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Article

Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against T. b. rhodesiense and P. falciparum Strain NF54

by
Nina Scheiber
1,
Gregor Blaser
1,
Eva-Maria Pferschy-Wenzig
2,
Marcel Kaiser
3,4,
Pascal Mäser
3,4 and
Armin Presser
1,*
1
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria
2
Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Beethovenstrasse 8, 8010 Graz, Austria
3
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland
4
Swiss Tropical and Public Health Institute, University of Basel, Petersplatz 1, 4001 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(19), 6559; https://doi.org/10.3390/molecules27196559
Submission received: 2 September 2022 / Revised: 21 September 2022 / Accepted: 29 September 2022 / Published: 4 October 2022
(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)
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Abstract

:
Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. We found that benzyl naphthoquinone 5c was the most active and selective molecule against T. brucei rhodesiense (IC50 = 0.08 μM, SI = 275). Furthermore, the antiprotozoal assays revealed no specific effects. In addition, some key physicochemical parameters of the synthesised compounds were calculated.

Graphical Abstract

1. Introduction

p-Quinols and quinones are cyclohexadienones and represent an important skeleton isolated from a variety of natural sources (bacteria, fungi, higher plants). Quinone derivatives are reported to exhibit a broad spectrum of biological activities such as anti-inflammatory [1,2], anticancer [3,4,5], antiviral [6], antitubercular [7,8], antifungal [9], antibacterial [2,7,10], and antiprotozoal [5,11,12], etc. Furthermore, the quinone and quinol moieties exhibit a strong preference for proteins containing cysteine thiols and serve therefore as potential covalent inhibitors of various biochemical targets [13,14].
As part of a program directed at the discovery of anticancer and antiprotozoal agents, we were interested in the synthesis of substituted naphthoquinones (NQs) and 4-hydroxycyclohexa-2,5-dien-1-ones because of their remarkable pharmacological activities [12,15,16,17,18,19]. Many methods are described in the literature for the oxidation of phenols to quinols and quinones [20,21,22,23,24], but most of them suffer from certain drawbacks, such as poor product selectivity or high toxicity of the catalysts.
For our purpose, hypervalent iodine (III) reagents like diacetoxy iodobenzene (PhI(OAc)2, PIDA), bis(trifluoroacetoxy) iodo benzene (PhI(OCOCF3)2, PIFA) and the μ-oxo-bridged phenyl iodine trifluoroacetate 1 (Figure 1) evolved as reagents of choice. These reagents have been extensively used in organic synthesis [25,26,27]. The continued interest in hypervalent iodine species has led to the development of several chiral hypervalent iodine reagents and catalysts [28,29,30,31].
In this paper we report on the general preparation of p-quinols and naphthoquinones via a hypervalent iodine(III) mediated oxidation of the corresponding phenolic starting products together with our findings on the antiprotozoal activity and cytotoxicity towards L6 cells of the synthesised cyclohexadienones.

2. Results and Discussion

2.1. Chemistry

p-Benzoquinones and p-quinols can both be prepared from phenols by oxidative dearomatization [25,27]; however, a p-substituted phenol and water as a nucleophile is necessary for the synthesis of the 4-hydroxy quinol framework (Scheme 1). Among all environmentally friendly and non-metallic organic oxidants, hypervalent iodine reagents represent one of the most promising tools for the oxidative dearomatization of phenolic compounds [26,32,33].
Although well established and widely used, the mechanism of this reaction is still unclear and various possibilities of this process are discussed [28,34].
We have evaluated the three most common hypervalent iodine compounds: PIDA, PIFA and μ-oxo-bridged phenyl iodine trifluoroacetate 1 for the construction of p-quinones and p-quinols. As model substances, we used the commercially available starting materials methyl 4-hydroxyphenylacetate (2a) for the synthesis of the p-quinols and 1-naphthol (3a) for the design of NQ-derivatives (Scheme 1).
First of all, we chose the already known conversion of phenols into 4-substituted 4-hydroxy-cyclohexa-2,5-dienones with PIDA [35,36,37], PIFA [38,39] and the μ-oxo dimer 1 [40] and compared the yields of the obtained p-quinols. In addition, we also evaluated the reactivity of the hypervalent iodine PIFA in combination with the stable radical oxidant TEMPO [41].
Optimal conversion of the starting material was achieved by using oxidant 1 at 0 °C within only 10 min (Table 1). However, since the μ-oxo-dimer 1 is rather tricky to obtain, PIDA was also used as an alternative for all further conversions, as this reagent provided the second highest yields. We found that PIDA-mediated oxidation with about 20 min requires slightly more time for the complete conversion of the starting material. Hypervalent iodine(III)-mediated dearomatizations of a variety of phenols (2a–i) provided the corresponding quinols (4a–i) in usually good to moderate yields according to the optimized conditions (Table 1). The oxidation of the substrates 2j–l failed and only led to decomposition products.
For the preparation of the NQ derivatives 5a–e we used the long-established preparation from 1-naphthol [42] and compared the obtained yields of our available hypervalent iodine reagents (Table 1). For compound 3a and 3b, PIDA and μ-oxo dimer 1 provided similar yields within 90 min, but PIDA was ahead in the conversion of all other applied naphthols 3c–e.
Dohi et al. reported an improved yield of 5a when a larger amount of μ-oxo dimer 1 is applied [25]. We also made this observation, however, due to the laborious preparation of this oxidant (see experimental section), for the synthesis of our NQ derivatives the μ-oxo dimer 1 provides no advantages compared to PIDA.

2.2. Antiprotozoal Activity

The antiprotozoal activity of 5a,b has already been described in the literature [43,44,45]. The synthesised p-quinols 4a–i and p-quinones 5c-e were now evaluated in vitro for their antiprotozoal activity against P. falciparum (NF54) and T. brucei rhodesiense (STIB900). Cytotoxicity was determined using L6 rat skeletal myoblasts to calculate a selectivity index for each parasite (SI = IC50(L6)/IC50(parasite)).
According to the recommended hit-to-lead identification criteria [46,47,48], all derivatives showed high activity towards NF54 (IC50 < 1 μM, Table 2), except 4g and 4h, which showed a moderate antiplasmodial effect (IC50 = 1–10 μM). However, the lack of selectivity of most compounds was disappointing in this series, and except for 4g (SI = >12) and 5c (SI = 24), all SI-values were in the single-digit ranges.
In contrast, promising trypanocidal activity was observed. According to the criteria set above, most of the tested derivatives showed high activity against T. brucei rhodesiense, and seven cyclhexadienones (4b–f, 5c, 5d) even showed an IC50 < 100 nM. The best results were found for the benzylnaphthoquinone 5c with an IC50 of 80 nM and an SI of 275.
The ProTox-II data [49] of the tested compounds predicted low systemic and behavioral toxicity with LD50 values not exceeding 300 mg/kg. Therefore, these derivatives may have high potential for the development of new trypanocidal drugs [50].

2.3. Physicochemical Properties

Physicochemical parameters play a crucial role in drug development for the selection of potential drug candidates [51,52,53,54]. For this reason, an assessment of drug-likeness was made, and various physicochemical properties were calculated for all of the tested compounds (Table 2 and Supplementary Materials).
Almost all synthesized derivatives fulfil Lipinsky’s rule of five [55], Veber’s rule [56] and the drug-likeness classifier defined by Ghose et al. [57]; only compound 5e failed in the Ghose filter.
It has been shown that log D7.4 (rather than log P) is one of the most significant physicochemical descriptors for optimizing permeability and solubility in drug development [58,59,60,61]. Accordingly, for all our synthesised cyclohexadienones, this parameter shows a certain correlation with the selectivity index (SI) of P. falciparum (R2 = 0.75) and T.b. rhodesiense (R2 = 0.80).
The use of ligand efficiency as a metric can also greatly simplify multi-parameter optimization in drug development [54,58,59,62]. The ligand efficiency metrics of our synthesised compounds (see the Supplementary Materials) closely agree with the values proposed for drug candidates, i.e., ligand efficiency (LE) > ~0.3, lipophilic ligand efficiency (LLE) > ~5, and lipophilicity-corrected ligand efficiency (LELP) −10 < LELP < 10 [63]. Furthermore, the observed selectivity indices and the calculated ligand efficiency metrics were strongly correlated (e.g., LLEP.f., R2 = 0.91; LELPT.b.r., R2 = 0.93).

3. Materials and Methods

3.1. Chemistry

3.1.1. General Information

All reagents and solvents were purchased from Merck and Fluorochem Ltd. (Glossop, UK) The μ-oxo hypervalent iodine compound 1 was prepared from PhI(OCOCF3)2 (PIFA) according to the literature procedure [64].
The moisture-sensitive reactions were carried out under an inert argon atmosphere. Each reaction was observed by TLC on Merck TLC plates (silica gel 60 F254 0.2 mm, 200 × 200 mm) and detected at 254 nm. All reaction products were purified by flash column chromatography using silica gel 60 (Merck, 70–230 mesh, pore-diameter 60 Å), unless otherwise stated. Purity and homogeneity of the final compounds were assessed by TLC and high-resolution mass spectrometry. The melting points were determined with a digital melting point device (Electrothermal IA 9200).
The accurate structure elucidation was confirmed by 1D and 2D NMR spectroscopy on a Varian Unity Inova 400 MHz instrument (at 298 K) using 5 mm tubes. The chemical shifts are expressed in δ (ppm) using tetramethylsilane (TMS) as internal standard or the 13C signal of the solvent (CDCl3 δ 77.04 ppm). 1H NMR peak patterns are as follows: s (singlet), d (doublet), t (triplet), dd (double doublet), ddd (double dd), m (multiplet), br (broad singlet), coupling constants (J) were reported in Hertz (Hz). 1H and 13C resonances are numbered as given in the formulae (see Supplementary Materials); the signals marked with an asterisk are interchangeable.
High-resolution EI mass spectra (70 eV, source temperature 220 °C) were recorded on an orthogonal TOF spectrometer (Waters GCT Premier) equipped with a direct insertion (DI) probe. High resolution ESI and APCI mass spectra were acquired by analyzing sample solutions on an Ultimate 3000 HPLC hyphenated with a Q Exactive™ Hybrid Quadrupole-Orbitrap™ mass spectrometer equipped with a heated ESI II source or APCI source (Thermo Fisher Scientific), in the positive or negative ionization mode.

3.1.2. General Procedure for the Dearomatization with µ-oxo dimer 1. Method A:

The µ-oxo-bridged dimer (0.6 mmol) was added to a stirred solution of the corresponding phenol or naphthol (1 mmol) in CH3CN (6.50 mL) and H2O (2 mL) at 0 °C. The reaction mixture was stirred vigorously at 0 °C until the TLC showed complete consumption of the starting material (10–90 min). After the removal of CH3CN under reduced pressure, the resulting residue was extracted with CH2Cl2 several times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography.
Methyl 2-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4a). Compound 4a was obtained after stirring for 10 min and purified by flash chromatography using CHCl3/CH3CN (5:2). Colourless oil; yield 45%; Rf = 0.38 (CHCl3:CH3CN = 5:2). The spectroscopic data were found to be identical to the ones described in Ref [65]. Although 4a represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 6.96 (d, J = 9.8 Hz, 2H, H-2, H-6), 6.21 (d, J =9.8 Hz, 2H, H-3, H-5), 3.98 (s, 1H, 1-OH), 3.76 (s, 3H, H-9), 2.71 (s, 2H, H-7) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.9 (C-4), 171.3 (COOCH3), 148.8 (C-2, C-6), 128.3 (C-3, C-5), 67.3 (C-1), 52.3 (C-9), 43.3 (C-7) ppm.
Methyl 2-(3-fluoro-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4b). Compound 4b was obtained after stirring for 10 min and purified by flash chromatography using CHCl3:CH3CN (3:1). Brownish oil; yield 32%; Rf = 0.53 (CHCl3:CH3CN = 3:1); 1H NMR (400 MHz, CDCl3): δ = 6.97 (dd, J = 10.1, 2.9 Hz, 1H, H-6), 6.54 (dd, 3JH,F = 12.3 Hz, 4JH,H = 2.9 Hz, 1H, H-2), 6.23 (dd, 3JH,H = 10.1 Hz, 4JH,F = 6.9 Hz, 1H, H-5), 4.06 (s, 1H, 1-OH), 3.78 (s, 3H, H-9), 2.80 (dd, J = 16.3, 1.3 Hz, 1H, H-7a), 2.74 (d, J = 16.3 Hz, 1H, H-7b) ppm; 13C NMR (100 MHz, CDCl3): δ = 177.8 (d, 2JC,F = 22.6 Hz, C-4), 171.2 (C-8), 153.0 (d, 1JC,F = 269.1 Hz, C-3), 149.5 (d, 4JC,F = 2.5 Hz, C-6), 127.1 (d, 3JC,F = 3.8 Hz, C-5), 124.4 (d, 2JC,F = 12.0 Hz, C-2), 69.6 (d, 3JC,F = 9.2 Hz, C-1), 52.5 (C-9), 43.3 (d, 4JC,F = 2.5 Hz, C-7) ppm. HRMS (EI) calcd. for C9H9FO4 [M]+ = 200.0485; found: 200.0499.
Methyl 2-(3-chloro-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4c). Compound 4c was obtained after stirring for 10 min and purified by flash chromatography using CH2Cl2/MeOH (25:1). Yellowish oil; yield 63%; Rf = 0.43 (CH2Cl2:MeOH = 25:1); 1H NMR (400 MHz, CDCl3: δ = 7.16 (s br, 1H, H-2), 6.98 (d br, J = 10.1 Hz, 1H, H-6), 6.30 (d, J = 10.1 Hz, 1H, H-5), 4.16 (s, 1H, 1-OH), 3.78 (s, 3H, H-9), 2.78 (d, J = 16.4 Hz, 1H, H-7a), 2.73 (d, J = 16.4 Hz, 1H, H-7b) ppm; 13C NMR (100 MHz, CDCl3): δ = 178.0 (C-4), 171.0 (C-8), 149.1 (C-6), 144.6 (C-2), 132.8 (C-3), 127.2 (C-5), 69.3 (C-1), 52.5 (C-9), 43.0 (C-7) ppm; HRMS (ESI) calcd. for C9H10ClO4 [M + H]+ = 217.0268; found: 217.0262.
Methyl 2-(3-bromo-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4d). Compound 4d was obtained after stirring for 10 min and purified by flash chromatography using toluene/EtOAc (5:1). Yellow oil; yield 62%; Rf = 0.44 (toluene:EtOAc = 5:1); 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 2.9 Hz, 1H, H-2), 6.98 (dd, J = 10.0, 2.9 Hz, 1H, H-6), 6.31 (d, J = 10.0 Hz, 1H, H-5), 4.08 (s, 1H, 1-OH), 3.78 (s, 3H, H-9), 2.77 (d, J = 16.2 Hz, 1H, H-7a), 2.72 (d, J = 16.2 Hz, 1H, H-7b) ppm; 13C NMR (100 MHz, CDCl3): δ = 177.7 (C-4), 171.0 (C-8), 148.9 (C-2, C-6), 126.8 (C-5), 124.8 (C-3), 69.9 (C-1), 52.5 (C-9), 42.7 (C-7) ppm; HRMS (EI) calcd. for C9H9BrO4 [M]+ = 259.9684; found: 259.9693.
Methyl 2-(3,5-dichloro-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4e). Compound 4e was obtained after stirring for 10 min and purified by flash chromatography using cyclohexane/EtOAc (2:1). Yellowish oil; yield 68%; Rf = 0.28 (cyclohexane:EtOAc = 2:1). The spectroscopic data were found to be identical to the ones described in Ref [66]. Although 4e represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 7.15 (s, 1H, H-2, H-6), 4.14 (s, 1H, 1-OH), 3.80 (s, 3H, H-9), 2.78 (s, 2H, H-7) ppm; 13C NMR (100 MHz, CDCl3): δ = 172.2 (C-4), 170.9 (C-8), 144.5 (C-2, C-6), 132.0 (C-3, C-5), 69.7 (C-1), 52.6 (C-9), 42.7 (C-7) ppm; HRMS (EI) calcd. for C9H8Cl2O4 [M]+ = 249.9800; found: 249.9813.
Methyl 2-(3,5-dibromo-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (4f). Compound 4f was obtained after stirring for 10 min and purified by flash chromatography using toluene/EtOAc (5:1). Yellowish oil; yield 62%; Rf = 0.38 (toluene:EtOAc = 5:1). The spectroscopic data were found to be identical to the ones described in Ref [66]. Although 4f represents an already known compound, to our knowledge the complete assignment of the NMR signals and also the HRMS data have yet to be published: 1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 2H, H-2, H-6), 4.14 (s, 1H, 1-OH), 3.80 (s, 3H, H-9), 2.77 (s, 2H, H-7) ppm; 13C NMR (100 MHz, CDCl3): δ = 171.7 (C-4), 170.8 (C-8), 148.9 (C-2, C-6), 122.5 (C-3, C-5), 71.6 (C-1), 52.7 (C-9), 42.2 (C-7) ppm; HRMS (EI) calcd. for C9H8Br2O4 [M]+ = 337.8789; found: 337.8789.
Methyl 3-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)propanoate (4g). Compound 4g was obtained after stirring for 20 min and purified by flash chromatography using CHCl3/CH3CN (5:2). Amber solid; yield 67%; Rf = 0.31 (CHCl3:CH3CN = 5:2); m.p.: 49-50 °C; 1H NMR (400 MHz, CDCl3): δ = 6.83 (d, J = 10.3 Hz, 2H, H-2, H-6), 6.20 (d, J = 10.3 Hz, 2H, H-3, H-5), 3.67 (s, 3H, H-10), 2.60 (s, 1H, 1-OH), 2.36 (t, J = 7.6 Hz, 2H, H-8), 2.12 (m, 2H, H-7) ppm; 13C NMR (100 MHz, CDCl3): δ = 185.1 (C4), 173.4 (C-9), 150.2 (C-2, C-6), 128.6 (C-3, C-5), 69.2 (C-1), 52.0 (C-10), 34.5 (C-7), 28.6 (C-8) ppm; HRMS (ESI) calcd. for C10H13O4 [M + H]+ = 197.0814; found: 197.0808.
1-Oxaspiro [4.5]deca-6,9-diene-2,8-dione (4h). Compound 4h was obtained after stirring for 20 min and purified by flash chromatography using CHCl3/CH3CN (5:2). Amber solid; yield 8%; Rf = 0.54 (CHCl3:CH3CN = 5:2); m.p.: 105–106 °C (lit [67] m.p. 104–106 °C). The spectroscopic data were found to be identical to the ones described in Ref [67]. Although 4h represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 6.86 (d, J = 10.1 Hz, 2H, H-2, 6), 6.29 (d, J = 10.1 Hz, 2H, H-3, 5), 2.79 (t, J = 8.3 Hz, 2H, H-8), 2.38 (t, J = 8.3 Hz, 2H, H-7) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.1 (C-4), 175.1 (C-9), 145.5 (C-2, C-6), 129.2 (C-3, C-5), 78.4 (C-1), 32.3 (C-7), 28.0 (C-8) ppm.
Methyl (2E)-3-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)prop-2-enoate (4i). Compound 4i was obtained after stirring for 10 min and purified by flash chromatography using CHCl3/CH3CN (7:1). Amber oil; yield 15%; Rf = 0.28 (CHCl3:CH3CN = 7:1). The spectroscopic data were found to be identical to the ones described in Ref [68]. Although 4i represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 6.76 (d, J = 10.1 Hz, 2H, H-2, H-6), 6.67 (d, J = 15.5 Hz, 1H, H-7), 6.29 (d, J = 15.5 Hz, 1H, H-8), 6.24 (d, J = 10.1 Hz, 2H, H-3, H-5), 3.76 (s, 3H, H-10) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.9 (C-4), 166.3 (C-9), 148.1 (C-2, C-6), 145.1 (C-7), 128.4 (C-3, C-5), 122.3 (C-8), 69.6 (C-1), 52.0 (C-10) ppm.
2-Methyl-1,4-dihydronaphthalene-1,4-dione (5b). Compound 5b was obtained after stirring for 90 min and purified by flash chromatography using CHCl3/cyclohexane (6:1). Amber solid; yield: 73%; Rf = 0.45 (CHCl3:cyclohexane = 6:1); m.p.: 107–108°C (lit [69] m.p. 106–107 °C). The analytical data agreed with the literature [69].

3.1.3. General Procedure for the Dearomatisation with PIDA. Method B:

Diacetoxy iodobenzene (PIDA) (1.30 equiv.) was added in small portions to a stirred solution of the corresponding phenol or naphthol (1 equiv.) in CH3CN (6.5 mL) and H2O (2 mL) at 0 °C. The reaction mixture was allowed to reach ambient temperature and stirred vigorously until the TLC showed complete consumption of the starting material (20–150 min). The orange coloured mixture was diluted with sat. aq NaHCO3 and then extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography.
1,4-Dihydronaphthalene-1,4-dione (5a). Compound 5a was obtained after stirring for 150 min and purified by flash chromatography using CHCl3/cyclohexane (6:1). Amber solid; yield: 76%; Rf = 0.64 (CHCl3:cyclohexane = 6:1); m.p.: 123–125° (lit [70] m.p. 124-125 °C). The analytical data agreed with the literature [71].
2-Benzyl-1,4-dihydronaphthalene-1,4-dione (5c). Compound 5c was obtained after stirring for 90 min and purified by flash chromatography using cyclohexane/EtOAc (8.5:1.5). Ochre solid; yield: 82%; Rf = 0.58 (cyclohexane:EtOAc = 8.5:1.5); m.p.: 92–93 °C (lit [72] m.p. 93–94 °C). The spectroscopic data were found to be identical to the ones described in [72]. Although 5c represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 8.11 (m, 1H, H-8), 8.04 (m, 1H, H-5), 7.72 (m, 2H, H-6, H-7), 7.34 (m, 2H, H-3′, H-5′), 7.26 (m, 1H, H-4′), 7.25 (m, 2H, H-2′, H-6′), 6.61 (t, J = 1.5 Hz, 1H, H-3), 3.90 (m, 2H, CH2-Bn) ppm; 13C NMR (100 MHz, CDCl3): δ = 185.2 (C-4), 185.0 (C-1), 150.9 (C-2), 136.7 (C-1′), 135.6 (C-3), 133.8* (C-6, C-7), 133.7* (C-6, C-7), 132.2 (C-8a), 132.1 (C-4a), 129.4 (C-2′, C-6′), 128.9 (C-3′, C-5′), 127.0 (C-4′), 126.7 (C-8), 126.1 (C-5), 35.7 (CH2-Bn) ppm; HRMS (EI) calcd. for C17H12O2 [M]+ = 248.0837; found: 248.0837.
6-Fluoro-1,4-dihydronaphthalene-1,4-dione (5d). Compound 5d was obtained after stirring for 90 min and purified by flash chromatography using cyclohexane/EtOAc (3:1). Amber solid; yield: 87%; Rf = 0.46 (cyclohexane:EtOAc = 3:1); m.p.: 119–120 °C (lit [73] m.p. 119.8–121.4 °C). The spectroscopic data were found to be identical to the ones described in Ref [73]. Although 5d represents an already known compound, to our knowledge the complete assignment of the NMR signals have not been published so far: 1H NMR (400 MHz, CDCl3): δ = 8.14 (dd, 3JH,H = 8.6, 4JH,F = 5.2 Hz, 1H, H-5), 7.73 (dd, 3JH,F = 8.5, 4JH,H = 2.6 Hz, 1H, H-8), 7.43 (td, 3JH,F = 8.5, 3JH,H = 8.5, 4JH,H = 2.6 Hz, 1H, H-6), 7.02 (d, J = 10.4 Hz, 1H, H-2), 6.99 (d, J = 10.4 Hz, 1H, H-3) ppm; 13C NMR (100 MHz, CDCl3): δ = 183.9 (d, 4JC,F = 1.5 Hz, C-1), 183.6 (d, 5JC,F = 1.0 Hz, C-4), 166.1 (d, 1JC,F = 257.6 Hz, C-7), 138.9 (C-3), 138.6 (d, 5JC,F = 2.0 Hz, C-2), 134.5 (d, 3JC,F = 8.0 Hz, C-8a), 129.8 (d, 3JC,F = 9.0 Hz, C-5), 128.5 (d, 4JC,F = 3.3 Hz, C-4a), 121.2 (d, 2JC,F = 22.6 Hz, C-6), 113.2 (d, 2JC,F = 23.6 Hz, C-8) ppm.
6,7-Difluoro-1,4-dihydronaphthalene-1,4-dione (5e). Compound 5e was obtained after stirring for 150 min at room temperature and purified by flash chromatography using cyclohexane/EtOAc (3:1). Amber solid; yield: 82%; Rf = 0.50 (cyclohexane:EtOAc = 3:1); mp: 128–130 °C. With the exception of the melting point, the compound was described as oil in the reference, and all spectroscopic data are identical to those given in Ref [74]. Although 5e represents an already known compound, to our knowledge the complete assignment of the NMR signals has not been published so far: 1H NMR (400 MHz, CDCl3): δ = 7.89 (t, 3JH,F = 8.6 Hz, 4JH,F = 8.6 Hz, 2H, H-5, H-8), 7.01 (s, 2H, H-2, H-3) ppm; 13C NMR (100 MHz, CDCl3): δ = 182.7 (C-1, C-4), 154.1 (dd, 1JC,F = 262.2, 2JC,F = 15.1 Hz, C-6, C-7), 138.8 (C-2, C-3), 129.8 (t, 3JC,F = 4.9, 4JC,F = 4.9 Hz, C-4a, C-8a), 116.0 (dd, 2JC,F = 13.4, 3JC,F = 7.5 Hz, C-5, C-8) ppm; HRMS (APCI) calcd. for C10H4F2O2 [M]− = 194.0179; found: 194.0183.

3.2. Biological Testing

3.2.1. Assay for In Vitro Antimalarial Activity

Antimalarial activity was determined in vitro against the erythrocytic stages of P. falciparum using the drug-sensitive strain NF54. Parasite proliferation was assessed by incorporation of [3H]-hypoxanthine using a modified version of [75]; for details, please refer to the Supplementary Materials. The positive control was chloroquine.

3.2.2. Assay for In Vitro Trypanocidal Activity

Trypanocidal activity was determined in vitro against axenically grown bloodstream-forms of T. b. rhodesiense STIB900 as described in Refs. [76,77] and detailed in the Supplementary Materials. Parasite proliferation was assessed via fluorescence of the redox-sensitive dye resazurin (Alamar blue). The drug melarsoprol was used as the positive control.

3.2.3. Assay for Cytotoxicity

Cytotoxicity was determined in vitro against rat L6 myoblasts as described [78]; details are listed in the supplement. Cell proliferation was assessed with resazurin, and the generally cytotoxic agent podophyllotoxin served as the positive control.

4. Conclusions

The μ-oxo-dimer 1 can be used instead of PIDA and PIFA for oxidative dearomatizations in aqueous media., This reagent provided the highest yields, especially in the conversion of phenols into substituted 4-hydroxy-cyclohexa-2,5-dienones. However, the laborious preparation prevents a general use of this oxidant.
Many of the synthesised compounds showed promising biological activities (Table 2) as well as favourable physicochemical properties. The trypanocidal effects were extraordinary, and remarkable selectivity could be achieved, especially in the case of 5c (IC50 = 0.08 μM; SI = 275). In contrast, assays on antiprotozoal activity revealed high activity but no specific effects. The results presented in this paper demonstrate the potential of quinols and quinones for the development of new anti-infectives and identify PIDA as the most probable reagent for the preparation of these valuable compounds

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27196559/s1, Table S1: Calculated physicochemical properties of the tested compounds; Table S2: Calculated ligand efficiency metrics of the tested compounds; Experimental of biological testing; 1H- and 13C-NMR spectra of the prepared compounds.

Author Contributions

Conceptualisation, A.P.; Data curation; N.S., G.B., E.-M.P.-W., M.K., P.M., A.P.; Formal analysis, A.P. and E.-M.P.-W.; Investigation, N.S., G.B., E.-M.P.-W., M.K; Methodology, N.S., G.B., E.-M.P.-W., M.K., P.M., A.P. Project administration, A.P.; Resources, A.P.; Supervision, A.P.; Validation, A.P., E.-M.P.-W., M.K.; Writing-original draft, A.P; Writing-review & editing, N.S., G.B., E.-M.P.-W., M.K., P.M., A.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from corresponding author.

Acknowledgments

The authors are grateful to R. Weis and W. Schuehly for discussions. NAWI Graz is acknowledged for supporting the Graz Central Lab Environmental, Plant & Microbial Metabolomics. Open Access Funding by the University of Graz.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Milackova, I.; Prnova, M.S.; Majekova, M.; Sotnikova, R.; Stasko, M.; Kovacikova, L.; Banerjee, S.; Veverka, M.; Stefek, M. 2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent. J. Enzyme Inhib. Med. Chem. 2015, 30, 107–113. [Google Scholar] [CrossRef] [PubMed]
  2. Sychrova, A.; Kolarikova, I.; Zemlicka, M.; Smejkal, K. Natural compounds with dual antimicrobial and anti-inflammatory effects. Phytochem. Rev. 2020, 19, 1471–1502. [Google Scholar] [CrossRef]
  3. Siddamurthi, S.; Gutti, G.; Jana, S.; Kumar, A.; Singh, S.K. Anthraquinone: A promising scaffold for the discovery and development of therapeutic agents in cancer therapy. Future Med. Chem. 2020, 12, 1037–1069. [Google Scholar] [CrossRef] [PubMed]
  4. Aminin, D.; Polonik, S. 1,4-Naphthoquinones: Some Biological Properties and Application. Chem. Pharm. Bull. 2020, 68, 46–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Da Silva Junior, E.N.; Jardim, G.A.M.; Jacob, C.; Dhawa, U.; Ackermann, L.; de Castro, S.L. Synthesis of quinones with highlighted biological applications: A critical update on the strategies towards bioactive compounds with emphasis on lapachones. Eur. J. Med. Chem. 2019, 179, 863–915. [Google Scholar] [CrossRef] [PubMed]
  6. Roa-Linares, V.C.; Miranda-Brand, Y.; Tangarife-Castano, V.; Ochoa, R.; Garcia, P.A.; Castro, M.A.; Betancur-Galvis, L.; Feliciano, A.S. Anti-herpetic, anti-dengue and antineoplastic activities of simple and heterocycle-fused derivatives of terpenyl-1,4-naphthoquinone and 1,4-anthraquinone. Molecules 2019, 24, 1279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Dey, D.; Ray, R.; Hazra, B. Antitubercular and Antibacterial Activity of Quinonoid Natural Products Against Multi-Drug Resistant Clinical Isolates. Phytother. Res. 2014, 28, 1014–1021. [Google Scholar] [CrossRef]
  8. Halicki, P.C.B.; Ferreira, L.A.; de Moura, K.C.G.; Carneiro, P.F.; Del Rio, K.P.; Carvalho, T.D.S.C.; Pinto, M.d.C.F.R.; da Silva, P.E.A.; Ramos, D.F. Naphthoquinone derivatives as scaffold to develop new drugs for tuberculosis treatment. Front. Microbiol. 2018, 9, 673. [Google Scholar] [CrossRef] [Green Version]
  9. Futuro, D.O.; Ferreira, V.F.; Ferreira, P.G.; Nicoletti, C.D.; Borba-Santos, L.P.; Rozental, S.; Silva, F.C.D. The Antifungal Activity of Naphthoquinones: An Integrative Review. An. Acad. Bras. Cienc. 2018, 90, 1187–1214. [Google Scholar] [CrossRef] [Green Version]
  10. Ravichandiran, P.; Maslyk, M.; Sheet, S.; Janeczko, M.; Premnath, D.; Kim, A.R.; Park, B.-H.; Han, M.-K.; Yoo, D.J. Synthesis and Antimicrobial Evaluation of 1,4-Naphthoquinone Derivatives as Potential Antibacterial Agents. ChemistryOpen 2019, 8, 589–600. [Google Scholar] [CrossRef]
  11. Prati, F.; Bergamini, C.; Molina, M.T.; Falchi, F.; Cavalli, A.; Kaiser, M.; Brun, R.; Fato, R.; Bolognesi, M.L. 2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile. J. Med. Chem. 2015, 58, 6422–6434. [Google Scholar] [CrossRef] [PubMed]
  12. Patel, O.P.S.; Beteck, R.M.; Legoabe, L.J. Antimalarial application of quinones: A recent update. Eur. J. Med. Chem. 2021, 210, 113084. [Google Scholar] [CrossRef] [PubMed]
  13. Baillie, T.A. Targeted Covalent Inhibitors for Drug Design. Angew. Chem. Int. Ed. 2016, 55, 13408–13421. [Google Scholar] [CrossRef] [PubMed]
  14. Oramas-Royo, S.; Lopez-Rojas, P.; Amesty, A.; Gutierrez, D.; Flores, N.; Martin-Rodriguez, P.; Fernandez-Perez, L.; Estevez-Braun, A. Synthesis and antiplasmodial activity of 1,2,3-triazole-naphthoquinone conjugates. Molecules 2019, 24, 3917. [Google Scholar] [CrossRef] [Green Version]
  15. Wells, G.; Berry, J.M.; Bradshaw, T.D.; Burger, A.M.; Seaton, A.; Wang, B.; Westwell, A.D.; Stevens, M.F.G. 4-Substituted 4-Hydroxycyclohexa-2,5-dien-1-ones with Selective Activities against Colon and Renal Cancer Cell Lines. J. Med. Chem. 2003, 46, 532–541. [Google Scholar] [CrossRef]
  16. Hughes, L.M.; Lanteri, C.A.; O’Neil, M.T.; Johnson, J.D.; Gribble, G.W.; Trumpower, B.L. Design of antiparasitic and antifungal hydroxy-naphthoquinones that are less susceptible to drug resistance. Mol. Biochem. Parasitol. 2011, 177, 12–19. [Google Scholar] [CrossRef] [Green Version]
  17. Barradas, S.; Hernandez-Torres, G.; Urbano, A.; Carreno, M.C. Total Synthesis of Natural p-Quinol Cochinchinenone. Org. Lett. 2012, 14, 5952–5955. [Google Scholar] [CrossRef]
  18. Morais, T.R.; Romoff, P.; Favero, O.A.; Reimao, J.Q.; Lourenco, W.C.; Tempone, A.G.; Hristov, A.D.; Di, S.S.M.; Lago, J.H.G.; Sartorelli, P.; et al. Anti-malarial, anti-trypanosomal, and anti-leishmanial activities of jacaranone isolated from Pentacalia desiderabilis (Vell.) Cuatrec. (Asteraceae). Parasitol. Res. 2012, 110, 95–101. [Google Scholar] [CrossRef]
  19. Kalt, M.-M.; Schuehly, W.; Ochensberger, S.; Solnier, J.; Bucar, F.; Saf, R.; Kaiser, M.; Presser, A. Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents. Eur. J. Med. Chem. 2020, 207, 112837. [Google Scholar] [CrossRef]
  20. Quideau, S.; Pouysegu, L.; Deffieux, D. Oxidative dearomatization of phenols. Why, how and what for? Synlett 2008, 4, 467–495. [Google Scholar] [CrossRef]
  21. Santhosh Reddy, R.; Shaikh, T.M.; Rawat, V.; Karabal, P.U.; Dewkar, G.; Suryavanshi, G.; Sudalai, A. A novel synthesis and characterization of titanium superoxide and its application in organic oxidative processes. Catal. Surv. Asia 2010, 14, 21–32. [Google Scholar] [CrossRef]
  22. Roche, S.P.; Porco, J.A., Jr. Dearomatization Strategies in the Synthesis of Complex Natural Products. Angew. Chem. Int. Ed. 2011, 50, 4068–4093. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Lin, Y.; Li, B.; Feng, Z.; Kim, Y.A.; Endo, M.; Su, D.S. Efficient Metal-Free Catalytic Reaction Pathway for Selective Oxidation of Substituted Phenols. ACS Catal. 2015, 5, 5921–5926. [Google Scholar] [CrossRef]
  24. Shanmugam, V.M.; Kulangiappar, K.; Ramaprakash, M.; Vasudevan, D.; Senthil Kumar, R.; Velayutham, D.; Raju, T. Electrochemical synthesis of quinones and other derivatives in biphasic medium. Tetrahedron Lett. 2017, 58, 2294–2297. [Google Scholar] [CrossRef]
  25. Dohi, T.; Nakae, T.; Takenaga, N.; Uchiyama, T.; Fukushima, K.; Fujioka, H.; Kita, Y. μ-oxo-bridged hypervalent iodine(III) compound as an extreme oxidant for aqueous oxidations. Synthesis 2012, 44, 1183–1189. [Google Scholar] [CrossRef]
  26. Yoshimura, A.; Zhdankin, V.V. Advances in Synthetic Applications of Hypervalent Iodine Compounds. Chem. Rev. 2016, 116, 3328–3435. [Google Scholar] [CrossRef]
  27. Chandra, G.; Patel, S. Molecular Complexity from Aromatics: Recent Advances in the Chemistry of para-Quinol and Masked para-Quinone Monoketal. ChemistrySelect 2020, 5, 12885–12909. [Google Scholar] [CrossRef]
  28. Harned, A.M. Asymmetric oxidative dearomatizations promoted by hypervalent iodine(III) reagents: An opportunity for rational catalyst design? Tetrahedron Lett. 2014, 55, 4681–4689. [Google Scholar] [CrossRef] [Green Version]
  29. Sun, W.; Li, G.; Hong, L.; Wang, R. Asymmetric dearomatization of phenols. Org. Biomol. Chem. 2016, 14, 2164–2176. [Google Scholar] [CrossRef]
  30. Wu, W.-T.; Zhang, L.; You, S.-L. Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives. Chem. Soc. Rev. 2016, 45, 1570–1580. [Google Scholar] [CrossRef]
  31. Baker Dockrey, S.A.; Lukowski, A.L.; Becker, M.R.; Narayan, A.R.H. Biocatalytic site- and enantioselective oxidative dearomatization of phenols. Nat. Chem. 2018, 10, 119–125. [Google Scholar] [CrossRef] [PubMed]
  32. Zhdankin, V.V.; Stang, P.J. Chemistry of Polyvalent Iodine. Chem. Rev. 2008, 108, 5299–5358. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Pouysegu, L.; Deffieux, D.; Quideau, S. Hypervalent iodine-mediated phenol dearomatization in natural product synthesis. Tetrahedron 2010, 66, 2235–2261. [Google Scholar] [CrossRef]
  34. Kraszewski, K.; Tomczyk, I.; Drabinska, A.; Bienkowski, K.; Solarska, R.; Kalek, M. Mechanism of Iodine(III)-Promoted Oxidative Dearomatizing Hydroxylation of Phenols: Evidence for a Radical-Chain Pathway. Chem. Eur. J. 2020, 26, 11584–11592. [Google Scholar] [CrossRef] [PubMed]
  35. Felpin, F.-X. Oxidation of 4-arylphenol trimethylsilyl ethers to p-arylquinols using hypervalent iodine(III) reagents. Tetrahedron Lett. 2007, 48, 409–412. [Google Scholar] [CrossRef]
  36. You, Z.; Hoveyda, A.H.; Snapper, M.L. Catalytic enantioselective silylation of acyclic and cyclic triols: Application to total syntheses of cleroindicins D, F, and C. Angew. Chem. Int. Ed. 2009, 48, 547–550. [Google Scholar] [CrossRef] [Green Version]
  37. Tello-Aburto, R.; Kalstabakken, K.A.; Volp, K.A.; Harned, A.M. Regioselective and stereoselective cyclizations of cyclohexadienones tethered to active methylene groups. Org. Biomol. Chem. 2011, 9, 7849–7859. [Google Scholar] [CrossRef]
  38. McKillop, A.; McLaren, L.; Taylor, R.J.K. A simple and efficient procedure for the preparation of p-quinols by hypervalent iodine oxidation of phenols and phenol tripropylsilyl ethers. J. Chem. Soc., Perkin Trans. 1994, 15, 2047–2048. [Google Scholar] [CrossRef]
  39. Jo, H.; Choi, M.; Viji, M.; Lee, Y.H.; Kwak, Y.-S.; Lee, K.; Choi, N.S.; Lee, Y.-J.; Lee, H.; Hong, J.T.; et al. Concise Synthesis of Broussonone A. Molecules 2015, 20, 15966–15975. [Google Scholar] [CrossRef] [Green Version]
  40. Dohi, T.; Uchiyama, T.; Yamashita, D.; Washimi, N.; Kita, Y. Efficient phenolic oxidations using μ-oxo-bridged phenyliodine trifluoroacetate. Tetrahedron Lett. 2011, 52, 2212–2215. [Google Scholar] [CrossRef]
  41. Lion, C.; Matthews, C.S.; Wells, G.; Bradshaw, T.D.; Stevens, M.F.G.; Westwell, A.D. Antitumor properties of fluorinated benzothiazole-substituted hydroxycyclohexa-2,5-dienones (‘quinols’). Bioorg. Med. Chem. Lett. 2006, 16, 5005–5008. [Google Scholar] [CrossRef] [PubMed]
  42. Barret, R.; Daudon, M. Oxidation of phenols to quinones by bis(trifluoroacetoxy)iodobenzene. Tetrahedron Lett. 1990, 31, 4871–4872. [Google Scholar] [CrossRef]
  43. Shahinas, D.; Liang, M.; Datti, A.; Pillai, D.R. A Repurposing Strategy Identifies Novel Synergistic Inhibitors of Plasmodium falciparum Heat Shock Protein 90. J. Med. Chem. 2010, 53, 3552–3557. [Google Scholar] [CrossRef] [PubMed]
  44. Blumenstiel, K.; Schoneck, R.; Yardley, V.; Croft, S.L.; Krauth-Siegel, R.L. Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase. Biochem. Pharmacol. 1999, 58, 1791–1799. [Google Scholar] [CrossRef]
  45. Salmon-Chemin, L.; Buisine, E.; Yardley, V.; Kohler, S.; Debreu, M.-A.; Landry, V.; Sergheraert, C.; Croft, S.L.; Krauth-Siegel, R.L.; Davioud-Charvet, E. 2- and 3-Substituted 1,4-Naphthoquinone Derivatives as Subversive Substrates of Trypanothione Reductase and Lipoamide Dehydrogenase from Trypanosoma cruzi: Synthesis and Correlation between Redox Cycling Activities and in Vitro Cytotoxicity. J. Med. Chem. 2001, 44, 548–565. [Google Scholar] [CrossRef]
  46. Nwaka, S.; Ramirez, B.; Brun, R.; Maes, L.; Douglas, F.; Ridley, R. Advancing drug innovation for neglected diseases-criteria for lead progression. PLoS Negl. Trop. Dis. 2009, 3, e440. [Google Scholar] [CrossRef]
  47. Katsuno, K.; Burrows, J.n.; Duncan, K.; van Huijsduijnen, R.H.; Kaneko, T.; Kita, K.; Mowbray, C.E.; Schmatz, D.; Warner, P.; Slingsby, B.T. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 2015, 14, 751–758. [Google Scholar] [CrossRef]
  48. Samby, K.; Willis, P.A.; Burrows, J.N.; Laleu, B.; Webborn, P.J.H. Actives from MMV Open Access Boxes? A suggested way forward. PLoS Pathog. 2021, 17, e1009384. [Google Scholar] [CrossRef]
  49. Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018, 46, W257. [Google Scholar] [CrossRef] [Green Version]
  50. Sena Pereira, V.S. de; Silva de Oliveira, Claudio Bruno; Fumagalli, F.; Da Silva Emery, F.; Da Silva, N.B.; Andrade-Neto, V.F. de. Cytotoxicity, hemolysis and in vivo acute toxicity of 2-hydroxy-3-anilino-1,4-naphthoquinone derivatives. Toxicol. Rep. 2016, 3, 756–762. [Google Scholar] [CrossRef]
  51. Gleeson, M.P.; Hersey, A.; Montanari, D.; Overington, J. Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat. Rev. Drug Discov. 2011, 10, 197–208. [Google Scholar] [CrossRef] [PubMed]
  52. Mignani, S.; Rodrigues, J.; Tomas, H.; Jalal, R.; Singh, P.P.; Majoral, J.-P.; Vishwakarma, R.A. Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: How far can they be simplified? Drug Discov. Today 2018, 23, 605–615. [Google Scholar] [CrossRef] [PubMed]
  53. Agoni, C.; Olotu, F.A.; Ramharack, P.; Soliman, M.E. Druggability and drug-likeness concepts in drug design: Are biomodelling and predictive tools having their say? J. Mol. Model. 2020, 26, 120. [Google Scholar] [CrossRef]
  54. Leeson, P.D.; Bento, A.P.; Gaulton, A.; Hersey, A.; Manners, E.J.; Radoux, C.J.; Leach, A.R. Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies. J. Med. Chem. 2021, 64, 7210–7230. [Google Scholar] [CrossRef] [PubMed]
  55. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2012, 64, 4–17. [Google Scholar] [CrossRef]
  56. Veber, D.F.; Johnson, S.R.; Cheng, H.-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615–2623. [Google Scholar] [CrossRef]
  57. Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999, 1, 55–68. [Google Scholar] [CrossRef] [PubMed]
  58. Johnson, T.W.; Gallego, R.A.; Edwards, M.P. Lipophilic efficiency as an important metric in drug design. J. Med. Chem. 2018, 61, 6401–6420. [Google Scholar] [CrossRef]
  59. Scott, J.S.; Waring, M.J. Practical application of ligand efficiency metrics in lead optimisation. Bioorg. Med. Chem. 2018, 26, 3006–3015. [Google Scholar] [CrossRef] [Green Version]
  60. Tinworth, C.P.; Young, R.J. Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data. J. Med. Chem. 2020, 63, 10091–10108. [Google Scholar] [CrossRef]
  61. Charman, S.A.; Andreu, A.; Barker, H.; Blundell, S.; Campbell, A.; Campbell, M.; Chen, G.; Chiu, F.C.K.; Crighton, E.; Katneni, K.; et al. An in vitro toolbox to accelerate anti-malarial drug discovery and development. Malar. J. 2020, 19, 1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Abad-Zapatero, C. Ligand efficiency indices for effective drug discovery: A unifying vector formulation. Expert Opin. Drug Discov. 2021, 16, 763–775. [Google Scholar] [CrossRef] [PubMed]
  63. Hopkins, A.L.; Keserü, G.M.; Leeson, P.D.; Rees, D.C.; Reynolds, C.H. The role of ligand efficiency metrics in drug discovery. Nat. Rev. Drug Discov. 2014, 13, 105–121. [Google Scholar] [CrossRef]
  64. Gallos, J.; Varvoglis, A.; Alcock, N.W. Oxo-bridged compounds of iodine(III): Syntheses, structure, and properties of μ-oxobis[trifluoroacetato(phenyl)iodine]. J. Chem. Soc. Perkin Trans. 1985, 757–763. [Google Scholar] [CrossRef]
  65. Hirukawa, M.; Zhang, M.; Echenique-Diaz, L.M.; Mizota, K.; Ohdachi, S.D.; Begue-Quiala, G.; Delgado-Labanino, J.L.; Gamez-Diez, J.; Alvarez-Lemus, J.; Machado, L.G.; et al. Isolation and structure-activity relationship studies of jacaranones: Anti-inflammatory quinoids from the Cuban endemic plant Jacaranda arborea (Bignoniaceae). Tetrahedron Lett. 2020, 61, 152005. [Google Scholar] [CrossRef]
  66. Shestak, O.P.; Novikov, V.L.; Ivanova, E.P.; Gorshkova, N.M. Synthesis and antimicrobial activity of [3,5-dibromo(dichloro)-1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl]acetic acids and their derivatives. Pharm. Chem. J. 2001, 35, 366–369. [Google Scholar] [CrossRef]
  67. Zhou, Z.-S.; He, X.-H. Convenient catalyzed spirocyclization of 4-(2-carboxyethyl)phenols. J. Chem. Res. 2017, 41, 57–59. [Google Scholar] [CrossRef]
  68. Fasi, L.; Di Meo, F.; Kuo, C.-Y.; Stojkovic Buric, S.; Martins, A.; Kusz, N.; Beni, Z.; Dekany, M.; Balogh, G.T.; Pesic, M.; et al. Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging. J. Med. Chem. 2019, 62, 1657–1668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Murahashi, S.; Miyaguchi, N.; Noda, S.; Naota, T.; Fujii, A.; Inubushi, Y.; Komiya, N. Ruthenium-Catalyzed Oxidative Dearomatization of Phenols to 4-(tert-Butylperoxy)-cyclohexadienones: Synthesis of 2-Substituted Quinones from p-Substituted Phenols. Eur. J. Org. Chem. 2011, 2011, 5355–5365. [Google Scholar] [CrossRef]
  70. Periasamy, M.; Bhatt, V.M. A new 1,2-shift in the oxidation of aromatic rings. Tetrahedron Lett. 1977, 18, 2357–2360. [Google Scholar] [CrossRef]
  71. Wellauer, J.; Miladinov, D.; Buchholz, T.; Schuetz, J.; Stemmler, R.T.; Medlock, J.A.; Bonrath, W.; Sparr, C. Organophotocatalytic Aerobic Oxygenation of Phenols in a Visible-Light Continuous-Flow Photoreactor. Chem. Eur. J. 2021, 27, 9748–9752. [Google Scholar] [CrossRef] [PubMed]
  72. Bunge, A.; Hamann, H.-J.; McCalmont, E.; Liebscher, J. Enantioselective epoxidation of 2-substituted 1,4-naphthoquinones using gem-dihydroperoxides. Tetrahedron Lett. 2009, 50, 4629–4632. [Google Scholar] [CrossRef]
  73. Ren, J.; Lu, L.; Xu, J.; Yu, T.; Zeng, B.-B. Selective Oxidation of 1-Tetralones to 1,2-Naphthoquinones with IBX and to 1,4-Naphthoquinones with Oxone and 2-Iodobenzoic Acid. Synthesis 2015, 47, 2270–2280. [Google Scholar] [CrossRef]
  74. Shu, C.; Shi, C.-Y.; Sun, Q.; Zhou, B.; Li, T.-Y.; He, Q.; Lu, X.; Liu, R.-S.; Ye, L.-W. Generation of Endocyclic Vinyl Carbene Complexes via Gold-Catalyzed Oxidative Cyclization of Terminal Diynes: Toward Naphthoquinones and Carbazolequinones. ACS Catal. 2019, 9, 1019–1025. [Google Scholar] [CrossRef]
  75. Matile, H.; Richard, J.; Pink, L. Plasmodium falciparum malaria parasite cultures and their use in immunology. In Immunological Methods, Volume IV; Lefkovits, I., Pernis, B., Eds.; Academic Press: Cambridge, MA, USA, 1990; pp. 221–234. ISBN 1483242536. [Google Scholar]
  76. Baltz, T.; Baltz, D.; Giroud, C.; Crockett, J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense. EMBO J. 1985, 4, 1273–1277. [Google Scholar] [CrossRef] [PubMed]
  77. Räz, B.; Iten, M.; Grether-Bühler, Y.; Kaminsky, R.; Brun, R. The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro. Acta Trop. 1997, 68, 139–147. [Google Scholar] [CrossRef]
  78. Presser, A.; Lainer, G.; Kretschmer, N.; Schuehly, W.; Saf, R.; Kaiser, M.; Kalt, M.-M. Synthesis of jacaranone-derived nitrogenous cyclohexadienones and their antiproliferative and antiprotozoal activities. Molecules 2018, 23, 2902. [Google Scholar] [CrossRef]
Molecules 27 06559 g001 550
Figure 1. PIDA, PIFA, and the μ-oxo-bridged dimer 1.
Figure 1. PIDA, PIFA, and the μ-oxo-bridged dimer 1.
Molecules 27 06559 g001
Molecules 27 06559 sch001 550
Scheme 1. Phenolic oxidation using hypervalent iodine(III) reagents.
Scheme 1. Phenolic oxidation using hypervalent iodine(III) reagents.
Molecules 27 06559 sch001
Table
Table 1. Oxidation of phenols (2a–l) and naphthols (3a–e) in aqueous CH3CN using PIDA, PIFA and the μ-oxo dimer 1.
Table 1. Oxidation of phenols (2a–l) and naphthols (3a–e) in aqueous CH3CN using PIDA, PIFA and the μ-oxo dimer 1.
Molecules 27 06559 i001
EntrySubstrateProductMethod aTime bYield/% c
1Molecules 27 06559 i002
2a		Molecules 27 06559 i003
4a		A
B
C
D		10
20
30
30		45
42
39
34
2Molecules 27 06559 i004
2b		Molecules 27 06559 i005
4b		A
B		10
20		32
29
3Molecules 27 06559 i006
2c		Molecules 27 06559 i007
4c		A
B		10
20		63
53
4Molecules 27 06559 i008
2d		Molecules 27 06559 i009
4d		A
B		10
20		62
41
5Molecules 27 06559 i010
2e		Molecules 27 06559 i011
4e		A
B		10
20		68
47
6Molecules 27 06559 i012
2f		Molecules 27 06559 i013
4f		A
B		10
20		62
34
7Molecules 27 06559 i014
2g		Molecules 27 06559 i015
4g		A
B		20
20		67
60
8Molecules 27 06559 i016
2h		Molecules 27 06559 i017
4h		A
B		20
20		8
6
9Molecules 27 06559 i018
2i		Molecules 27 06559 i019
4i		A
B		10
20		15
11
10Molecules 27 06559 i020
2j		Molecules 27 06559 i021
4j		A
B		10
20		0
0
11Molecules 27 06559 i022
2k		Molecules 27 06559 i023
4k		A
B		10
20		0
0
12Molecules 27 06559 i024
2l		Molecules 27 06559 i025
4l		A
B		10
20		0
0
13Molecules 27 06559 i026
3a		Molecules 27 06559 i027
5a		A
B
C
D		90
90
60
90		75
76
28
46
14Molecules 27 06559 i028
3b		Molecules 27 06559 i029
5b		A
B		90
90		73
71
15Molecules 27 06559 i030
3c		Molecules 27 06559 i031
5c		A
B		90
90		65
82
16Molecules 27 06559 i032
3d		Molecules 27 06559 i033
5d		A
B		90
90		74
87
17Molecules 27 06559 i034
3e		Molecules 27 06559 i035
5e		A
B		90
150		71
82
a Reagents and conditions: phenolic substrates (2a–l, 3a–e); method A: μ-oxo dimer 1, CH3CN/H2O), 0 °C; method B: PhI(OAc)2, CH3CN/H2O, 0 °C (quinols), 0 °C → RT (quinones); method C: PhI(OCOCF3)2, CH3CN/H2O, 0 °C; method D: PhI(OCOCF3)2, TEMPO, CH3CN/H2O, RT. b Reaction time (min); c Isolated yield.
Table
Table 2. In vitro antiparasitic activity, host toxicity and key physicochemical properties of the tested compounds.
Table 2. In vitro antiparasitic activity, host toxicity and key physicochemical properties of the tested compounds.
ID No.P. falc.aSI bT. b. rhod. cSI bCyt. L6 dChemicallog Plog D7.4
IC50 μM IC50 μM IC50 μMStructure
Chl.0.00245,500 91.1
Mel. 0.004605024.2
Pod. 0.007
4a0.9690.400.5880.660.391Molecules 27 06559 i0360.110.19
4b0.6441.020.0788.420.657Molecules 27 06559 i037−0.370.12
4c0.8370.530.0479.360.440Molecules 27 06559 i0380.010.58
4d0.3010.710.0425.090.214Molecules 27 06559 i0390.280.75
4e0.2450.470.0111.60.116Molecules 27 06559 i040−0.090.97
4f0.3910.510.0248.290.199Molecules 27 06559 i0410.461.30
4g8.16>12.34.87>20.5>100Molecules 27 06559 i0420.360.48
4h2.750.154.890.090.425Molecules 27 06559 i0430.931.00
4i0.6570.870.1085.270.569Molecules 27 06559 i0441.280.87
5c0.91723.970.08274.7521.98Molecules 27 06559 i0452.933.47
5d0.6773.210.09323.332.17Molecules 27 06559 i0461.181.64
5e0.6896.970.16628.924.80Molecules 27 06559 i0471.321.78
aP. falciparum, strain NF54, erythrocytic stages; b SI is defined as the ratio: IC50 in L6 cells/IC50 in each parasite; c T. brucei rhodesiense, strain STIB900 trypomastigote forms; d cytotoxicity L6 cells rat skeletal myoblasts. Reference drugs: P. falc., chloroquine (chl.), T. b. rhod., melarsoprol (mel.), Cyt. L6, podophyllotoxin (pod.). The IC50 value of each reference drug is the mean from multiple measurements in parallel with the compounds of interest. The physical properties were predicted by using MarvinSketch 21.13.0, ChemAxon (https://www.chemaxon.com acceseed on 27 September 2022). IC50 values of the tested compounds are the means of two to three measurements. The SD was <5%.
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Scheiber, N.; Blaser, G.; Pferschy-Wenzig, E.-M.; Kaiser, M.; Mäser, P.; Presser, A. Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against T. b. rhodesiense and P. falciparum Strain NF54. Molecules 2022, 27, 6559. https://doi.org/10.3390/molecules27196559

AMA Style

Scheiber N, Blaser G, Pferschy-Wenzig E-M, Kaiser M, Mäser P, Presser A. Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against T. b. rhodesiense and P. falciparum Strain NF54. Molecules. 2022; 27(19):6559. https://doi.org/10.3390/molecules27196559

Chicago/Turabian Style

Scheiber, Nina, Gregor Blaser, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Mäser, and Armin Presser. 2022. "Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against T. b. rhodesiense and P. falciparum Strain NF54" Molecules 27, no. 19: 6559. https://doi.org/10.3390/molecules27196559

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