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. 2023 Oct 24;14(45):12941-12952.
doi: 10.1039/d3sc03661h. eCollection 2023 Nov 22.

Autofluorescent antimalarials by hybridization of artemisinin and coumarin: in vitro/ in vivo studies and live-cell imaging

Lars Herrmann  1 , Maria Leidenberger  2 , Adrielle Sacramento de Morais  3 , Christina Mai  1 , Aysun Çapci  1 , Mariana da Cruz Borges Silva  3 , Fabian Plass  4   5 , Axel Kahnt  4   5 , Diogo R M Moreira  3 , Barbara Kappes  2 , Svetlana B Tsogoeva  1
Affiliations

Autofluorescent antimalarials by hybridization of artemisinin and coumarin: in vitro/ in vivo studies and live-cell imaging

Lars Herrmann et al. Chem Sci. .

Abstract

Malaria is one of our planet's most widespread and deadliest diseases, and there is an ever-consistent need for new and improved pharmaceuticals. Natural products have been an essential source of hit and lead compounds for drug discovery. Antimalarial drug artemisinin (ART), a highly effective natural product, is an enantiopure sesquiterpene lactone and occurs in Artemisia annua L. The development of improved antimalarial drugs, which are highly potent and at the same time inherently fluorescent is particularly favorable and highly desirable since they can be used for live-cell imaging, avoiding the requirement of the drug's linkage to an external fluorescent label. Herein, we present the first antimalarial autofluorescent artemisinin-coumarin hybrids with high fluorescence quantum yields of up to 0.94 and exhibiting excellent activity in vitro against CQ-resistant and multidrug-resistant P. falciparum strains (IC50 (Dd2) down to 0.5 nM; IC50 (K1) down to 0.3 nM) compared to reference drugs CQ (IC50 (Dd2) 165.3 nM; IC50 (K1) 302.8 nM) and artemisinin (IC50 (Dd2) 11.3 nM; IC50 (K1) 5.4 nM). Furthermore, a clear correlation between in vitro potency and in vivo efficacy of antimalarial autofluorescent hybrids was demonstrated. Moreover, deliberately designed autofluorescent artemisinin-coumarin hybrids, were not only able to overcome drug resistance, they were also of high value in investigating their mode of action via time-dependent imaging resolution in living P. falciparum-infected red blood cells.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (a) Structures of established antimalarials chloroquine, artemisinin and artesunic acid and their in vitro activity against CQ-resistant and multidrug-resistant P. falciparum strains Dd2 and K1. (b) The first systematic comparison of antimalarial activities of differently linked monomeric and dimeric artemisinin-based hybrid model drugs using in vitro, in vivo and live-cell bioimaging methods.
Scheme 1
Scheme 1. (a) Synthesis of non-cleavable linker-containing artemisinin-coumarin hybrids 1 and 3 derived from DHA. (b) Synthesis of cleavable linker-containing artemisinin-coumarin hybrids 2 and 4 derived from artesunic acid. (c) Synthesis of reference coumarin-triazoles 5 and 6 bearing no artemisinin unit. Reagents and conditions: (i) H3PW12O40·H2O (10 mol%), DCM, r.t., 6 h; (ii) coumarin-azide 11, CuSO4·5H2O (10 mol%), sodium ascorbate (20 mol%), CH2Cl2 : H2O (1 : 1), r.t., o/n; (iii) BF3·Et2O, Et2O, N2, r.t., 24 h; (iv) coumarin-azide 11, [Cp*Ru(cod)Cl] (2 mol%), DMF, Ar., r.t., 24 h; (v) EDCI, DMAP, DCM, N2, 0 °C to r.t., o/n.; (vi) coumarin-azide 11, CuSO4·5H2O (20 mol%), sodium ascorbate (40 mol%), DMF, Ar., r.t., 1 h; (vii) EDCI, DMAP, DCM/acetonitrile (6/1), 0 °C to r.t., o/n.; (viii) CuSO4·5H2O (20 mol%), sodium ascorbate (40 mol%), DMF, Ar., r.t., 1 h.
Fig. 2
Fig. 2. Panel (a) shows the experimental design for determining the parasite-mediated drug degradation effect. Panel (b) shows the time-dependency concentration for the controls DHA (short-living) and AQ (long-lasting). Panel (c) shows the time-dependency concentration for the hybrids 1–4. Panel (d) compares the drug concentration remaining in the supernatants harvested after 24 h. For panels (b–d): values are the median ± standard error of the mean (S.E.M.) of three independent experiments (each concentration in duplicate). uRBC = uninfected red blood cells; DHA = dihydroartemisinin; AQ = amodiaquine. Full data is disclosed in Table S3.
Fig. 3
Fig. 3. Bright-field and fluorescence images of ring, trophozoite and schizont stages incubated with 1 for 30 min (rows 1–3) and 2 h (rows 4 and 5) before imaging. Syto 13 staining (blue) indicates the position of nuclei. Column A – bright field image, column B – 1 fluorescence (green), column C – Syto 13 fluorescence (blue); column D – merge of the fluorescence of 1 and Syto 13. White bars represent 5 μm.
Fig. 4
Fig. 4. Bright-field and fluorescence images of schizonts incubated with 1 for 4 h (rows 1 and 2) and 8 h (rows 3 and 4). Syto 13 staining (blue) indicates position of nuclei. Column A – bright field image, column B – 1 fluorescence (green), column C – Syto 13 fluorescence (blue); column D – merge I of the fluorescence of 1 and Syto 13; column E − Nile Red fluorescence: Nile Red stains neutral lipid, in particular neutral lipid bodies; column F – merge II of the fluorescence of 1, Syto 13 and Nile Red; White bars represent 5 μm. The white arrows indicate the position of NLBs.
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References

    1. Newman D. J. Cragg G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016;79:629–661. doi: 10.1021/acs.jnatprod.5b01055. - DOI - PubMed
    1. Su X.-Z. Miller L. H. The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. Sci. China: Life Sci. 2015;58:1175–1179. doi: 10.1007/s11427-015-4948-7. - DOI - PMC - PubMed
    1. Tu Y. Artemisinin—A Gift from Traditional Chinese Medicine to the World (Nobel Lecture) Angew. Chem., Int. Ed. 2016;55:10210–10226. doi: 10.1002/anie.201601967. - DOI - PubMed
    1. Efferth T. Dunstan H. Sauerbrey A. Miyachi H. Chitambar C. R. The anti-malarial artesunate is also active against cancer. Int. J. Oncol. 2001;18:767–773. - PubMed
    1. Slack R. D. Jacobine A. M. Posner G. H. Antimalarial peroxides: advances in drug discovery and design. MedChemComm. 2012;3:281–297. doi: 10.1039/C2MD00277A. - DOI