Abstract
Building on the discovery that synthetic ozonides have not only antimalarial but also antischistosomal properties, we now report the synthesis and antischistosomal activity of a series of ozonide glycine ethyl esters. We identified ozonide glycine zwitterion 19 and its ethyl ester 17 as new antischistosomal lead compounds. Ozonides 17 and 19 had high in vivo antischistosomal activity against adult worms and low cytotoxicity. Based on C max and AUC0–24 h values, exposure of 19 after administration of its ethyl ester 17 was approximately 1.5-fold higher than that observed after dosing 19 itself.
Keywords: antischistosomal; glycine ethyl esters; ozonide; prodrugs; 1,2,4-trioxolane
The semisynthetic artemisinins are most widely known for their potent antimalarial activities, − but they also have high activity against schistosomesanother hemoglobin-degrading pathogen. − The pharmacophoric peroxide bond of semisynthetic artemisinins (Figure ) and other antimalarial peroxides undergoes reductive activation by heme released during parasite hemoglobin digestion to produce carbon-centered radicals that alkylate heme and parasite proteins. −
1.
Semisynthetic artemisinins dihydroartemisinin (DHA), artemether (AM), and artesunate (AS).
As exemplified by OZ418 (1) (Figure ), we discovered that synthetic ozonides (1,2,4-trioxolanes) have promising antischistosomal activities, especially against juvenile worms. ,− OZ418 (1) is a carboxylic acid analog of antimalarial ozonide OZ439 (2) (artefenomel). Interestingly, weak-base ozonides 2 and OZ277 (3) (arterolane) (Figure ) also have antischistosomal activity, but they are less active than their ozonide carboxylic acid counterparts. , We also demonstrated that the peroxide bond and spiroadamantane substructure were essential for activity, and that ozonides (1,2,4-trioxolanes) were superior to the corresponding 1,2,4-trioxanes or 1,2,4,5-tetraoxanes.
2.
Ozonides OZ418 (1), OZ439 (2) (artefenomel), OZ277 (3) (arterolane), OZ740 (4), OZ772 (5), OZ780 (6), and OZ781 (7). S. m. (Schistosoma mansoni) single dose ED50 values in mice, AUC values from single 100 mg/kg oral doses in mice.
We later discovered that OZ740 (4) and OZ772 (5), two ozonides with zwitterionic glycine substructures, (Figure ) had high antischistosomal activity. , Ozonides 4 and 5 were more active than 1 against adult Schistosoma mansoni in the mouse model despite their much lower systemic plasma exposures (AUC). We also found that OZ780 (6) and OZ781 (7), the corresponding ethyl esters of 4 and 5, were rapidly transformed to the latter and were also active against S. mansoni in this same mouse model. Leveraging our library of antimalarial weak base ozonides with primary and secondary aliphatic amino functional groups, we now report the synthesis, physicochemical properties, antischistosomal activity, and cytotoxicity of ozonide glycine ethyl esters 8–17, ozonide glycine isopropyl ester 18, and ozonide glycine zwitterion 19. Ozonides 8–19 were screened at single oral doses of 200 mg/kg against adult S. mansoni in the mouse model as worm burden reduction (WBR) data from this dose readily identifies only the most active compounds.
Ozonides 8–19 were quite hydrophobic with calculated log P values ranging from 4.1 to 5.9 (Table ). Not surprisingly, the calculated polar surface area (PSA) values of between 66 and 84 Å2 indicate that the polarity of these compounds is unlikely to be a rate-limiting factor for membrane permeability and oral bioavailability. Ozonide esters 8–18 had S. mansoni IC50 values ranging from 11 to 52 μM against adult worms; in contrast, ozonide carboxylic acid 19, with an IC50 of 71 μM, was somewhat less potent. Seven (9, 11, 13, 15–18) of the 11 new ozonide esters administered at single 200 mg/kg oral doses significantly reduced S. mansoni worm burden. Interestingly, although these seven ozonides were three to four orders of magnitude less potent than praziquantel (PZQ) against S. mansoni in vitro, they had comparable in vivo efficacy. With IC50 values of >50 to >100 μM against the human foreskin fibroblast (HFF) cell line, ozonides 8–19 had relatively low cytotoxicity.
1. Physicochemical, Antischistosomal, and Cytotoxicity Data for Ozonides 1 and 4–19 .
| Compd | log P | PSA (Å2) | S. mansoni adult IC50 (SE) (μM) | S. mansoni % WBR (SE) 1 × 200 mg/kg po | HFF IC50 (μM) |
|---|---|---|---|---|---|
| 1 | 4.0 | 74 | 39 (1.7) | 17 (13) | >100 |
| 4 | 2.9 | 77 | 37 (1.5) | 65 (18) | >100 |
| 5 | 3.9 | 77 | 57 (8.7) | 74 (7) | >50 |
| 6 | 4.5 | 66 | >10 | 65 (12) | ND |
| 7 | 4.9 | 66 | >10 | 76 (8) | >100 |
| 8 | 4.7 | 84 | 18 (16) | 31 (23) | >100 |
| 9 | 4.8 | 75 | 11 | 66 (4) | 75 |
| 10 | 5.3 | 75 | 20 (12) | 31 (18) | >100 |
| 11 | 5.3 | 75 | 22 (13) | 75 (9) | >100 |
| 12 | 4.7 | 75 | 12 (1.7) | 38 (5) | 60 |
| 13 | 5.3 | 75 | 22 (0.4) | 67 (13) | >100 |
| 14 | 4.1 | 78 | 24 (19) | 51 (8) | >100 |
| 15 | 4.5 | 70 | 24 (15) | 68 (5) | >100 |
| 16 | 5.2 | 66 | 52 | 77 (4) | >50 |
| 17 | 5.6 | 66 | 30 (13) | 91 (11) | >50 |
| 18 | 5.9 | 66 | 16 (0.2) | 59 (5) | >100 |
| 19 | 4.4 | 77 | 71 (18) | 68 (3) | >50 |
| PZQ | 2.5 | 41 | 0.05 | 65 (17) | ND |
Calculated log P and PSA values were generated using SwissADME.
72 h incubation time in RPMI, n = 3, SE values could not be determined for 9 and 16.
Groups of four S. mansoni-infected NMRI mice were treated on day 49 post-infection with ozonides dissolved or suspended in 7% v/v Tween 80, 3% v/v ethanol. At 28 d post-treatment, animals were sacrificed and dissected to assess total worm burden reduction (WBR).
Human foreskin fibroblast (HFF) cell line, positive control puromycin IC50 0.7–1.2 μM. ND = not determined.
Antischistosomal data from Biendl et al.
Chromatographically determined g log D 7.4 values for 1 and 4 were 2.9 and 3.3, respectively.
did not dissolve or remain in solution at 100 μM.
Antischistosomal data from Lombardo et al.
p <0.02 from the Kruskal–Wallis test comparing the medians of the responses between the treatment and control groups.
Comparing 6 and 8 reveals that adding a second glycine substructure did not significantly alter in vitro antischistosomal potency, but effectively abolished (from 65% WBR to 31% WBR) in vivo efficacy. For the closely related analogs 9–11, in vitro potency fell in the narrow range of 11 to 22 μM, but only 9 and 11 had high in-vivo efficacy. In contrast, 10, the gem-dimethyl analogue of 9, had no significant in-vivo activity. Adding an alkyne to rigidify the link between the phenyl ether and glycine substructure in 12 maintained good in-vitro potency but not in-vivo efficacy. In contrast, 13, a conformationally restricted analogue of 9, was as active as the latter in vivo. Replacing the ether in 7 with a carboxamide in 14 decreased lipophilicity (c log P 4.9 to 4.1) but reduced in vivo efficacy (76 to 51% WBR). For the piperidine-containing homologous series 5, 16, and 17, lipophilicity (c log P 3.9, 5.2, and 5.6) and antischistosomal activity (IC50 = 57, 52, and 30 μM, WBR = 74%, 77%, and 91%) increased in parallel. This trend is consistent in a comparison of 17 (log P 5.6, 91% WBR) and its less lipophilic piperazine analogue 15 (log P 4.5, 68% WBR).
From these data, we identified 17 as the most active member of these new ozonide glycine ethyl esters (Table ). Assuming a rapid in vivo ester hydrolysis of 17 to its corresponding ozonide carboxylic acid zwitterion 19, as we had previously documented for the conversion of 6 to 4 and 7 to 5 (Figure ), we generated pharmacokinetic data for 17, 19 and the corresponding isopropyl ester 18 (Tables and , Figures and ). Interestingly, ozonide esters 17 and 18 were approximately 2 to 4-fold more potent than 19 against S. mansoni in vitro.
3.
Plasma concentrations of 17 (green) and 18 (black) in male Swiss outbred mice following oral administration of 100 mg/kg doses.
2. Plasma Exposure Parameters Following Oral Administration of Single 100 mg/kg Doses of Ozonide Esters 17 and 18 in Male Swiss Outbred Mice.
| 17 | 18 | |
|---|---|---|
| Apparent half-life (h) | 4.7 | 5.9 |
| C max (μg/mL) | 5.73 | 40.0 |
| T max (h) | 1.0 | 1.0 |
| AUC0‑inf (h μg/mL) | 9.60 | 81.8 |
The terminal elimination phase has been estimated based on the last two time points; therefore, values based on extrapolation to infinity are approximations only.
3. Plasma Exposure Parameters for 19 Following Oral Administration of Single 100 mg/kg Doses of 17, 18, and 19 in Male Swiss Outbred Mice.
| PO dosing of 17 | PO dosing of 18 | PO dosing of 19 | |
|---|---|---|---|
| Apparent half-life (h) | 8.8 | 9.4 | 8.5 |
| C max (μg/mL) | 9.67 ± 1.10 | 6.36 ± 0.301 | 6.87 ± 0.884 |
| T max (h) | 7.5 | 4.0 | 7.5 |
| AUC0‑inf (h μg/mL) | 177 | 120 | 116 |
| AUC0–24 h , (h μg/mL) | 156 ± 7.47 | 102 ± 2.57 | 103 ± 5.39 |
The terminal elimination phase has been estimated based on the last two time points; therefore, values based on extrapolation to infinity are approximations only.
Statistical analysis of C max and AUC0–24 h values (GraphPad Prism software, version 10.4.1, using a one-way ANOVA and Tukey’s test) showed no significant differences (p > 0.05) between 18 and 19 dosing groups and a significant difference (p < 0.05) following administration of 17 compared with 18 and 19.
The AUC0–24 h and associated standard error values were calculated using Bailer’s method in RStudio (version 2024.04.2 Build 764) with the PKNCA package (Version 0.12.0).
4.
Plasma concentrations of 19 in male Swiss outbred mice following single oral dose administration of 19 (blue) or the two esters 17 (red) and 18 (green) at 100 mg/kg. Concentrations of 19 after administration of 17 and 18 have been normalized to a molar dose equivalent to 100 mg/kg of 19.
We then compared the systemic exposure of 19 in male Swiss outbred mice following oral administration of its ethyl (17) or isopropyl (18) esters with that following oral administration of 19 itself. First, we measured the plasma concentration versus time profiles (Figure ) and exposure parameters (Table ) of the two ozonide esters 17 and 18. These data reveal that isopropyl ester 18 had a longer half-life and substantially higher C max and AUC values than ethyl ester 17. This is in accord with higher stability of the more sterically hindered isopropyl , (18) vs ethyl (17) ester to plasma esterases. Based on C max and AUC0–24 h values, we then found that exposure of 19 after administration of its ethyl ester (17) was approximately 1.5-fold higher than that observed after dosing 19 itself; in contrast, no increase in exposure of 19 was observed after administration of its isopropyl ester (18) (Figure , Table ). Finally, we note that, even though 19 has high in vivo antischistosomal efficacy, its C max value of 9.67 μg/mL (18 μM), attained after oral administration of ethyl ester 17, is 4-fold lower than its IC50 of 71 μM against S. mansoni in vitro.
Ozonides 8–19 were synthesized as shown in Scheme . Starting material amino ozonides 20–29 were synthesized as previously described. ,,, Ozonides 8–17 were obtained in 41%–85% yield by alkylation of 20–29 with ethyl bromoacetate in aq. THF in the presence of potassium carbonate. Ozonide 18 was similarly obtained by alkylation of 29 with isopropyl bromoacetate in 75% yield. Finally, 19 was obtained by sodium hydroxide-mediated ester hydrolysis of 17 in 81% yield.
1. Synthesis of Ozonides 8–19 .
a Reagents and conditions: (a) ethyl 2-bromoacetate, K2CO3, 6–12:1 THF/H2O, rt, 12 h; (b) isopropyl 2-bromoacetate, K2CO3, 6:1 THF/H2O, rt, 12 h; (c) 1N aq. NaOH, 50 °C, 12 h, then AcOH to pH 6.
In summary, we identified ozonide glycine zwitterion 19 and its ethyl ester 17 as new antischistosomal lead compounds. Ozonides 17 and 19 had high antischistosomal activity against adult worms and low cytotoxicity. In our ongoing work, we seek to improve antischistosomal activity with more polar and soluble analogs of 17 and 19. The promising antischistosomal efficacies of Synriam, the antimalarial drug combination of OZ277 (3) (arterolane) and piperaquine, with and without praziquantel (PZQ), − also provide the impetus to investigate various ozonide drug combinations.
Supplementary Material
Acknowledgments
We acknowledge Professor D.J. Murry (College of Pharmacy, University of Nebraska Medical Center) for his help in generating the HPLC purity data.
Glossary
Abbreviations
- EA
ethyl acetate
- NTS
newly transformed schistosomula
- PZQ
praziquantel
- WBR
worm burden reduction
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00330.
Antischistosomal and phamacokinetic assays, compound synthesis and characterization, 1H and 13C{1H} NMR spectra, HPLC traces (PDF)
R.R., C.H., G.C., S.K.S., and K.M.B. generated and analyzed data. R.R., C.H., G.C., P.H.D., Y.D., S.A.C., J.K., and J.L.V. analyzed data and wrote the paper.
We acknowledge the U.S. National Institutes of Health (AI116723–01) and the European Research Council (ERC-2020–101019223 DRUGSBUGS) for financial support. A Waters Xevo and helium recovery system supporting the Bruker FT-ICR was purchased with support from the NCIBC Systems Biology Core (NIH NIGMS P20 GM113126). The Centre for Drug Candidate Optimisation, Monash University is partially supported by the Monash University Technology Research Platform network and Therapeutic Innovation Australia (TIA) through the Australian Government National Collaborative Research Infrastructure Strategy (NCRIS) program.
SAFETY STATEMENT: Differential scanning calorimetry experiments demonstrate that this class of ozonides has good thermal stability. Although we encountered no difficulties in working with these ozonides, routine precautions, such as the use of shields and fume hoods and the avoidance of metal salts, should be observed whenever possible.
The authors declare no competing financial interest.
Published as part of ACS Medicinal Chemistry Letters special issue “Bridging Gaps in Global Health with Medicinal Chemistry”.
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