Novel Thioethers of Dihydroartemisinin Exhibiting Their Biological Activities

Truong, Ngoc Hung; Tran, Thi Hong Ha; Hoang, Kim Chi; Ninh, Duc Bao; Le, Viet Duc; Le, Duc Anh; Luu, Van Chinh

doi:https://doi.org/10.1155/2023/6761186

Heteroatom Chemistry

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Abstract Introduction Materials and Methods Results and Discussion Conclusions Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 6761186 | https://doi.org/10.1155/2023/6761186

Novel Thioethers of Dihydroartemisinin Exhibiting Their Biological Activities

Ngoc Hung Truong,¹Thi Hong Ha Tran,¹Kim Chi Hoang,¹Duc Bao Ninh,²Viet Duc Le,³Duc Anh Le,⁴and Van Chinh Luu¹

Academic Editor: Vijay Kumar Siripuram

Received27 Oct 2022

Revised20 Dec 2022

Accepted20 Jan 2023

Published09 Feb 2023

Abstract

Eleven conjugates between dihydroartemisinin (DHA) with thiols containing both ether and thioether bonds were designed, synthesized by a two-step procedure including etherification and S-alkylation. Analysis of the NMR spectral data indicated that the dimer of DHA with thiols 6-mercaptopurine and 2-mercaptoimidazole was produced with yields of 31% and 62%, respectively. Furthermore, the tautomerization of thiol 5-methoxy-2-mercaptobenzimidazole led to the formation of a mixture of two isomers in which they might be interchangeable through a dynamic tautomeric equilibrium in the solution. Screening in vitro biological activities revealed that most of the synthesized conjugates showed good cytotoxic and anti-inflammatory activity, while three of them displayed α-glucosidase inhibitory activity. Notably, two conjugates 5d and 5e of DHA with thiols 2-mercaptopyrimidine and 2-mercaptobenzothiazole had an effect in all tested activities in which conjugate 5e is the most potent.

1. Introduction

Artemisinin, a sesquiterpene lactone, has been isolated on a large-scale from Artemisia annua L. in Vietnam [1]. Artemisinin has excellent antimalarial activity due to an endoperoxide bridge that is an active center for biological activity [2]. Discovery of artemisinin was considered a revolution in the treatment of severe malaria in the 90s of the last century [3]. In a short time, many artemisinin derivatives were introduced and screened for antimalarial activity to find new drugs for the treatment of this disease with the aim of improving efficacy and resistance [4]. Among these derivatives, dihydroartemisinin 1 (DHA), artemether 1a, and artesunate 1b (Figure 1) are three candidates that have the earliest been approved for use in the treatment of malarial disease [5, 6]. Although the antimalarial activity is improved compared with artemisinin, over time resistance to these drugs has also been discovered, and their effectiveness is also significantly reduced [7, 8]. Thus, various artemisinin derivatives were prepared and probed for antimalarial activity, for example, DHA α-alkylbenzylic ethers [9], derivatives containing a sugar moiety [10], water-soluble derivatives [11, 12]. Apparently, artemisinin scaffold is still the best selection for new antimalarial drug development.

In addition to antimalarial activity, artemisinin and its derivatives have also been discovered as potential candidates for anti-inflammatory and antitumor activities [13–19]. Reports show that artesunate is a potent inhibitor of many cancer cell lines and effectively prevents metastasis of tumor cells [20–23]. Interestingly, artesunate 1b is less toxic to healthy cells, and suitable for clinical trial studies. Based on the artesunate 1b structure, a dimethylene bridge in the ether C-O-C linkage at C10 was used as a template for the synthesis of dihydroartemisinin derivatives. Several structures like 1c and 1d were also reported to have potential in vitro anticancer activity [24, 25]. Therefore, artemisinin 1 scaffold is an ideal target for searching and developing a new drug that can be used for both antimalarial and antitumor purposes.

In pharmaceutical chemistry research, thiols are considered as substances with a broad spectrum of activities, including anti-inflammatory and anticancer activities [26–29]. They are widely used in drug design, and several thiols are important components of drugs such as omeprazole and lansomeprazole [30, 31]. In our previous report [32], the conjugates of thiol with zerumbone, another naturally occurring sesquiterpene, exhibited activity against HepG2, A549, and HeLa cell lines with the IC₅₀ ranging from 0.93 to 22.40 μM, that were approximately 4-fold to 20-fold stronger cytotoxic activity than that of zerumbone. Therefore, the strategy of using thiols in combination with the artemisinin skeleton can be effective. Currently, there are few studies on the conjugates of thiols with DHA [33–35]. Notably, three thioethers between DHA and mercaptothiadiazoles, mercaptotetrazole via a dimethylene bridge as well as their antibacterial activity were reported [35]. In line with our continuing study into the chemical modification at C-10 of DHA, in the present work, new derivatives of DHA with a series of heterocyclic thiols via thioether and ether linkages were designed, synthesized, and evaluated for their cytotoxic, anti-inflammatory, and α-glucosidase inhibitory activities.

2. Materials and Methods

2.1. Chemistry

Dihydroartemisinin is commercially available in Vietnam. Other chemicals were purchased from Sigma-Aldrich and used without further purification. ¹H-NMR and ¹³C-NMR spectra were recorded at ambient temperature on a Bruker Avance 600 MHz spectrometer in DMSO-d₆. Chemical shifts δ are quoted in parts per million (ppm) referenced to the residual solvent peak, (DMSO-d₆ at 2.49 ppm and 39.5 ppm) relative to TMS. High-resolution mass spectra were recorded by using a X500R QTOF LC-MS system, SCIEX, US. Thin-layer chromatography (TLC) was performed on a precoated aluminum sheet of Silica Gel 60 F254 (Merck), and products were visualized by using a UV lamp at 254 nm. Column chromatography was carried out on silica gel (40–230 mesh).

Synthesis of 2-(10-β-dihydroarteminoxy) ethyl bromide 3: 2-(10-β-dihydroarteminoxy) ethyl bromide 3 was obtained in 46% yield by the etherification of DHA with 2-bromoethanol 2 catalyzed by BF₃. Et₂O in dichloromethane according to a known procedure [36].

General procedure for the synthesis of artemisinin derivatives 5a–k: Each mercapto compound 2-mercaptopyridine 4a, 4-mercaptopyridine 4b, 2-mercaptopyrimidine 4c, 2-mercaptobenzoxazole 4d, 2-mercaptobenzothiazole 4e, methyl 2-mercaptobenzoate 4f, 2-mercaptoimidazole 4g, 6-mercaptopurine 4h, 2-mercaptobenzimidazole 4i, or 5-methoxy-2-mercaptobenzimidazole 4k (1 mmol, 1.0 equiv.) was dissolved in dry DMF (5 mL), then potassium carbonate (1.5 equiv.) and compound 2 (1.0 equiv.) were added. Reaction mixtures were stirred at room temperature overnight and monitored by TLC. At the end of the reaction, cool water (15 mL) was added, and then the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over anhydrous Na₂SO₄, then filtered and evaporated under reduced pressure. Crude products 5a–5k were purified by column chromatography on silica gel eluting with n-hexane/acetone to obtain the desired products.

4-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-epoxy[1,2]dio-xepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)pyridine, 5a: Yield 69%, white solid, m.p. 95–97°C; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 8.42 (m, 1H, H-6′), 7.60 (m, 1H, H-5′), 7.30 (m, 1H, H-3′), 7.11 (m, 1H, H-4′), 5.36 (s, 1H, H-12), 4.73 (d, J = 3.0 Hz, 1H, H-10), 3.88 (m, 1H, 10-O-CH_2a-), 3.62 (m, 1H, 10-O-CH_2b-), 3.40 (m, 2H, S-CH₂-), 2.39 (m, 1H, H-9), 2.17 (m, 1H, H-4a), 1.99 (m, 1H, H-4b), 1.79 (m, 1H, H-5a), 1.71 (m, 1H, H-8a), 1.55 (m, 1H, H-8b), 1.49 (m, 1H, H-7a), 1.35 (m, 2H, H-8A, H-5b), 1.27 (s, 3H, H-13), 1.24 (m, 1H, H-6), 1.13 (m, 1H, H-5A), 0.89 (d, J = 6.6 Hz, 3H, H-14), 0.85 (m, 1H, H-7b), 0.83 (d, J = 7.2 Hz, 3H, H-15); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 157.8 (C-2′), 149.3 (C-6'), 136.5 (C-4′), 121.8 (C-3'), 119.7 (C-5′), 103.2 (C-3), 100.6 (C-10), 87.0 (C-12), 80.4 (C-12A), 66.3 (10-O-CH₂-), 52.0 (C-5A), 43.8 (C-8A), 36.6 (C-6), 36.0 (C-4), 34.1 (C-7), 30.4 (C-9), 29.0 (S-CH₂-), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₂H₃₂NO₅S: [M + H]⁺ 422.2001, found 422.1984.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimet-hyldecahydro-12H-3,12-epoxy[1,2]dio-xepino[4,3-i]isochr-omen-10-yl)oxy)ethyl)thio)pyridine, 5b: Yield 70%, white solid, m.p. 91–93°C; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 8.36 (dd, J₁ = 1.5 Hz, J₂ = 4.5 Hz, 2H, H-2′, H-6′), 7.30 (dd, J₁ = 1.5 Hz, J₂ = 4.5 Hz, 2H, H-3′, H-5′), 5.35 (s, 1H, H-12), 4.74 (d, J = 3.0 Hz, 1H, H-10), 3.91 (m, 1H, 10-O−CH_2a−), 3.63 (m, 1H, 10-O−CH_2b−), 3.31 (m, 2H, S−CH₂−), 2.38 (m, 1H, H-9), 2.17 (m, 1H, H-4a), 1.99 (m, 1H, H-4b), 1.79 (m, 1H, H-5a), 1.68 (m, 1H, H-8a), 1.53 (m, 1H, H-8b), 1.48 (m, 1H, H-7a), 1.34 (m, 2H, H-8A, H-5b), 1.28 (s, 3H, H-13), 1.24 (m, 1H, H-6), 1.13 (m, 1H, H-5A), 0.89 (d, J = 6.6 Hz, 3H, H-14), 0.84 (m, 1H, H-7b), 0.81 (d, J = 6.6 Hz, 3H, H-15); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 149.1 (C-3′, C-5′), 148.2 (C-1′), 120.6 (C-2′, C-6′), 100.3 (C-3), 100.8 (C-10), 87.0 (C-12), 80.4 (C-12A), 52.0 (C-5A), 65.8 (10-O-CH₂-), 43.7 (C-8A), 36.6 (C-6), 36.0 (C-4), 34.1 (C-7), 30.4 (C-9), 29.9 (S-CH₂-), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₂H₃₂NO₅S: [M + H]⁺ 422.2001, found 422.1975.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimet-hyldecahydro-12H-3,12-epoxy[1,2]dio-xepino[4,3-i]isochr-omen-10-yl)oxy)ethyl)thio)pyrimidine, 5c: Yield 66%, white solid, m.p. 144–146°C; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 8.64 (dd, J₁ = 1.2 Hz, J₂ = 4.8 Hz, 2H, H-4′, H-6′), 7.21 (t, J₁ = 4.8 Hz, 1H, H-5′), 5.35 (s, 1H, H-12), 4.74 (d, J = 3.0 Hz, 1H, H-10), 3.91 (m, 1H, 10-O−CH_2a−), 3.67 (m, 1H, 10-O−CH_2b−), 3.39 (t, J = 5.7 Hz, 2H, S−CH₂−), 2.31 (m, 1H, H-9), 2.17 (m, 1H, H-4a), 1.99 (m, 1H, H-4b), 1.80 (m, 1H, H-5a), 1.69 (m, 1H, H-8a), 1.55 (m, 1H, H-8b), 1.49 (m, 1H, H-7a), 1.34 (m, 2H, H-8A, H-5b), 1.28 (s, 3H, H-13), 1.24 (m, 1H, H-6), 1.13 (m, 1H, H-5A), 0.89 (d, J = 6.6 Hz, 3H, H-14), 0.85 (m, 1H, H-7b), 0.83 (d, J = 7.2 Hz, 3H, H-15); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 170.7 (C-2′), 157,7 (C-4′, C-6'), 117.2 (C-5′), 103.3 (C-3), 100,6 (C-10), 87.0 (C-12), 80.4 (C-12A), 66.0 (10-O-CH₂-), 52.0 (C-5A), 43.8 (C-8A), 36.6 (C-6), 36.0 (C-4), 34.1 (C-7), 30.4 (C-9), 30.1 (S-CH₂-), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₁H₃₁N₂O₅S: [M + H]⁺ 423.1953, found 423.1933.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimet-hyldecahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3-i]isochr-omen-10-yl)oxy)ethyl)thio)benzo[d]oxazole, 5d: Yield 63%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 7.63 (dd, J₁ = 1.8 Hz, J₂ = 7.2 Hz, 2H, 2H, H-5′, H-6′), 7.32 (m, 2H, H-4′, H-7′), 5.34 (s, 1H, H-12), 4.76 (d, J = 3.6 Hz, 1H, H-10), 4.04 (m, 1H, 10-O-CH_2a-), 3.75 (m, 1H, 10-O-CH_2b-), 3.61 (t, J = 5.7 Hz, 2H, S-CH₂-), 2.39 (m, 1H, H-9), 2.16 (m, 1H, H-4a), 1.97 (m, 1H, H-4b), 1.76 (m, 1H, H-5a), 1.57 (m, 1H, H-8a), 1.44 (m, 1H, H-8b), 1.29 (m, 3H, H-7a, H-8A, H-5b), 1.27 (s, 3H, H-13), 1.16 (m, 1H, H-6), 1.09 (m, 1H, H-5A), 0.83 (d, J = 6.6 Hz, 3H, H-14), 0.80 (d, J = 7.8 Hz, 3H, H-15), 0.74 (m, 1H, H-7b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 164.2 (C-2′), 151.2 (C-3′a), 141.3 (C-7′a), 124.5 (C-6′), 124.1 (C-5), 118.1 (C-7′), 110.0 (C-4′), 103.2 (C-3), 100.7 (C-10), 87.0 (C-12), 80.3 (C-12A), 65.9 (10-O-CH₂-), 51.9 (C-5A), 43.6 (C-8A), 36.6 (C-6), 35.9 (C-4), 33.9 (C-7), 32.1 (S-CH₂-), 30.4 (C-9), 25.5 (C-13), 24.1 (C-5), 23.7 (C-8), 20.0 (C-14), 12.5 (C-15); ESI-HRMS calculated for C₂₄H₃₂NO₆S: [M + H]⁺ 462.1950, found 462.1928.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimet-hyldecahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3-i]isochr-omen-10-yl)oxy)ethyl)thio)benzo[d]oxazole, 5e: Yield 68%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 8.00 (dd, J₁ = 1.2 Hz, J₂ = 7.8 Hz, 1H, H-7′), 7.84 (d, J = 7.8 Hz, 1H, H-4′), 7.46 (dt, J₁ = 1.2 Hz, J₂ = 7.8 Hz, 1H, H-5′), 7.36 (dt, J₁ = 1.2 Hz, J₂ = 7.8 Hz, 1H, H-6′), 5.34 (s, 1H, H-12), 4.75 (d, J = 3.0 Hz, 1H, H-10), 4.02 (m, 1H, 10-O-CH_2a-), 3.74 (m, 1H, 10-O-CH_2b-), 3.64 (m, 2H, S-CH₂-), 2.38 (m, 1H, H-9), 2.16 (m, 1H, H-4a), 1.97 (m, 1H, H-4b), 1.76 (m, 1H, H-5a), 1.59 (m, 1H, H-8a), 1.45 (m, 1H, H-8b), 1.31 (m, 2H, H-7a, H-8A), 1.27 (s, 3H, H-13), 1.25 (m, 1H, H-5b), 1.15 (m, 1H, H-6), 1.08 (m, 1H, H-5A), 0.82 (m, 6H, H-14, H-15), 0.73 (m, 1H, H-7b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 166.6 (C-2′), 152.6 (C-7′a), 134.5 (C-3′a), 126.3 (C-5′), 124.4 (C-6′), 121.7 (C-7′), 121.0 (C-4′), 103.3 (C-3), 100.7 (C-10), 87.0 (C-12), 80.4 (C-12A), 66.0 (10-O-CH₂-), 52.0 (C-5A), 43.7 (C-8A), 36.6 (C-6), 35.9 (C-4), 34.0 (C-7), 33.0 (S-CH₂-), 30.4 (C-9), 25.5 (C-13), 24.2 (C-5), 23.8 (C-8), 20.0 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₄H₃₂NO₅S₂: [M + H]⁺ 478.1722, found 478.1701.

Methyl-2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy-[1,2]di-oxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)benzoate, 5f: Yield 60%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 7.85 (dd, J₁ = 1.2 Hz, J₂ = 7.8 Hz, 1H, H-6′), 7.52 (m, 2H, H-3′, H-4′), 7.24 (dt, J₁ = 1.2 Hz, J₂ = 7.8 Hz, 1H, H-5′), 5.36 (s, 1H, H-12), 4.73 (d, J = 3.0 Hz, 1H, H-10), 3.89 (m, 1H, 10-O-CH_2a-), 3.82 (s, 3H, OCH₃), 3.64 (m, 1H, 10-O-CH_2b-), 3.21 (m, 2H, S-CH₂-), 2.39 (m, 1H, H-9), 2.17 (m, 1H, H-4a), 1.98 (m, 1H, H-4b), 1.78 (m, 2H, H-5a, H-8a), 1.55 (m, 1H, H-8b), 1.49 (m, 1H, H-7a), 1.34 (m, 4H, H-5b, H-8A, H-6), 1.27 (s, 3H, H-13), 1.12 (m, 1H, H-5A), 0.89 (d, J = 6.6 Hz, 3H, H-14), 0.85 (m, 1H, H-7b), 0.83 (d, J = 7.2 Hz, 3H, H-15); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 166.1 (C-7′), 140.2 (C-2′), 132.5 (C-4′), 130.6 (C-6'), 127.7 (C-1′), 126.1 (C-3′), 124.1 (C-5′), 103.2 (C-3), 100.6 (C-10), 87.0 (C-12), 80.4 (C-12A), 65.3 (10-O-CH₂-), 52.0 (C-5A), 51.9 (C-8′), 43.8 (C-8A), 36.4 (C-6), 36.0 (C-4), 34.1 (C-7), 31.3 (S-CH₂-), 30.4 (C-9), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15). ESI-HRMS calculated for C₂₅H₃₄O₇SNa: [M + Na]⁺ 501.1922, found 501.1900.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimet-hyldecahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3-i]isochr-omen-10-yl)oxy)ethyl)thio)imidazole, 5g1: Yield 46%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 7.27 (d, J = 1.2 Hz, 1H, H-5′), 6.95 (d, J = 1.2 Hz, 1H, H-4′), 5.34 (s, 1H, H-12), 4.97 (s, 1H, H-12″), 4.73 (d, J = 3.6 Hz, 1H, H-10), 4.64 (d, J = 3.6 Hz, 1H, H-10″), 4.19 (m, 1H, 10″-O-CH_2a-), 4.10 (m, 1H, 10″-O-CH_2b-), 4.00 (m, 1H, 10-O-CH_2a-), 3.84 (m, 1H, 10-O-CH_2b-), 3.58 (N-CH₂-), 3.18 (S-CH₂-), 2.40 (m, 1H, H-9), 2.34 (m, 1H, H-9″), 2.17 (m, 2H, H-4a, H-4″a), 1.99 (m, 2H, H-4b, H-4″b), 1.78 (m, 3H, H-5a, H-5″a, H-8a), 1.64 (m, H-8b), 1,54 (m, 2H, H-8″a, H-8″b), 1.49 (m, 2H, H-7a, H-7″a), 1.34 (m, 6H, H-8A, H-8″A, H-5b, H-5″b, H-6, H-6″), 1,28 (s, 3H, H-13), 1.27 (s, 3H, H-13″), 1.16 (m, 2H, H-5A, H-5″A), 1.08 (m, 1H, H-7b), 0.90 (d, J = 6.6 Hz, 3H, H-14), 0.87 (d, J = 6.6 Hz, 3H, H-14″), 0.85 (d, J = 7.8 Hz, 1H, H-5), 0,80 (m, 1H, H-7″b), 0.75 (d, J = 7.2 Hz, 3H, H-15″); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 140.2 (C-2′), 128.6 (C-4′), 121.7 (C-5'), 103.3 (C-3), 103.2 (C-3″), 100.7 (C-10), 100.4 (C-10″), 87.0 (C-12), 86.8 (C-12″), 80.4 (C-12A), 80.3 (C-12″A), 66.3 (10-O-CH₂-), 65.8 (10″-O-CH₂-), 52.0 (C-5A), 51.9 (C-5″A), 45.6 (N-CH₂-), 43.8 (C-8A), 43.6 (C-8″A), 36.7 (C-6), 36.4 (C-6″), 36.0 (C-4), 35.9 (C-4″), 34.1 (C-7), 34.0 (C-7″), 30.6 (C-9), 30.4 (C-9″), 30.2 (S-CH₂-), 25.6 (C-13), 25.5 (C-13″), 24.3 (C-5), 24.2 (C-5″), 23.9 (C-8), 23.8 (C-8″), 12.7 (C-15), 12.5 (C-15″); ESI-HRMS calculated for C₃₇H₅₇N₂O₁₀S: [M+H]⁺ 721.3734, found 721.3657.

1-(2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimeth-yldecahydro-12H-3,12-epoxy[1,2]dio-xepino[4,3-i]isochro-men-10-yl)oxy)ethyl)-2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)-1H-imidazole, 5g2: Yield 31%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 12.17 (s, 1H, N-H), 7.02 (s, 2H, H-4′, H-5'), 5.36 (s, 1H, H-12), 4.72 (d, J = 3.6 Hz, 1H, H-10), 3.85 (m, 1H, 10-O−CH_2a−), 3.58 (m, 1H, 10-O−CH_2b−), 3.22 (m, 2H, S−CH₂−),2.39 (m, 1H, H-9), 2.18 (m, 1H, H-4a), 1.99 (m, 1H, H-4b), 1.80 (m, 1H, H-5a), 1.73 (m, 1H, H-8a), 1.61 (m, 1H, H-8b), 1.56 (m, 1H, H-7a), 1.36 (m, 4H, H-5b, H-8A, H-6), 1.28 (s, 3H, H-13), 1.14 (m, 1H, H-5A), 0.90 (d, J = 6.6 Hz, 3H, H-14), 0.87 (m, 1H, H-7b), 0.85 (d, J = 7.2 Hz, 3H, H-15); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 138.7 (C-2′), 103.3 (C-3), 100.7 (C-10), 87.0 (C-12), 80.4 (C-12A), 66.6 (10-O-CH2-), 52.1 (C-5A), 43.8 (C-8A), 36.5 (C-6), 36.0 (C-4), 34.1 (C-7), 32.9 (S-CH2-), 30.4 (C-9), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.7 (C-15); ESI-HRMS calculated for C₂₀H₃₁N₂O₅S: [M+H]⁺ 411.1953, found 411.1932.

9-(2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimeth-yldecahydro-12H-3,12-epoxy[1,2]dio-xepino[4,3-i]isochro-men-10-yl)oxy)ethyl)-6-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)-9H-purine, 5h: Yield 62%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 8.70 (s, 1H, H-8′), 8.50 (s, 1H, H-82'), 5.34 (s, 1H, H-12), 4,75 (d, J = 3.3 Hz, 1H, H-10), 4.64 (, J = 3.3 Hz, 1H, H-10″), 4.55 (m, 1H, 10″-O-CH_2a-), 4.48 (s, 1H, H-12″), 4.40 (m, 1H, 10″-O-CH_2b-), 4.22 (m, 1H, 10-O-CH_2a-), 3.97 (m, 1H, 10-O-CH_2b-), 3.71 (m, 3H, S-CH₂-, N-CH_2a-), 3.57 (m, 1H, N-CH_2b-), 2.39 (m, 1H, H-9), 2.26 (m, 1H, H-9″), 2.15 (m, 1H, H-4a), 2.08 (m, 1H, H-4″a), 1.94 (m, 2H, H-4b, H-4″b), 1.78 (m, 1H, H-5a), 1.69 (m, 1H, H-5″a), 1.63 (m, 1H, H-8a), 1.50 (m, 1H, H-8b), 1.31 (m, 4H, H-7a, H-7″a, H-5b, H-5″b), 1,27 (s, 3H, H-13), 1.24 (s, 3H, H-13″), 1.17 (m, 2H, H-8A, H-8″A), 1.11 (m, 2H, H-6, H-6″), 0.95 (m, 1H, H-5A), 0.87 (m, 1H, H-5″A), 0.84 (d, J = 7.2 Hz, 3H, H-14), 0.82 (d, J = 7.2 Hz, 3H, H-14″), 0.80 (d, J = 6.0 Hz, 3H, H-15), 0.65 (d, J = 7.2 Hz, 3H, H-15″), 0.63 (m, 1H, H-7b), 0,54 (m, 1H, H-7″b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 159.1 (C-6′), 151.1 (C-2′), 148.6 (C-4'), 144.6 (C-8′), 130.6 (C-5'), 103.24 (C-3), 103.16 (C-3″), 100.6 (C-10), 100.1 (C-10″), 87.0 (C-12), 86.6 (C-12″), 80.4 (C-12A), 80.0 (C-12″A), 66.2 (10-O-CH₂-), 64.6 (10″-O-CH₂-), 52.0 (C-5A), 51.7 (C-5″A), 43.7 (N-CH₂-), 43.3 (C-8A), 43.2 (C-8″A), 36.5 (C-6), 36.4 (C-6″), 36.0 (C-4), 35.9 (C-4″), 34.0 (C-7), 33.7 (C-7″), 30.4 (C-9), 30.1 (C-9″), 25.6 (C-13), 25.5 (C-13″), 24.2 (C-5), 24.1 (C-5″), 23.7 (C-8), 23.4 (C-8″), 20.03 (C-14), 20.00 (C-14″), 12.6 (C-15), 12.4 (C-15″); ESI-HRMS calculated for C₃₉H₅₇N₄O₁₀S: [M+H]⁺ 773.3795, found 773.3800.

2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-epoxy[1,2]di -oxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)-1H-benzo[d]imidazole, 5i: Yield 65%, colorless oil; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)): 12.50 (s, 1H, N-H), 7.49 (s, 1H, H-4′, H-7'), 7.34 (s, 1H, H-7′), 7.10 (dt, J₁ = 3.6 Hz, J₂ = 7.2 Hz 2H, H-5′, H-6′), 5.37 (s, 1H, H-12), 4.75 (d, J = 3.6 Hz, 1H, H-10), 3.98 (m, 1H, 10-O−CH_2a−), 3.72 (m, 1H, 10-O−CH_2b−), 3.55 (m, 2H, S−CH₂ −), 2.39 (m, 1H, H-9), 2.17 (m, 1H, H-4a), 1.97 (m, 1H, H-4b), 1.78 (m, 1H, H-5a), 1.65 (m, 1H, H-8a), 1.50 (m, 1H, H-8b), 1.34 (m, 3H, H-7a, H-5b, H-8A), 1.27 (s, 3H, H-13), 1.22 (m, 1H, H-6), 1.10 (m, 1H, H-5A), 0.85 (d, J = 6.0 Hz, 3H, H-14), 0.83 (d, J = 7.2 Hz, 3H, H-15), 0.77 (m, 1H, H-7b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 150.0 (C-2′), 143.6 (C-3′a), 135.5 (C-7′a), 121.4 (C-4′), 121.0 (C-7'), 117.2 (C-6′), 110.2 (C-5'), 103.3 (C-3), 100.7 (C-10), 87.0 (C-12), 80.4 (C-12A), 66.5 (10-CH2-), 52.0 (C-5A), 43.8 (C-8A), 36.6 (C-6), 36.0 (C-4), 34.0 (C-7), 31.3 (S-CH2-), 30.4 (C-9), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₄H₃₃N₂O₅S: [M+H]⁺ 461.2110, found 461.2083.

5-Methoxy-2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-ep oxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)-1H-benzo[d]imidazole, 5k1: Yield 41%, white solid, m.p. 94–96°C; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)):12.34 (s, 1H, NH), 7.37 (d, J = 7.8 Hz, 1H, H-7′), 6.85 (s, 1H, H-4'), 6.73 (d, J = 7.8 Hz, 1H, H-6′), 5.36 (s, 1H, H-12), 4.74 (d, J = 3.0 Hz, 1H, H-10), 3.96 (m, 1H, 10-O-CH_2a-), 3.75 (s, 3H, -OCH₃), 3.70 (m, 1H, 10-O-CH_2b-), 3.49 (m, 2H, S-CH₂-), 3.38 (m, 1H, H-9), 2.16 (m, 1H, H-4a), 1.97 (m, 1H, H-4b), 1.78 (m, 1H, H-5a), 1.65 (m, 1H, H-8a)1.51 (m, 1H, H-8b), 1.35 (m, 3H, H-8A, H-7a, H-5b), 1.27 (s, 3H, H-13), 1.23 (m, 1H, H-6), 1.11 (m, 1H, H-5A), 0.86 (d, J = 7.2 Hz, 3H, H-14), 0.83 (d, J = 7.2 Hz, 3H, H-15), 0.78 (m, 1H, H-7b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 103.3 (C-3), 100.7 (C-10), 87.0 (C-12), 80.4 (C-12A), 65.5 (10-O-CH₂-), 55.8 (OCH₃), 52.0 (C-5A), 43.8 (C-8A), 36.6 (C-6), 36.0 (C-4), 34.0 (C-7), 30.6 (S-CH₂-), 30.4 (C-9), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₅H₃₅N₂O₆S: [M+H]⁺ 491.2216, found 491.2186.

6-Methoxy-2-((2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-ep oxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)thio)-1H-benzo[d]imidazole, 5k2: Yield 33%, white solid, m.p. 95–97°C; ¹H-NMR (600 MHz, DMSO-d₆, δ (ppm)):12.34 (s, 1H, NH), 7.21 (d, J = 7.8 Hz, 1H, H-4′), 7.06 (s, 1H, H-7'), 6.73 (d, J = 7.8 Hz, 1H, H-5′), 5.36 (s, 1H, H-12), 4.74 (d, J = 3.0 Hz, 1H, H-10), 3.96 (m, 1H, 10-O-CH_2a-), 3.75 (s, 3H, -OCH₃), 3.70 (m, 1H, 10-O-CH_2b-), 3.49 (m, 2H, S-CH₂-), 3.38 (m, 1H, H-9), 2.16 (m, 1H, H-4a), 1.97 (m, 1H, H-4b), 1.78 (m, 1H, H-5a), 1.65 (m, 1H, H-8a), 1.51 (m, 1H, H-8b), 1.35 (m, 3H, H-8A, H-7a, H-5b), 1.27 (s, 3H, H-13), 1.23 (m, 1H, H-6), 1.11 (m, 1H, H-5A), 0.86 (d, J = 7.2 Hz, 3H, H-14), 0.83 (d, J = 7.2 Hz, 3H, H-15), 0.78 (m, 1H, H-7b); ¹³C-NMR (150 MHz, DMSO-d₆, δ (ppm)): 103.3 (C-3), 100.7 (C-10), 87.0 (C-12), 80.4 (C-12A), 65.5 (10-O-CH₂-), 55.8 (OCH₃), 52.0 (C-5A), 43.8 (C-8A), 36.6 (C-6), 36.0 (C-4), 30.6 (S-CH₂-), 34.0 (C-7), 30.4 (C-9), 25.6 (C-13), 24.2 (C-5), 23.8 (C-8), 20.1 (C-14), 12.6 (C-15); ESI-HRMS calculated for C₂₅H₃₅N₂O₆S: [M+H]⁺ 491.2216, found 491.2186.

2.2. Biology

The in vitro anti-inflammatory activity of tested compounds was determined using a nitrite assay in murine macrophages following published methods with minor modifications [37, 38]. Prior to nitrite assay, cell viability of RAW 264.7 macrophages in exposure to test compounds was evaluated by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric method [39].

The alpha-glucosidase inhibitory activity of test compounds was determined based on the conversion of substrate p-nitrophenyl-α-D-glucopyranoside (pNPG) to yellow-colored product p-nitrophenol (pNP) following the described method of Ting and coworkers [40] with modifications.

The in vitro cytotoxic evaluation against Hep-G2 and LU-1 cancer cell lines was carried out according to the described protocols [41, 42].

3. Results and Discussion

3.1. Chemistry

The objective of this research was to synthesize the thioethers of dihydroartemisinin that were obtained by the connection of thiols 4a–4k with the DHA via ether and thioether linkages as outlined in Scheme 1. The ether bridge of intermediate 3 was created by an etherification between DHA with 2-bromoethanol according to a known procedure [36], followed by the S-alkylation of thiols 4a–4k with 3 at room temperature catalyzed by a weak base K₂CO₃ in DMF to produce thioethers 5a–k in 31–70% yields.

Most of the conjugates between DHA 1 and thiols were successfully obtained as designed. However, some thiols are tautomerized leading to the formation of products that are not as originally designed. Besides, dimer products of both S- and N-alkylation were also observed and isolated. The first is the case of 2-mercaptoimidazole 4g. TLC showed that two products were formed including 5g2 and 5g1 that were easily separated by column chromatography/silica gel eluting with n-hexane : acetone = 2 : 1. Their ¹H and ¹³C-NMR spectra indicated that 5g1 is a product of S-alkylation, and 5g2 is another product of both the S-alkylation and N-alkylation reactions that contains two DHA units (Scheme 1). The assignment of signals was accomplished based on the current NMR data of 5g1 and references [43]. Accordingly, the assigned data of the DHA moiety are also in good agreement with the 1D- and 2D-NMR spectra of 5f.

In the case of 6-mercaptopurine 4h, this compound can exist in several structural forms due to the tautomerization [42]. Theoretically, the alkylation reaction can create products with different structures. However, the observation of the TLC of the reaction under a UV lamp at 254 nm revealed that only one product 5h was formed and easily purified by column chromatography/silica gel eluted with n-hexane: acetone = 2 : 1. The NMR spectra of the product show that alkylation occurred at both -SH and -NH groups, evidenced by the observation that all signals of the protons and carbons in the two DHA moieties appear in pairs at the same positions, respectively. For example, 2 doublets of H-10 and H-10″ (J = 3.3 Hz) can be found in the ¹H-NMR spectrum at 4.75 and 4.64 ppm, respectively. The signals of C-10 and C-10″ atoms were also found to be 100.7 and 100.4 ppm, respectively.

Lastly, in the cases of 5k, the tautomerization of the benzimidazole ring also resulted in the formation of a mixture of two isomers. The TLC of the reaction (n-hexane : acetone = 2 : 1) gives an unique spot visualized at 254 nm under a UV lamp. However, the NMR signal in the aromatic region of the obtained product suggests that this is a mixture of 5-OMe and 6-OMe forms [44] (Figure 2), these isomers could not separate from each other by column chromatography.

The ¹H-NMR and ¹³C-NMR spectra of 5k (5k1 and 5k2) show all 5 protons of the benzimidazole moiety including 12.5 ppm (s, 1H, N1-H), 7.49 ppm (s, broad, 1H, H-7), 7.34 ppm (s, broad, H-4′), and 7.10 ppm (m, 2H, H-5′, H-6′). However, the tautomerization leads to no splitting of these signals. Moreover, in the ¹³C-NMR spectrum the signals of the carbon atoms in the benzimidazole ring were found at low intensity.

Spectral analysis of the mixture of 5k1 and 5k2 isomers also revealed that the signals of H-4′, H-6′ of the 5-OMe isomer and H-5′, H-7′ of 6-OMe one were split as pairs, corresponding to a 5 : 4 ratio, which was determined by its ¹H-NMR. While the signal region of aromatic carbon atoms of this moiety in the ¹³C-NMR spectrum was very weak and difficult to attribute.

3.2. Biological Activities

3.2.1. Anti-Inflammatory Activity

(1) Cell Viability. Figure 3 depicts the cytotoxic half-maximal inhibitory concentrations (IC₅₀) of test compounds on RAW 264.7 cells, as well as concentrations eliciting no significant cytotoxicity for further assessment.

The effects of test compounds on RAW 264.7 viability were determined in terms of viable cell percentages measured by the MTT test. Results revealed cell viabilities ranging from 0 to 23.77 ± 2.18% when incubating with test compounds at a concentration of 20 µg/mL (data not shown), suggesting lower amounts of test compounds for application in nitrite assay.

3.2.2. Reduction of NO Production

The in vitro anti-inflammatory activity of test compounds was evaluated by measuring the reduced NO production in cell culture supernatants of LPS-stimulated RAW 264.7 cells. The results showed that nine out of ten compounds inhibited NO production with percentages of inhibition ranging from 59.74 ± 3.04 to 77.93 ± 0.88% (Table 1). Among the tested compounds, 5i was the sole causing no NO reduction. While the inhibition of NO production to the culture medium in wells treated with LPS was taken as 0%, the percentage by incubation with positive control (dexamethasone) was 62.46 ± 1.27% (Table 1).

3.2.3. Antidiabetes Activity

Table 2 presented the result of the α-glucosidase inhibitory assay for the obtained conjugates. Accordingly, three products 5a, 5e, and 5i expressed a good effect in suppressing the α-glucosidase, especially compound 5i with the IC₅₀ of 0.21 mM was found to be stronger than the positive control. This is expected to be a promising finding in research of antidiabetes activity of DHA derivatives that has not drawn a worthy attention.

3.2.4. Cytotoxic Activity

The result of in vitro cytotoxicity evaluation of the prepared products was summarized in Table 3. The synthesized thioethers were screened for cytotoxic activity against HepG2 and LU-1 cell lines together with DHA. The results showed that eight compounds had stronger cytotoxic activity than DHA against both tested cancer cell lines except for 5c and 5g1 that contained heterocycles 2-mercaptopyrimidine and 2-mercaptoimidazole. Among synthesized thioethers, the conjugate of DHA with 6-mercaptopurine 5h exhibited the most potent activity against HepG2 and LU-1 cell lines with the IC₅₀ of 2.73 and 13.06 µM, that is about 6-fold to 8-fold stronger than that of DHA. Notably, compounds 5a and 5e displayed an effect in all three tested assays.

4. Conclusions

A convenient procedure was applied to prepare novel derivatives of DHA containing both C-O-C and C-S-C linkages. Anomalies of the signal in NMR spectra were discussed and explained by the tautomerization of thiols bearing imidazole and benzimidazole rings. Screening for the in vitro cytotoxicity has indicated that almost all the synthesized compounds had a stronger activity than DHA against HepG2 and LU-1 cancer cell lines. For evaluation of in vitro anti-inflammatory activity, apart from 5c, nine out of ten tested products showed NO production inhibition with the IC₅₀ values ranging from 1.48 to 8.39 µM. Additionally, three compounds 5a, 5e, and 5i showed inhibitory activity on α-glucosidase with the IC₅₀ values of 0.47, 0.41, and 0.21 mM, respectively. In view of the above obtained findings, it is appropriate to conclude that the presence of 2-mercaptopyridine or 2-mercaptobenzothiazole can be beneficial structures for the biological activities of the conjugates of DHA in this study.

Data Availability

The data used to support the study can be made available upon request to the corresponding author.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This study was financially supported by the Vietnam Academy of Science and Technology under the project with the code VAST 02.04/21-22.

References

B. T. T. Thu, T. Van Minh, B. P. Lim, and C. L. Keng, “Effects of environmental factors on growth and Artemisinin content of Artemisia annua L,” Tropical Life Sciences Research, vol. 22, no. 2, pp. 37–43, 2011.
View at: Google Scholar
C. J. Woodrow, R. K. Haynes, and S. Krishna, “Artemisinins,” Postgraduate Medicine Journal, vol. 81, no. 952, pp. 71–78, 2005.
View at: Google Scholar
X. Z. Su and L. H. Miller, “The discovery of artemisinin and the nobel prize in physiology or medicine,” Science China Life Sciences, vol. 58, no. 11, pp. 1175–1179, 2015.
View at: Publisher Site | Google Scholar
H. M. McIntosh and P. Olliaro, “Artemisinin derivatives for treating uncomplicated malaria,” Cochrane Database of Systematic Reviews, vol. 2000, no. 1999, Article ID CD000256, 1999.
View at: Publisher Site | Google Scholar
H. A. Karunajeewa, “Artemisinins: artemisinin, dihydroartemisinin, artemether and artesunate,” Milestones in Drug Therapy, vol. 41, pp. 157–190, 2012.
View at: Google Scholar
D. M. Callender and G. Hsue, “Artesunate: investigational drug for the treatment of severe falciparum malaria in Hawai'i,” Hawaii Medical Journal, vol. 70, no. 4, pp. 77–79, 2011.
View at: Google Scholar
S. Krishna and P. G. Kremsner, “Antidogmatic approaches to artemisinin resistance: reappraisal as treatment failure with artemisinin combination therapy,” Trends in Parasitology, vol. 29, no. 7, pp. 313–317, 2013.
View at: Publisher Site | Google Scholar
A. P. Phyo, S. Nkhoma, K. Stepniewska et al., “Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study,” The Lancet, vol. 379, no. 9830, pp. 1960–1966, 2012.
View at: Publisher Site | Google Scholar
A. J. Lin and R. E. Miller, “Antimalarial activity of new dihydroartemisinin derivatives. 6. .alpha.-Alkylbenzylic ethers,” Journal of Medicinal Chemistry, vol. 38, no. 5, pp. 764–770, 1995.
View at: Publisher Site | Google Scholar
A. J. Lin, L. Q. Li, S. L. Andersen, and D. L. Klayman, “Antimalarial activity of new dihydroartemisinin derivatives. 5. Sugar analogs,” Journal of Medicinal Chemistry, vol. 35, no. 9, pp. 1639–1642, 1992.
View at: Publisher Site | Google Scholar
A. J. Lin, L. Q. Li, D. L. Klayman, C. F. George, and J. L. Flippen-Anderson, “Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 3. Aromatic amine analogs,” Journal of Medicinal Chemistry, vol. 33, no. 9, pp. 2610–2614, 1990.
View at: Publisher Site | Google Scholar
A. J. Lin, D. L. Klayman, and W. K. Milhous, “Antimalarial activity of new water-soluble dihydroartemisinin derivatives,” Journal of Medicinal Chemistry, vol. 30, no. 11, pp. 2147–2150, 1987.
View at: Publisher Site | Google Scholar
R. Yu, G. Jin, and M. Fujimoto, “Dihydroartemisinin: a potential drug for the treatment of malignancies and inflammatory diseases,” Frontiers in Oncology, vol. 11, Article ID 722331, 2021.
View at: Publisher Site | Google Scholar
W. Y. Yu, W. J. Kan, P. X. Yu, M. M. Li, J. S. Song, and F. Zhao, “Anti-inflammatory effect and mechanism of artemisinin and dihydroartemisinin,” China Journal of Chinese Materia Medica, vol. 37, no. 17, pp. 2618–2521, 2012.
View at: Google Scholar
Q. Li, Q. Ma, J. Cheng et al., “Dihydroartemisinin as a sensitizing agent in cancer therapies,” OncoTargets and Therapy, vol. 14, pp. 2563–2573, 2021.
View at: Publisher Site | Google Scholar
M. P. Crespo-Ortiz and M. Q. Wei, “Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 247597, 18 pages, 2012.
View at: Publisher Site | Google Scholar
C. C. Xu, T. Deng, M. L. Fan, W. B. Lv, J. H. Liu, and B. Y. Yu, “Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives,” European Journal of Medicinal Chemistry, vol. 107, pp. 192–203, 2016.
View at: Publisher Site | Google Scholar
X. Zou, C. Liu, C. Li et al., “Study on the structure-activity relationship of dihydroartemisinin derivatives: discovery, synthesis, and biological evaluation of dihydroartemisinin-bile acid conjugates as potential anticancer agents,” European Journal of Medicinal Chemistry, vol. 225, Article ID 113754, 2021.
View at: Publisher Site | Google Scholar
X. Yang, W. Wang, J. Tan et al., “Synthesis of a series of novel dihydroartemisinin derivatives containing a substituted chalcone with greater cytotoxic effects in leukemia cells,” Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 15, pp. 4385–4388, 2009.
View at: Publisher Site | Google Scholar
J. D. Ma, J. Jing, J. W. Wang et al., “A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients,” Arthritis Research and Therapy, vol. 21, no. 1, p. 153, 2019.
View at: Publisher Site | Google Scholar
Z. Xu, X. Liu, and D. Zhuang, “Artesunate inhibits proliferation, migration, and invasion of thyroid cancer cells by regulating the PI3K/AKT/FKHR pathway,” Biochemistry and Cell Biology, vol. 100, no. 1, pp. 85–92, 2022.
View at: Publisher Site | Google Scholar
J. Zheng, X. Li, W. Yang, and F. Zhang, “Dihydroartemisinin regulates apoptosis, migration, and invasion of ovarian cancer cells via mediating RECK,” Journal of Pharmacological Sciences, vol. 146, no. 2, pp. 71–81, 2021.
View at: Publisher Site | Google Scholar
Y. Liu, S. Gao, J. Zhu, Y. Zheng, H. Zhang, and H. Sun, “Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway,” Cancer Medicine, vol. 7, no. 11, pp. 5704–5715, 2018.
View at: Publisher Site | Google Scholar
V. T. Chinh, P. T. Loan, V. X. Duong, T. K. Vu, and L. V. Chinh, “Synthesis of new zerumbone derivatives and their in vitro anti-cancer activity,” Chiang Mai Journal of Science, vol. 47, no. 1, pp. 181–194, 2020.
View at: Google Scholar
R. Gaur, A. S. Pathania, F. A. Malik, R. S. Bhakuni, and R. K. Verma, “Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity,” European Journal of Medicinal Chemistry, vol. 122, pp. 232–246, 2016.
View at: Publisher Site | Google Scholar
M. A. Azam, B. Suresh, S. S. Kalsi, and A. S. Antony, “Synthesis and biological evaluation of some novel 2-mercaptobenzothiazoles carrying 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole moieties,” South African Journal of Chemistry, vol. 63, pp. 114–122, 2010.
View at: Google Scholar
H. Amer, O. Ali, and I. K. El-kafaween, “Synthesis of some new nucleosides derived from 2-mercapto benzimidazole with expected biological activity,” Oriental Journal of Chemistry, vol. 33, no. 5, pp. 2303–2310, 2017.
View at: Publisher Site | Google Scholar
Y. Q. Ma, “Synthesis, anti-cancer activity and mechanism study of 6-mercapto-purine derivatives,” Letters in Drug Design and Discovery, vol. 13, no. 6, pp. 570–576, 2016.
View at: Publisher Site | Google Scholar
A. T. Mavrova, S. Dimov, D. Yancheva, M. Rangelov, D. Wesselinova, and J. A. Tsenov, “Synthesis, anticancer activity and photostability of novel 3-ethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-ones,” European Journal of Medicinal Chemistry, vol. 123, pp. 69–79, 2016.
View at: Publisher Site | Google Scholar
S. Saini, C. Majee, G. Chakraborthy, and S. Salahuddin, “Novel synthesis of omeprazole and pharmaceutical impurities of proton pump inhibitors: a review,” International Journal of PharmTech Research, vol. 12, no. 3, pp. 57–70, 2019.
View at: Publisher Site | Google Scholar
M. Javed, M. H. Ali, M. S. Tanveer, and M. H. Tanveer, “Gastroesophageal reflux disease: omeprazole versus lansoprazole – a systematic literature review,” Journal of Medical Research and Innovation, vol. 4, no. 2, pp. 1–10, 2020.
View at: Google Scholar
T. N. Hung, L. V. Chinh, L. X. Hieu et al., “Novel derivatives based on zerumbone scaffold as potential anticancer inhibitors,” Letters in Organic Chemistry, vol. 19, no. 12, pp. 1062–1069, 2022.
View at: Publisher Site | Google Scholar
R. Gour, F. Ahmad, S. K. Prajapati et al., “Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity,” European Journal of Medicinal Chemistry, vol. 178, pp. 552–570, 2019.
View at: Publisher Site | Google Scholar
B. Venugopalan, P. J. Karnik, C. P. Bapat, D. K. Chatterjee, N. Iyer, and D. Lepcha, “Antimalarial activity of new ethers and thioethers of dihydroartemisinin,” European Journal of Medicinal Chemistry, vol. 30, no. 9, pp. 697–706, 1995.
View at: Publisher Site | Google Scholar
C. Wu, J. Liu, X. Pan et al., “Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives,” Molecules, vol. 18, no. 6, pp. 6866–6882, 2013.
View at: Publisher Site | Google Scholar
Y. Liu, Z. Liu, J. Shi et al., “Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups,” Molecules, vol. 18, no. 3, pp. 2864–2877, 2013.
View at: Publisher Site | Google Scholar
D. Tsikas, “Analysis of nitrite and nitrate in biological fluids by assays based on the Griess reaction: appraisal of the Griess reaction in the L-arginine/nitric oxide area of research,” Journal of Chromatography B, vol. 851, no. 1-2, pp. 51–70, 2007.
View at: Publisher Site | Google Scholar
L. G. Chen, L. L. Yang, and C. C. Wang, “Anti-inflammatory activity of mangostins from Garcinia mangostana,” Food and Chemical Toxicology, vol. 46, no. 2, pp. 688–693, 2008.
View at: Publisher Site | Google Scholar
M. V. Berridge, P. M. Herst, and A. S. Tan, “Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction,” Biotechnology Annual Review, vol. 11, pp. 127–152, 2005.
View at: Publisher Site | Google Scholar
T. Li, X. Zhang, Y. Song, and J. Liu, “A microplate-based screening method for alpha-glucosidase inhibitors,” Chinese Journal of Clinical Pharmacology and Therapeutics, vol. 10, no. 10, pp. 1128–1134, 2005.
View at: Google Scholar
K. Likhitwitayawuid, C. K. Angerhofer, G. A. Cordell, J. M. Pezzuto, and N. Ruangrungsi, “Cytotoxic and antimalarial bisbenzylisoquinolme alkaloids from stephania erecta,” Journal of Natural Products, vol. 56, no. 1, pp. 30–38, 1993.
View at: Publisher Site | Google Scholar
P. Skehan, R. Storeng, D. Scudiero et al., “New colorimetric cytotoxicity assay for anticancer-drug screening,” JNCI Journal of the National Cancer Institute, vol. 82, no. 13, pp. 1107–1112, 1990.
View at: Publisher Site | Google Scholar
L. Pazderski, I. Łakomska, A. Wojtczak et al., “The studies of tautomerism in 6-mercaptopurine derivatives by ¹H–¹³C, ¹H–¹⁵N NMR and ¹³C, ¹⁵N CPMAS-experimental and quantum chemical approach,” Journal of Molecular Structure, vol. 785, no. 1-3, pp. 205–215, 2006.
View at: Publisher Site | Google Scholar
R. M. Claramunt, C. López, I. Alkorta, J. Elguero, R. Yang, and S. Schulman, “The tautomerism of Omeprazole in solution: a ¹H and ¹³C NMR study,” Magnetic Resonance in Chemistry, vol. 42, no. 8, pp. 712–714, 2004.
View at: Publisher Site | Google Scholar

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Copyright © 2023 Ngoc Hung Truong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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