Synthesis and in vitro biological evaluation of aminoacridines and artemisinin–acridine hybrids

Joubert, Juan Paul; Smit, Frans J.; Plessis, Lissinda H. Du; Smith, Peter J.; N’Da, David D.

doi:10.1016/j.ejps.2014.01.014

Cited by 41 publications

(32 citation statements)

References 62 publications

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“…The reaction mixture was stirred overnight as the temperature increased from 0 8Ca nd then washed with deionized water (3 20 mL), the crude mixture was extracted with diethyl ether (3 20 mL) and the combined extracts were dried over MgSO 4 .A fter removing the MgSO 4 by filtration, the filtrate was concentrated under reduced pressure and the products 19, 21, 23 and 25 were obtained by column chromatography and elution with ethyl acetate/hexane (v/v). [44] Compound 19.T he product 18 (850 mg, 2.17 mmol) from the previous step was used and the final product was obtained by column chromatography and eluting with ethyl acetate/hexane (6:4, v/v)a sw hite amorphous solid (695 mg, 39.5 %) that started softening at 120 8Ca nd was completely molten at 175 8C; R f 0. 19.32 (C-19''), 18.68 (C-21''), 13.08 (C-15), 11.82 ppm (C-18''); IR (ATR):…”

Section: Preparation Of C-10 O-linked Artemisinin Cholesteryl Carbamamentioning

confidence: 99%

“…22 (hexane/ethyl acetate 4:6); 1 HNMR (600 MHz, CDCl 3 ): d = 5.41 (s, 1H,H -12), 5.35 (t, J = 4.8 Hz, 1H,H -6''), 4.78 (d, J = 3.3 Hz, 1H,H -10), 4.52-4.46 (m, 1H,H -3''), 4.00 (s, 2H,H -1'), 3.64-3.45 (m, 4H,H -7',H -5'), 2.65-2.57 (m, 4H,H -8',H -4'), 2.36-2.25 (m, 2H,H -4''), 1.40 (s, 3H,H -13), 0.99 (s, 3H,H -19''), 0.93 (d, J = 6.3 Hz, 3H,H -15), 0.88 (d, J = 7.0 Hz, 3H,H -14), 0.86 (s, 3H,H -21''), 0.83 (dd, J = 6.6, 2.7 Hz, 6H,H -26'',H-27''), 0.65 ppm (s, 3H,H -18''); 13 CNMR (151 MHz, CDCl 3 ): d = 139.89 (C-5''), 122.55 (C-6''), 104.10 (C-3), 102.00 (C-10),ChemMedChem 2018, 13,67-77 www.chemmedchem.org 87.90 (C-12), 80.99 (C-12a), 56.63 (C-23), 56.08 (C-17''), 52.96 (C-2', C-8'), 52.50 (C-5a), 49.95 (C-1',C -7'),44.27 (C-8a), 42.27 (C-13''),31.87 (C-6), 28.17 (C-16''),24.67 (C-13),22.79 (C-26'',C -27''), 20.34 (C-14),19.33 (C-19''),18.68 (C-21''),13.06 (C-15), 11.82 ppm (C-18''); IR(ATR): ñ max = 2934, 2866, 1699, 1459, 1431, 1376, 1235 cm À1 ;M S: m/z:c alcd for C 49 H 81 N 2 O 7 + :809.6044 [M + H] + ,found:8 09.6034. Compound 20.3 -Bromo-1-propanol was used and the pure product was obtained by recrystallization from methanol as aw hite solid (576 mg, 40 %), mp 88-91 8C; 1 HNMR (600 MHz, CDCl 3 ): d = 5.44 (s, 1H,H -12), 4.82 (d, J = 3.5 Hz, 1H,H -10), 4.02 (ddd, J = 10.2, 6.2, 5.4 Hz, 2H,H -1'), 3.55-3.47 (m, 2H,H -3'), 2.66 (dt, J = 7.7, 3.5 Hz, 1H,H -8a), 2.39 (td, J = 14.0, 4.0 Hz, 2H,H -2'), 1.46 (s, 3H,H -13), 0.97 (d, J = 6.4 Hz, 3H,H -15), 0.93 ppm (d, J = 7.3 Hz, 3H,H -14); 13 CNMR (151 MHz, CDCl 3 ): d = 104.13 (C-3), 102.12 (C-10), 87.95 (C-12), 81.07 (C-12a), 65.71 (C-1'), 52.29 (C-5a), 44.40 (C-8a), 37.47 (C-9), 36.44 (C-4), 34.65 (C-7), 32.56 (C-2'), 30.91 (C-6), 26.21 (C-3'), 24.68 (C-13), 24.54 (C-8), 20.39 (C-15), 13.00 ppm (C-14): ñ max = 2990, 2945, 2928, 2865, 1480, 1452, 1384, 1373, 1361, 1250, 1011cm À1 in agreement with published data.…”

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Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

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To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.

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Section: Preparation Of C-10 O-linked Artemisinin Cholesteryl Carbamamentioning

confidence: 99%

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confidence: 99%

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

et al. 2017

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“…Very low solubility and absorption levels of artemisinin-acridine hybrids have been attributed to inherent pharmacokinetic limitations of artemisinin, viz., poor water solubility, absorption, and plasma bioavailability (35). Hepatotoxicity of acridine and neurotoxicity of dihydroartemisinin are also well reported (89,90).…”

Section: Some Metabolic Liabilities Persist After Molecular Hybridizamentioning

confidence: 99%

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

Agarwal

Gupta

Awasthi

2017

Antimicrob Agents Chemother

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Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

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“…[7] Recent years, modifications of the parent structure of artemisinin could produce potentially important derivatives, which were found to be more biologically effective than the staring one. [4,5,[8][9][10][11][12][13] . Previous studies already indicated that the incorporation of artemisinin and triazole moeity gave hybrid compounds with improved cytotoxic activity, compared to the individual parent compounds [5,[10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel artemisinin–triazole hybrids

Giang

Anh

Phương

et al. 2018

Vietnam Journal of Chemistry

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Several substituted triazole–artemisinin hybrids were synthesized based on ‘click’ chemistry between propargyl‐substituted derivatives and artemisinin containing a 2‐hydroxypropane unit. The structures of all obtained compounds were confirmed by means of IR, NMR, and MS spectroscopy. Four new hybrids were evaluated as cytotoxic agents, revealing an interesting anticancer activity of 1‐(4‐(3‐Aminophenyl)‐1H‐1,2,3‐triazol‐1‐yl)‐3‐(((3R,6R,8aS,9R,10S,12R,12aR)‐3,6,9‐trimethyl‐decahydro‐12H‐3,12‐epoxy[1,2]dioxepino[4,3‐i]isochromen‐10‐yl)oxy)propan‐2‐ol compound in KB and HepG2 cancer cell lines.

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Synthesis and in vitro biological evaluation of aminoacridines and artemisinin–acridine hybrids

Cited by 41 publications

References 62 publications

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

Synthesis of novel artemisinin–triazole hybrids

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