): 174.82, 108.15, 107.04, 51.47, 41.24, 31.50, 30.06, 29.37, 27.90, 25.15, 24.40, 23.67, 21.80. ESI-MS (m/z (%)): 339.36 (100), 327.35 ([M+Na+H 2 O] +, 50), 313.40 ([M+CH+H] +, 35) 304.37 ([M+H 2 O] +, 35), 288.34 (55), 285.37 ([M] +, 95), 257.25 (45), 244.31 (85), 142.26 (65), 209.23 (10), 187.19 (10), 155.20 (45), 141.20 (25), 118.24 (15), 100.32 (10), 68.41 (30).