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. 2020 Mar 24;11(5):921–927. doi: 10.1021/acsmedchemlett.9b00669

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

Dionissia A Pepe †, Dimitra Toumpa †, Christiane André-Barrès ‡, Christophe Menendez ‡, Elisabeth Mouray §, Michel Baltas ‡,*, Philippe Grellier §,*, Dionissios Papaioannou †, Constantinos M Athanassopoulos †,*
PMCID: PMC7236259  PMID: 32435406

Abstract

graphic file with name ml9b00669_0005.jpg

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50 values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.

Keywords: Artemisinin, phytormones G-factors, chloroquine, hybrids, conjugates, antimalarials

Malaria is a serious parasitic disease affecting approximately 200 million humans every year and causing almost half a million deaths among infected individuals, according to WHO (World Health Organization). Two main families of drugs are essentially being used for the treatment of malaria. The first one is based on the alkaloid quinine (QN), its more potent analogue chloroquine (CQ) and other quinoline-based antimalarials (e.g., mefloquine or piperaquine), that have been developed thereafter (Figure 1).1,2 Unfortunately, P. falciparum has already developed resistance for CQ and quinoline-based antimalarials. The second family is based on the natural product Artemisin (ART), that was first isolated from the Chinese medicinal plant Artemisia annua L. in 1972 by Tu Youyou.3 ART is a sesquiterpene lactone that incorporates an endoperoxide functionality demonstrated to be important for its antimalarial activity.4 Because of its low bioavailability and an unfavorable pharmacokinetic profile in vivo, intensive research efforts have been concentrated to the development of improved hemisynthetic and fully synthetic ART analogs and derivatives. These efforts have been culminated to the development of the C-10 oxa-substituted ART-based drugs, such as the dihydroartemisinin (DHA), the lipophilic artemether, the hydrophilic sodium artesunate (Figure 1) but more importantly to the corresponding C-10-carba-substituted ART with improved ADMET properties. In that respect we can mention as attractive intermediate the acid (1)8,9 or ART hybrids (see below), such as the anilide 2.9 In addition, C-10-carba-substituted ART dimers or trimers, molecules with two or even three ART moieties connected through symmetric or asymmetric linkers have shown more potent biological (antimalarial or anticancer) activity, depending from the nature of the linker.10−12 Unfortunately, P. falciparum resistance to ART derivatives in the South East Asia and particularly in Cambodia has been observed.13 In a seminal work,5 molecular marker of ART resistance that is the kelch propeller protein (K13-propeller) has recently been identified and should be important in the continuing efforts to restrain ART resistance.6,7

Figure 1.

Figure 1

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Molecular structures of known antimalarial agents.

Inspired by ART, many groups developed methods for constructing trioxanes, entities known to exhibit antimalarial activity in a similar manner to ART. Synthetic molecules of this type with strong activities have been reported by the groups of Posner, Kepler, Singh, and Griesbeck.14−16 Also of high importance are the efforts of Meunier’s group toward the development of trioxaquines that are molecules based on the covalent bitherapy, obtained by attachement of a trioxane entity to an aminoquinoline entity.17,18

For many years now, we have been interested in the naturally occurring phytormones known as G- factors (G1, G2, G3) synthesized from syncarpic acid and incorporating an endocyclic endoperoxide frame.19 The natural compounds and many synthetic analogs have been synthesized.20,21 Among them, the methylated compound G3Me (Figure 1) and its derivatives have been shown to be potent antimalarial agents. In particular, the G3Me-derived amino-endoperoxide spiro compound (endoperoxide GMeP, 3), suitable for the synthesis of G factor hybrids through a succinic acid type linker (compound 4), has been developed and two compounds also incorporating CQ proved to be very active.21

Because of the emerging resistance of P. falciparum to artemisinins, WHO urgently recommends the use of artemisinin-based combination therapies (ACTs), which involve the combination of a potent but short-lived ART derivative, e.g., artemether or sodium artesunate, with one or even two longer-lasting partner drugs with a different mechanism of action, e.g., a quinoline-based drug. Such combinations are, for example, “artesunate-MQ” or “artesunate-MQ-PQ”. Recently, the combination of two antimalarial drugs in one single molecular entity (coined as hybrid or conjugate) has been described as being more efficient against diseases such as malaria and cancer. Hybrid molecules have probably less chance to develop drug resistance.1 Examples of ART–CQ (S1-S2)1,11 or a G-factor–CQ (S3) hybrids,21 and of conjugates (S4–S6) of ART with the naturally occurring polyamines (PAs), e.g. spermidine (Spd) or spermine (Spm),22−24 of relevance to the present work are provided in Figure S1. It should be noted that naturally occurring and synthetic PAs, their analogs, and conjugates with other biologically active molecules are compounds with a variety of interesting biological properties.25,26 Conjugation of organic or bioorganic molecules with PAs has been used as a mean to improve or combine the biological properties of the constituent molecules. PAs can form the basis for the development of novel pharmaceuticals.27,28

Accordingly, we now wish to report our first results on the synthesis of two types of artemisinin hybrids/conjugates with the endoperoxide GMeP (3) or the 4-aminosubstituted 7-chloroquinoline (ACQ) core of CQ, and the biological evaluation of their antimalarial potential. Hybrids of the first type are compounds 5, 6, and 7 (Figure 2) in which the two pharmacophores are joined with an amide bond using suitable linkers. For the sake of comparison, hybrid 8(19) of endoperoxide-GMeP (3) with ACQ was also synthesized. Conjugates of the second type (Figure 2) are characterized by two molecules of ART and one molecule of endoperoxide-GMeP (compounds 9 and 10) or ACQ (compounds 11 and 12). For the sake of comparison, conjugates bearing two molecules of 3 and one molecule of ACQ (13 and 14) per molecule of PA were also synthesized.

Figure 2.

Figure 2

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Structures of synthesized ART–endoperoxide GMeP (5), ART–ACQ (6 and 7) and ACQ–endoperoxide GMeP (8) hybrids, and ART–Spd and – Hsd mixed conjugates with endoperoxide GMeP and ACQ (9, 10 and 11, 12, respectively) and endoperoxide GMeP–Spd and −Hsd mixed conjugates with ACQ (13 and 14).

With these new hybrids/conjugates, we wished to determine the various factors affecting their potential antimalarial activity, such as (a) the influence of the other antimalarial agents linked with ART (comparing for example conjugates 5 and 6 or 9 and 11), (b) the structure (conformationally restricted or not) or the length (Spd against Hsd chain) of the linker (comparing, for example, conjugates 6 and 7 or 9 and 10, respectively) and (c) the number (one against two) of ART or endoperoxide-GMeP residues in the conjugate (comparing, for example, conjugates 5 and 9 or 8 and 13, respectively).

The synthesis of ART conjugates 5, 6, and 7 requires the ART-derived carboxylic acid 1 as key-intermediate. This compound was prepared (Scheme S1) in 58% overall yield from ART according to a published five-step procedure.8,9 On the other hand, endoperoxide GMeP (3) was synthesized from syncarpic acid in a sequence of three in situ reactions (Mannich, dienol formation, oxygen uptake) followed by tert-butyloxycarbonyl (Boc) deprotection in an overall yield of 50%, according to our published procedure (Supporting Information).21 The required syncarpic acid was synthesized (Supporting Information), essentially through a reported procedure starting from 2′,4′,6′-trihydroxyacetophenone.29 An alternative synthesis of this key-intermediate has been also previously described.19

Finally, the N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine (15) and the 7-chloro-4-(piperazin-1-yl)quinoline (16) were readily obtained in 56 and 76% yield, respectively, from the commercially available 4,7-dichloroquinoline through the nucleophilic aromatic substitution of the latter with 1,2-diaminoethane and piperazine, respectively (Scheme S1).21

Having in our hands all the above needed intermediates we proceeded to the synthesis of the hybrids and conjugates as described in Schemes 1 and 2, respectively. Thus, condensation of acid 1 with amines 3 (GMeP), 15, and 16, in the presence of the coupling agent HBTU and DIPEA produced unexceptionally the anticipated conjugates 5, 6, and 7 in 95, 80, and 72% yields, respectively (Scheme 1).

Scheme 1. Synthesis of ART–Endoperoxide GMeP (5), ART–ACQ (6 and 7) and ACQ–Endoperoxide GMeP (8) hybrids.

Scheme 1

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Reagents and reaction conditions: (i) HBTU, DIPEA, CH2Cl2, 0 °C to rt, 3–12 h.

Scheme 2. Synthesis of ART–Spd and −Hsd Mixed Conjugates with Endoperoxide GMeP or ACQ (9-12) and Endoperoxide GMeP–Spd and −Hsd Mixed Conjugates with ACQ (13 and 14).

Scheme 2

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Reagents and reaction conditions: (i) HBTU, DIPEA, CH2Cl2, 0 °C to rt, 3–12 h; (ii) succinic anhydride, DMAP, CH2Cl2, 0 °C to rt, 12 h; (iii) 3–6% TFA in CH2Cl2, CF3CH2OH, 0 °C, 2–12 h.

On the other hand, the synthesis of the conjugate 8 involved the initial reaction of amine 15 with succinic anhydride to give the corresponding carboxylic acid 17 in 100% yield. This acid was then coupled with endoperoxide GMeP (3), also in the presence of HBTU and DIPEA, to give conjugate 8 in 72% yield.

The synthesis of ART-Spd and Art-Hsd mixed conjugates 9, 10, 11, and 12 with endoperoxide GMeP (3) or ACQ, as well as the endoperoxide GMeP-Spd and endoperoxide GMeP-Hsd mixed conjugate 13 and 14 with ACQ, required the availability of suitably protected triamines, such as the N1,N8-ditritylspermidine (18)30,31 and N1,N9-ditritylhomospermidine (19). These compounds are readily available, in 48% overall yield, from butane-1,4-diamine (putrescine, Put) through a three-steps sequence, depicted in Scheme S1.

Reaction of PA derivatives 18 and 19 with succinic anhydride gave the anticipated monocarboxylic acid derivatives 20 and 21, respectively, in quantitative yield. These compounds were then coupled with endoperoxide GMeP (3) in the presence of HBTU and DIPEA to give the protected PA conjugates 22 and 23 in 40 and 67% yield, respectively. The final products 9 and 10 were obtained in 64 and 40% yield, respectively, upon N-deprotection followed by coupling with ART-derived acid 1, in the presence of HBTU and DIPEA (Scheme 2).

On the other hand, coupling of partially protected PAs 18 and 19 with the ACQ-derived acid 17, in the presence of HBTU and DIPEA, produced PA conjugates 24 and 25 in 86% yield. From these conjugates, the final products 11 and 12 were unexceptionally obtained in 61 and 32% yields upon detritylation and coupling with ART-derived acid 1. Similarly, the conjugates 13 and 14 were readily obtained (Scheme 2) from the same polyamine conjugates 24 and 25, in 40 and 34% yield, respectively, upon deprotection of the latter followed by coupling with endoperoxide GMeP-derived acid 4. The latter was readily obtained in 98% from the reaction of endoperoxide GMeP and succinic anhydride (Scheme S1). The experimental details for the synthesis of (a) all above-described fragments, which are necessary for the assembly of the proposed hybrids/conjugates, and (b) the final products, that are hybrids/conjugates 5–14, are provided in the Supporting Information.

The synthesized conjugates were evaluated for their antiplasmodial activity against the CQ-resistant P. falciparum FcB1/Colombia strain, according to published procedure.32,33 The cytotoxicity of the compounds was evaluated using the primary human fibroblast cell line AB943, also according to published procedure,34 which allowed the calculation of their selectivity index (SI). In Table 1 (see also Table S1), the measured IC50 values or the % inhibition at 10 nΜ, in cases where IC50 values could not be determined, and SIs for the synthesized hybrids/conjugates are reported. IC50 values for ART, CQ, and endoperoxide GMeP (3) are also provided for the sake of comparison.

Table 1. Evaluation of Antiplasmodial Activities of Synthesized Compounds with CQ-Resistant P. falciparum FcB1/Colombia Strain and Selectivity Indexes (SI).

compd IC50 (nΜ) or % inhibition at 10 nM SI compd IC50 (nΜ) or % inhibition at 10 nM SI
5 2.6 ± 1.0 16 372 12 52.3 ± 15.9 328
6 11%   13 >167  
7 11%   14 >167  
8 124.3 ± 40.4 144 ART 55 ± 13.6 >4545
9 8.4 ± 3.7 2108 CQ 72 ± 7.4 347
10 10.6 ± 2.3 983 3 >250  
11 33%        
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From Table 1, it is apparent that three out of seven of the synthesized hybrids/conjugates of ART, incorporating one or two molecules of ART per hybrid/conjugate, are significantly more potent (IC50 values ranging from 2.6 to 10.6 nM) than the parent compound, one conjugate (12) was almost equipotent to ART but with at least 13 times lower SI value and the rest showed low inhibition values (11–33%) at 10 nM. In particular, the hybrid 5 of ART with endoperoxide GMeP is the most potent in this series of compounds with an IC50 value 21 times lower than that of ART. Interestingly, this compound appears to be the safest compound for use as antimalarial (SI = 16 372) as its SI is significantly higher than that of ART and ca. 8–17 times higher than the other two best synthesized conjugates (9 and 10). A comparison of hybrid 5 (IC50 = 2.6 nM, SI = 16 372), bearing one molecule of ART, with the conjugates 9 (IC50 = 8.4 nM, SI = 2,108) and 10 (IC50 = 10.6 nM, SI = 983), bearing two molecules of ART held together through a PA chain, showed that a second ART molecule does not offer any particular advantage but also leads to significant lowering of the SI value. On the other hand, comparison of the two conjugates 9 and 10, differing only in the length of the PA chain, shows that the two compounds have comparable IC50 but the one with the Hsd longer chain is ca. 2.1 times less safe than the one with the Spd shorter chain. On the other hand, the hybrids 6 and 7 of ART with the CQ core show identically low inhibition values (11% inhibition. at 10 nM), indicating that (a) the CQ core does not offer any advantage to ART and (b) the structure of the diamine linker seems not to be important for the antiplasmodial activity.

Comparison of the couples of conjugates 9 (IC50 = 8.4 nM, SI = 2108) and 11 (33% inh. at 10 nM) and 10 (IC50 = 10.6 nM, SI = 983) and 12 (IC50 = 52.3 nM, SI = 460), bearing the Spd and the Hsd PA core linkers, respectively, two ART molecules and either a molecule of the endoperoxide GMeP or the CQ core, shows that the endoperoxide GMeP substructure is more important for biological activity than the CQ core providing safer conjugates. Finally, the hybrid 8 of endoperoxide GMeP with the CQ core is almost 2.5 times less active than ART having almost 10 times higher SI value. Moreover, comparison of conjugate 8 (IC50 = 124.3 nM, SI = 144) with the conjugates 13 (IC50 > 167 nM) and 14 (IC50 > 167 nM), incorporating two molecules of endoperoxide GMeP per molecule of conjugate, shows that the former is slightly more active than the latter conjugates.

In conclusion, a series of novel hybrids of ART with either endoperoxide GMeP or the ACQ core of CQ and conjugates of the same compounds with the PAs Spd (an asymmetric PA) and Hsd (a symmetric, with longer chain, PA), bearing either two molecules of ART or of endoperoxide GMeP, were synthesized and their antiplasmodial activities and selectivity indexes (SI) were evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain and the primary human fibroblasts cell line AB943 (for SI calculations), respectively. These studies showed that the most potent combination with the highest SI value was that between ART and the endoperoxide GMeP, in particular when the two molecules participate in the construct (hybrid/conjugate) in the ratio 1:1, that is without the intervention of a PA chain. Combinations between endoperoxide GMeP and ACQ seem not to be particularly effective, whereas the length of the PA chain or the geometry (symmetric or asymmetric) of the construct, defined by the PA used, does not seem to play any significant role. It seems that combinations of two endoperoxide-type compounds can form the basis for the development of more potent and safer antimalarial and therefore we are currently engaged in this line of research. Moreover, it should be important to study in a further work, if the three hybrid compounds possessing two different trioxane frames and different linkers between them can affect the spread of ART resistance and mitigate its impact on malaria treatment.

Acknowledgments

We thank the CNRS, the University Paul Sabatier, and the University of Patras for financial support. We thank the Erasmus+ Program for financing D. Pepe’s traineeship and the University Paul Sabatier for financing the visiting professorship of Assoc. Prof. C.M. Athanassopoulos, 2017. The authors would like to acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery”. The NMR Facility (ICT, Toulouse, France, http://ict.ups-tlse.fr/?RMN-103) and the Instrumental Analysis Laboratory (School of Natural Sciences, University of Patras) are gratefully acknowledged for carrying out the NMR analyses. The ICT Mass Spectrometry facility (http://ict.ups-tlse.fr/?HPLC-102) is also acknowledged for the recording of HRMS spectra.

Glossary

Abbreviations

ACQ

4-amino-7-chloroquinoline

ACTs

Artemisinin-based combination therapies

ADMET

Absorption, Distribution, Metabolism, Excretion and Toxicity

ART

artemisinin

Boc

tert-butoxycarbonyl

CQ

chloroquine

DIPEA

diisopropylethylamine

DMAP

4-Dimethylaminopyridine

GMeP

phytormone endoperoxide G-factor analogue

HBTU

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

Hsd

homospermidine

MQ

mefloquine

PAs

polyamines

PQ

piperaquine

Put

putrescine

QN

quinine

rt

room temperature

SI

selectivity index

Spd

spermidine

Spm

spermine

TFA

Trifluoroacetic acid

WHO

World Health Organization

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00669.

  • Synthetic and bioassay protocols, as well as copies of 1H and 13C NMR spectra for all the synthesized compounds (PDF)

Author Contributions

D.A.P. and D.T. carried out the synthetic work and prepared the Supporting Information; C.M.A. conceived and directed the whole project and wrote part of the manuscript; M.B. codirected the project, followed up the program in Toulouse, and wrote part of the manuscript; C.A.B. followed up synthetic steps in Toulouse of the G3 endoperoxide part and a final compound; C.M. supported analytical and preparative chromatography; P.G. and E.M. directed and performed all biological studies; D.P. supervised the polyamine synthetic part and wrote part of the manuscript.

The authors declare no competing financial interest.

Dedication

This article is dedicated to the memory of our good friend, Professor Maurizio Botta.

Supplementary Material

ml9b00669_si_001.pdf (3.1MB, pdf)

References

  1. Çapci A.; Lorion M. M.; Wang H.; Simon N.; Leidenberger M.; Borges Silva M. C.; Moreira D. R. M.; Zhu Y.; Meng Y.; Chen J. Y.; Lee Y. M.; Friedrich O.; Kappes B.; Wang J.; Ackermann L.; Tsogoeva S. B. Artemisinin-(Iso)quinoline Hybrids by C-H Activation and Click Chemistry: Combating Multidrug-Resistant Malaria. Angew. Chem., Int. Ed. 2019, 58, 13066–13079. and references cited therein 10.1002/anie.201907224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Rudrapal M.; Chetia D. Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold. Drug Des., Dev. Ther. 2016, 10, 3575–3590. and references cited therein 10.2147/DDDT.S118116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Tu Y. Artemisinin-A Gift from Traditional Chinese Medicine to the World (Nobel Lecture. Angew. Chem., Int. Ed. 2016, 55, 10210–10226. 10.1002/anie.201601967. [DOI] [PubMed] [Google Scholar]
  4. Li J.; Zhou B. Biological Actions of Artemisinins: Insights from Medicinal Chemistry Studies. Molecules 2010, 15, 1378–1397. 10.3390/molecules15031378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ariey F.; Witkowski B.; Amaratunga C.; Beghain J.; Langlois A.-C.; Khim N.; Kim S.; Duru V.; Bouchier C.; Ma L.; Lim P.; Leang R.; Duong S.; Sreng S.; Suon S.; Chuor C. M.; Bout D. M.; Menard S.; Rogers W. O.; Genton B.; Fandeur T.; Miotto O.; Ringwald P.; Le Bras J.; Berry A.; Barale J.-C.; Fairhurst R. M.; Benoit-Vical F.; Mercereau-Puijalon O.; Menard D. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014, 505, 50–55. 10.1038/nature12876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Straimer J.; Gnadig N. F.; Witkowski B.; Amaratunga C.; Duru V.; Ramadani A. P.; Dacheux M.; Khim N.; Zhang L.; Lam S.; Gregory P. D.; Urnov F. D.; Mercereau-Puijalon O.; Benoit-Vical F.; Fairhurst R. M.; Menard D.; Fidock D. A. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 2015, 347, 428–431. 10.1126/science.1260867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ouji M.; Augereau J.-M.; Paloque L.; Benoit-Vical F. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination. Parasite 2018, 25, 24. 10.1051/parasite/2018021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ma J.; Katz E.; Kyle D. E.; Ziffer H. Syntheses and Antimalarial Activities of 10-Substituted Deoxoartemisinins. J. Med. Chem. 2000, 43, 4228–4232. 10.1021/jm000195l. [DOI] [PubMed] [Google Scholar]
  9. Woodard L. E.; Chang W.; Chen X.; Liu J. O.; Shapiro T. A.; Posner G. H. Malaria-Infected Mice Live until at Least Day 30 after New Monomeric Trioxane Combined with Mefloquine Are Administered Together in a Single Low Oral Dose. J. Med. Chem. 2009, 52, 7458–7462. 10.1021/jm9005934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Posner G. H.; Ploypradith P.; Parker M. H.; O’Dowd H.; Woo S.-H.; Northrop J.; Krasavin M.; Dolan P.; Kensler T. W.; Xie S.; Shapiro T. A. Antimalarial, Antiproliferative, and Antitumor Activities of Artemisinin-Derived, Chemically Robust, Trioxan Dimers. J. Med. Chem. 1999, 42, 4275–4280. 10.1021/jm990363d. [DOI] [PubMed] [Google Scholar]
  11. Jung M.; Lee S.; Ham J.; Lee K.; Kim H.; Kim S. K. Antitumor Activity of Novel Deoxoartemisinin Monomers, Dimers, and Trimer. J. Med. Chem. 2003, 46, 987–994. 10.1021/jm020119d. [DOI] [PubMed] [Google Scholar]
  12. Lombard M. C.; N’Da D. D.; Breytenbach J. C.; Kolesnikova N. I.; Tran Van Ba C.; Wein S.; Norman J.; Denti P.; Vial H.; Wiesner L. Antimalarial and anticancer activities of artemisinin-quinoline hybrid-dimers and pharmacokinetic properties in mice. Eur. J. Pharm. Sci. 2012, 47, 834–841. 10.1016/j.ejps.2012.09.019. [DOI] [PubMed] [Google Scholar]
  13. Miotto O.; Almagro-Garcia J.; Manske M.; Macinnis B.; Campino S.; Rockett K. A.; Amaratunga C.; Lim P.; Suon S.; Sreng S.; Anderson J. M.; Duong S.; Nguon C.; Chuor C. M.; Saunders D.; Se Y.; Lon C.; Fukuda M. M.; Amenga-Etego L.; Hodgson A. V.; Asoala V.; Imwong M.; Takala-Harrison S.; Nosten F.; Su X. Z.; Ringwald P.; Ariey F.; Dolecek C.; Hien T. T.; Boni M. F.; Thai C. Q.; Amambua-Ngwa A.; Conway D. J.; Djimde A. A.; Doumbo O. K.; Zongo I.; Ouedraogo J. B.; Alcock D.; Drury E.; Auburn S.; Koch O.; Sanders M.; Hubbart C.; Maslen G.; Ruano-Rubio V.; Jyothi D.; Miles A.; O’Brien J.; Gamble C.; Oyola S. O.; Rayner J. C.; Newbold C. I.; Berriman M.; Spencer C. C.; McVean G.; Day N. P.; White N. J.; Bethell D.; Dondorp A. M.; Plowe C. V.; Fairhurst R. M.; Kwiatkowski D. P. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat. Genet. 2013, 45 (6), 648–655. 10.1038/ng.2624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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 (4), 713–716. 10.1021/jm00399a004. [DOI] [PubMed] [Google Scholar]
  15. Singh C.; Gupta N.; Puri S. K. Photo-oxygenation of geraniol: synthesis of a novel series of hydroxy-functionalized anti-malarial 1,2,4-trioxanes. Bioorg. Med. Chem. Lett. 2002, 12 (15), 1913–1916. 10.1016/S0960-894X(02)00320-7. [DOI] [PubMed] [Google Scholar]
  16. 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 (3), 595–597. 10.1016/j.bmcl.2004.11.043. [DOI] [PubMed] [Google Scholar]
  17. Dechy-Cabaret O.; Benoit-Vical F.; Loup C.; Robert A.; Gornitzka H.; Bonhoure A.; Vial H.; Magnaval J. F.; Seguela J. P.; Meunier B. Synthesis and antimalarial activity of trioxaquine derivatives. Chem. - Eur. J. 2004, 10 (7), 1625–1636. 10.1002/chem.200305576. [DOI] [PubMed] [Google Scholar]
  18. Meunier B. Hybrid molecules with a dual mode of action: dream or reality?. Acc. Chem. Res. 2008, 41 (1), 69–77. 10.1021/ar7000843. [DOI] [PubMed] [Google Scholar]
  19. Benbakkar M.; Baltas M.; Gorrichon L.; Gorrichon J. P. Synthesis of Syncarpic Acid and Related β-Oxo δ-Enol Lactone via Selective O- or C- Acylation of Preformed Enolates. Synth. Commun. 1989, 19, 3241–3247. 10.1080/00397918908052724. [DOI] [Google Scholar]
  20. Najjar F.; Gorrichon L.; Baltas M.; Vial H.; Tzedakis T.; André-Barrès C. Crucial role of peroxyketal function for antimalarial activity in the G-factors series. Bioorg. Med. Chem. Lett. 2004, 14, 1433–1436. and references therein 10.1016/j.bmcl.2004.01.024. [DOI] [PubMed] [Google Scholar]
  21. Ruiz J.; Azéma J.; Payrastre C.; Baltas M.; Tuccio B.; Vial H.; André-Barrès C. Antimalarial bicyclic peroxides belonging to the G-factor family: mechanistic aspects of their formation and iron (II) induced reduction. Curr. Top. Med. Chem. 2014, 14, 1668–1683. and references therein 10.2174/1568026614666140808154326. [DOI] [PubMed] [Google Scholar]
  22. Pearce A. N.; Kaiser M.; Copp B. R. Synthesis and antimalarial evaluation of artesunate-polyamine and trioxolane-polyamine conjugates. Eur. J. Med. Chem. 2017, 140, 595–603. 10.1016/j.ejmech.2017.09.040. [DOI] [PubMed] [Google Scholar]
  23. Magoulas G. E.; Tsigkou T.; Skondra L.; Lamprou M.; Tsoukala P.; Kokkinogouli V.; Pantazaka E.; Papaioannou D.; Athanassopoulos C. M.; Papadimitriou E. Synthesis of novel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents. Bioorg. Med. Chem. 2017, 25, 3756–3767. 10.1016/j.bmc.2017.05.018. [DOI] [PubMed] [Google Scholar]
  24. Chadwick J.; Jones M.; Mercer A. E.; Stocks P. A.; Ward S. A.; Park B. K.; O’Neill P. M. Design, synthesis and antimalarial/anticancer evaluation of spermidine linked artemisin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines. Bioorg. Med. Chem. 2010, 18, 2586–2597. 10.1016/j.bmc.2010.02.035. [DOI] [PubMed] [Google Scholar]
  25. Karigiannis G.; Papaioannou D. Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates. Eur. J. Org. Chem. 2000, 2000, 1841–1863. . [DOI] [Google Scholar]
  26. Hahn F.; Schepers U.. Solid phase chemistry for the directed synthesis of biologically active polyamine analogs, derivatives, and conjugates. Combinatorial Chemistry on Solid Supports; Bräse S., Ed.; Springer: Berlin, 2007; Vol. 278, pp 135–208. [Google Scholar]
  27. Polyamine Drug Discovery; Woster P. M., Casero R. A. Jr., Εds.; RSC Publishing, 2011. [Google Scholar]
  28. Melchiorre C.; Bolognesi M. L.; Minarini A.; Rosini M.; Tumiatti V. Polyamines in drug discovery: From the universal template approach to the multi-targeted ligand design strategy. J. Med. Chem. 2010, 53, 5906–5914. 10.1021/jm100293f. [DOI] [PubMed] [Google Scholar]
  29. Morkunas M.; Dube L.; Götz F.; Maier M. E. Synthesis of the acylphloroglucinols rhodomyrtone and rhodomyrtosone B. Tetrahedron 2013, 69, 8559–8563. 10.1016/j.tet.2013.07.091. [DOI] [Google Scholar]
  30. Magoulas G. E.; Bariamis S. E.; Athanassopoulos C. M.; Papaioannou D. Synthetic studies toward the development of novel minoxidil analogs and conjugates with polyamines. Tetrahedron Lett. 2010, 51, 1989–1993. 10.1016/j.tetlet.2010.02.037. [DOI] [Google Scholar]
  31. Tsiakopoulos N.; Damianakos C.; Karigiannis G.; Vahliotis D.; Papaioannou D.; Sindona G.. Syntheses of crowned polyamines using isolable succinimidyl esters of N-tritylated linear amino acids and peptides. ARKIVOC 2002 ( (xii), ) 79–104. [Google Scholar]
  32. Grayfer T. D.; Grellier P.; Mouray E.; Dodd R. H.; Dubois J.; Cariou K. Mallotojaponins B and C: Total Synthesis, Antiparasitic Evaluation, and Preliminary SAR Studies. Org. Lett. 2016, 18, 708–711. 10.1021/acs.orglett.5b03676. [DOI] [PubMed] [Google Scholar]
  33. Bosc D.; Mouray E.; Cojean S.; Franco C. H.; Loiseau P. M.; Freitas-Junior L. H.; Moraes C. B.; Grellier P.; Dubois J. Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors. Eur. J. Med. Chem. 2016, 109, 173–186. 10.1016/j.ejmech.2015.12.045. [DOI] [PubMed] [Google Scholar]
  34. Kryshchyshyn A.; Kaminskyy D.; Karpenko O.; Gzella A.; Grellier P.; Lesyk R. Thiazolidinone/thiazole based hybrids - new class of antitrypanosomal agents. Eur. J. Med. Chem. 2019, 174, 292–308. 10.1016/j.ejmech.2019.04.052. [DOI] [PubMed] [Google Scholar]

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