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Article

Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties

by
Armin Presser
1,*,
Gregor Blaser
1,
Eva-Maria Pferschy-Wenzig
2,
Marcel Kaiser
3,4,
Pascal Mäser
3,4 and
Wolfgang Schuehly
2
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
Faculty of Philosophy and Natural Sciences, University of Basel, Petersplatz 1, 4003 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(5), 2114; https://doi.org/10.3390/ijms26052114
Submission received: 31 January 2025 / Revised: 24 February 2025 / Accepted: 25 February 2025 / Published: 27 February 2025
(This article belongs to the Special Issue Advanced Synthetic Methodologies in Drug Development)
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Abstract

:
Malaria remains a major global health problem that has been exacerbated by the impact of the COVID-19 pandemic on health systems. To combat this, the World Health Organization (WHO) has set a target of driving forward research into innovative treatment methods such as new drugs and vaccines. Quinones, particularly 1,4-naphthoquinones, have been identified as promising candidates for the development of antiprotozoal drugs. Herein, we report several methods for the preparation of 2-benzyl-1,4-naphthoquinones. In particular, the silver-catalyzed Kochi–Anderson radical decarboxylation is well suited for the preparation of these compounds. The antiprotozoal activity of all synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. The synthesized compounds exhibited good antiplasmodial activity against the P. falciparum (NF54) strain, particularly (2-fluoro-5-trifluoromethylbenzyl)-menadione 2e, which showed strong efficacy and high selectivity (IC50 = 0.006 µM, SI = 7495). In addition, these compounds also displayed favorable physicochemical properties, suggesting that the benzylnaphthoquinone scaffold may be a viable option for new antiplasmodial drugs.

Graphical Abstract

1. Introduction

Malaria, one of the world’s most malignant diseases, continues to be a major global health problem, especially in tropical and subtropical regions. In 2022, the World Health Organization (WHO) reported 249 million cases of malaria worldwide that caused an estimated 608,000 deaths in 85 countries [1]. This number demonstrates a significant worsening of the malaria situation compared to 2019 as a consequence of the global COVID-19 pandemic, which has resulted in strained health systems and diverted resources. In response to the ongoing challenges, WHO has updated its malaria strategy and its aims at reducing malaria cases and deaths by 90% by 2030 [2]. This ambitious goal may only be achieved through a renewed commitment to innovative strategies, e.g., effective malaria vaccines [3] and the development of new antimalarial drugs [4].
Quinones have recently regained increasing interest in the field of medicinal chemistry, particularly in the discovery of new drugs for the treatment of neglected tropical parasitic diseases [5,6,7,8]. The quinone scaffold is found in a variety of secondary plant metabolites, e.g., lapachol or plumbagin (Figure 1), with a broad spectrum of biological activities [9,10,11,12,13]. Among the various quinone types, the 1,4-naphthoquinone (NQ) scaffold has been identified as a promising pharmacophore for further drug development due to its activity against various apicomplexan parasites, above all, the malaria pathogens of the subgroup Plasmodium [13,14,15,16,17].
In this context, a redox-active compound called plasmodione (2b), a member of the benzylmenadione family with a unique mechanism of action, has shown particularly promising profiles [18,19,20,21,22]. Plasmodione kills parasites as efficiently as the currently most efficient available drug, i.e., artemisinin, besides, it is effective against many drug-resistant parasites and shows a low potential for the development of genetic resistance [21]. Furthermore, despite its chemical similarity to the common antimalarial drug atovaquone, plasmodione does not target the same mitochondrial protein and is therefore effective against atovaquone-resistant strains [23].
In the present study, we synthesized 27 plasmodione-like derivatives with a benzylnaphthoquinone core to investigate their antimalarial potential in comparison to the original lead plasmodione. To assess the druggability of our synthesized compounds, we also analyzed the safety profile, various physicochemical parameters, and ligand efficiency metrics.

2. Results and Discussion

2.1. Synthetic Chemistry

There are several chemical routes to introduce a benzyl moiety into the 1,4-naphthoquinone scaffold [24,25], including a silver-catalyzed decarboxylative cross-coupling of the 1,4-naphthoquinone core with carboxylic acids [20,26], an iron-catalyzed or light-induced radical benzylation of quinones starting from benzyl bromides [27,28], or optionally via a four-step route based on tetralone [26,29].
The silver-catalyzed radical decarboxylation reaction (Kochi–Anderson reaction) [30] provides a powerful tool for fast and easy access to 2-methyl-1,4-naphthoquinone (menadione, 1) derivatives in only one step. By using this method, we first synthesized a series of menadione (MD) derivatives (2a–i) from commercial phenylacetic acids in good to moderate yields (55–88%, Scheme 1, route A). The reaction was compatible with a wide range of substituents, such as halogens, trifluoromethoxy, or nitro groups. For the preparation of benzylated desmethyl derivatives (4a–e), the conditions had to be slightly modified to avoid the formation of disubstituted products (Scheme 1, route B).
Trifluoromenadione has also been proposed as a promising core for antimalarial drugs [31]. Therefore, a series of benzylated trifluoromenadiones (5a–c) were prepared from the previously obtained naphthoquinones 4a–c via a direct copper-catalyzed C-H trifluoromethylation [32,33,34]. Interestingly, the reaction was only successful when a different approach to the published procedure was applied, such as the mandatory addition of bis(pinacolato)diboron (B2pin2) and the presence of CuI as a catalyst. Under these optimized conditions (which are described in detail in Section 3), the trifluoromenadiones 5a–c could be obtained in satisfactory yields.
Urgin and co-workers [35] investigated the antimalarial potential of N-substituted benzylmenadiones and found unexpectedly high antimalarial activity in their N-tert-butoxycarbonyl-protected intermediates. The same authors also report that a Kochi–Anderson benzylation of unprotected amino phenylacetic acids is not successful and leads mainly to degradation of the starting materials. We have taken these observations as an incentive to investigate the antimalarial potential of a few (mainly fluorinated) amidobenzylmenadiones wherein a microwave-assisted N-acetyl-protection strategy was used to achieve this goal (Scheme 1, route C). In this way, the acetamidobenzyl derivatives 2j,k were obtained excellently and the fluorinated derivatives 2l–o in good to moderate yields.
Due to the limited choice of commercially available phenylacetic acids, we have taken an alternative 4-step route, starting from commercial tetralone via the corresponding α-methylene ketones and α-benzylnaphthols to the final benzylmenadione derivatives (Scheme 1, route D). In this alternative scenario, the final benzylic chain is already introduced in the first step by coupling with various benzaldehydes [26,29]. However, the tedious synthetic route in combination with the rather poor stability of the methyl radical in the final Kochi–Anderson step has led to overall not impressive yields for the benzylmenadiones 2p–s. Nevertheless, sufficient material for biological evaluations could be obtained. Overall yields of all synthesized naphthoquinone and menadione derivatives are presented in Table 1.

2.2. Biological Evaluation

The synthesized benzylmenadione and naphthoquinone derivatives were tested in vitro for their antiprotozoal activity against P. falciparum (NF54) erythrocytic stages and T. brucei rhodesiense (STIB900) bloodstream forms. Cytotoxicity was assessed towards rat L6 skeletal muscle cells to calculate a selectivity index for each parasite (SI = IC50(L6)/IC50(parasite)).
According to the recommended hit-to-lead identification criteria [36,37,38], most of the derivatives showed good to very good antiplasmodial activity against NF54 (Table 2), with the (2-fluoro-5-trifluoromethylbenzyl) menadione 2e exhibiting the strongest activity (IC50 = 0.006 μM) along with the highest selectivity (SI = 7495). Trypanocidal activity was also observed (strongest with benzyl-NQ 4a), but generally much lower.
Toxicity prediction was performed using the online platform ProTox-3.0 [39], a web-based service that allows prediction of toxicity using different machine-learning models. These calculations predicted low acute oral toxicity for our compounds with LD50 values not lower than 500 mg/kg. The antiplasmodial top performer 2e together with 2f and 4e achieved herein the best result with a calculated LD50 of 2000 mg/kg. Therefore, substituted 2-benzylnaphthoquinone derivatives may have a high potential for the development of new antiprotozoal drugs [40].

2.3. Physicochemical Investigations

Calculated physicochemical parameters play a pivotal role in drug development, as they help to assess the pharmacological profiles of candidates for new drugs in terms of pharmacokinetics, efficacy, and safety [41,42,43]. The fundamental work of Lipinski et al. [44,45], who established the ‘rule of five’, provides a framework for evaluating the drug suitability of compounds based on their physicochemical properties and emphasizes the importance of these parameters in the early stages of drug discovery. For this reason, all tested compounds were subjected to a detailed drug suitability evaluation, and a number of physicochemical parameters were calculated. All synthesized compounds have relatively low molecular weights (from 248 to 402 g mol−1), and the logD values (at pH 7.4) are also suitable [38]. Furthermore, they fulfill the drug-likeness criteria proposed by Lipinski et al. [44,45] and Veber et al. [46].
Efficacy and physicochemical properties must be given equal consideration in drug development [47,48,49,50]. In recent years, ligand efficiency indices and multi-parameter scores such as ligand efficiency metrics (LE), lipophilic ligand efficiency (LLE), and binding efficiency indices (BEI) have proven to be useful tools in lead discovery and optimization, thus providing a benchmark for assessing the pharmacological value of small molecules [51,52,53,54,55].
However, ligand efficiency (LE) is not the best choice to find a drug candidate across a wide range of ligand sizes. In certain cases, size-independent metrics such as SILE (size-independent ligand efficiency) should be preferred [51,56,57]. While Lipinski’s Rule of 5 (Ro5) describes the chemical space with the highest probability of good oral absorption, there is now increasing interest in new therapeutic agents that may not strictly follow this rule (bRo5) [43,49,58,59]. This requires more advanced tools such as the AbbVie Multi-Parameter Score (Abb-MPS) [60] or the Property Forecast Index (PFI) [61].
We have calculated the main physicochemical parameters, ligand efficiency indices and multi-parameter scores of our tested compounds and have listed them in Tables S1 and S2 in the Supplementary Materials.

2.4. Structure–Activity Relationships (SAR) of the Antiplasmodial Activity

Nearly all the compounds in this study met AB-MPS [60], PFI [61], CNS multiparameter optimization(CNS-MPO) [62,63], and Quantitative estimate of drug-likeness (QED) [64,65] recommendations.
Most remarkable was the strong correlation of some of the calculated ligand efficiency metrics (especially size-independent ligand efficiency (SILE)) with the obtained antiplasmodial activity of our synthesized compounds (e.g., SILEP.f., ρ = −0.95; LLEP.f., ρ = −0.75). The Spearman correlation (ρ) used for this purpose is robust against outliers, as it evaluates the relationship between two variables without assuming a linear association or requiring normally distributed data. Interestingly, other size-independent ligand efficiency metrics such as ligand efficiency lipophilic price (LELP) [51] or Astex lipophilic ligand efficiency (LLEAT) [66] showed no notable correlation with the efficacy of our substances.
Closer examination of LLE and SILE values of our benzylnaphthoquinone derivatives revealed a clear clustering of compounds with similar structural elements and their respective antiplasmodial activities (Figure 2 and Figure S1 in the Supplementary Materials).
The 3-(trifluoromethyl)-NQs (5a–c) located in the lower left corner of the plot show the least exciting values of LLE < 1.2, SILE < 2.2 and pIC50 ≤ 5.8. The NQ derivatives (4a–e) also showed a rather low level of activity against P. falciparum and SILE values ≤ 2.4. Among the menadione derivatives, only the 4,4,4-trifluorobutanamidobenzyl menadione 2o displayed comparably poor levels (with a pIC50 of 6.2). All other benzylmenadione derivatives, especially the polyfluorinated ones, are highly effective (pIC50 in most cases ≥ 7) and lie in the upper right quadrant.
The trajectories of selected compounds in LLE and SILE space are also visualized in Figure 2. The concept of trajectory mapping provides an excellent strategic framework to evaluate the optimization process in drug development [67]. For example, the introduction of a methyl group into the NQ backbone (4b→2b, 4e→2f) leads to a significant increase in potency, as indicated by a clear shift towards the north-eastern part of the SILE-LLE region. Inserting a CF3 group, on the other hand (4a→5a, 4b→5b, 4c→5c), tends to reduce efficiency (shift to the bottom left). Furthermore, it can easily be deduced how the efficacy of the model substance plasmodione (2b) can be enhanced by further fluorination and subsequent rearrangement of the fluorinated building blocks (2b→2c→2e). These results underline the benefit of the SILE vs. LLE plot as very useful for assessing the efficacy of different functional groups and residues in a drug development process.
Abad-Zapatero et al. describe an equally useful mathematical approach that integrates different ligand efficiency indices (LEIs) and defines binding affinity as a function of ligand size (usually expressed as binding affinity per non-hydrogen atom or per molecular weight) and polarity [55,68]. The application of LEIs goes beyond simple efficacy assessment; they are an important tool for Cartesian mapping of chemical–biological space, a concept referred to as AtlasCBS [69]. This mapping allows the identification and visualization of promising drug candidates and the comparison of different ligands for various targets. The pair of variables (NSEI, nBEI) is particularly useful to determine the ’direction’ of the optimization path, which is specified by the corresponding framework. In the NSEI-nBEI plot, the compounds appear along a series of lines with slopes equal to NPOL (number of polar atoms). The most efficient compounds in terms of size and polarity are found in the north-eastern region of the plane and are therefore considered the more promising candidates for further drug development.
The application of AtlasCBS to our synthesized compounds gave a very similar result to the LLE/SILE scatterplot (Figure 2). Again, the potent polyfluorinated menadione derivatives were located in the preferred northeastern part of the NSEI-nBEI plane, with 2e leading the way, while the less potent NQ and 3-trifluoro-NQ derivatives tended to be found in the lower left region (Figure 3 and Figure S2 in the Supplementary Materials).
The concept of trajectory mapping can also be applied very well to the NSEI/nBEI plot; the increase in efficiency due to the introduction of a methyl group in the NQ backbone (4b→2b, 4e→2f), as well as the introduction of fluorine atoms (2g→2h; 2j→2l; 2b→2c→2e) are clearly reflected by a significant shift towards the preferred northeastern part of the NSEI-nBEI plane.
The excellent potential of (poly)fluorinated menadiones for the development of new antiplasmodial agents is also reflected in the SILE/log SI correlation plot (Figure 4 and Figure S3 in the Supplementary Materials), where most of these compounds showed more than 300-fold selectivity (log SI > 2.5) between the IC50 for the rat L6 skeletal cell line and the IC50 for Plasmodium falc., as well as adequate ligand efficiency indices. Compounds with SI > ~300 and pIC50 values greater than 7 (corresponding to activity < 0.1 mM) combine high activity with acceptable selectivity against an L6 cell line and are thus considered promising drug candidates for further studies [36,37,38]. However, the SILE/log SI scatterplot also proves that (even fluorinated) menadiones with an acid amide moiety 2j–o do not lead to acceptable results.

3. Materials and Methods

3.1. Chemistry

3.1.1. General Information

All reagents and solvents were obtained from Merck and Fluorochem Ltd. (Pune, India) Moisture-sensitive reactions were performed under an inert argon atmosphere. Each reaction was monitored 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 on silica gel 60 (Merck, Darmstadt, Germany, 70–230 mesh, pore diameter 60 Å) unless otherwise stated. Purity and homogeneity of the final compounds were checked by TLC and high-resolution mass spectrometry. Melting points were determined using a digital melting point meter (Electrothermal IA 9200, Thermo Fisher Scientific, Birmingham, UK). Microwave-assisted reactions were carried out in a CEM Discover/Explorer system in sealed 10 cm3 standard vessels with temperature control.
Accurate structural elucidation was confirmed by 1D and 2D NMR spectroscopy on a Bruker Avance Neo 400 MHz instrument (at 298 K) using 5 mm tubes. Chemical shifts were expressed in δ (ppm) using either tetramethylsilane (TMS) or the 13C signal of the solvents (CDCl3 δ 77.04 ppm, DMSO-d6 δ 39.45 ppm) as the internal standard. 1H and 13C resonances were numbered according to the formulae (see Supplementary Materials); signals marked with an asterisk are interchangeable.
ESI and APCI mass spectra were acquired by analyzing sample solutions on an Ultimate 3000 HPLC with a Q Exactive™ Hybrid Quadrupole-Orbitrap™ mass spectrometer equipped with a heated ESI II source or an APCI source (Thermo Fisher Scientific, Birmingham, UK) in positive or negative ionization mode.

3.1.2. General Synthetic Procedure for Benzylmenadiones 2a–i (Route A)

Menadione (1.0 mmol) was added to a stirred solution of the respective phenylacetic acid derivative (1.4 equiv.) in CH3CN (9 mL) and H2O (3 mL) and heated to 85 °C. AgNO3 (0.35 equiv.) was added first and then (NH4)2S2O8 (1.3 equiv.) dissolved in 4 mL CH3CN/H2O (3:1) dropwise over a period of 5 min. Stirring at 85 °C was continued until TLC showed complete consumption of the starting material (1–4 h). After cooling to ambient temperature, the mixture was extracted three times with CH2Cl2 (20 mL). The combined organic layers were washed with H2O, dried over Na2SO4, and concentrated in vacuo to give a residue, which was purified by flash chromatography as detailed below.
2-Benzyl-3-methyl-1,4-naphthoquinone (2a). Compound 2a was obtained after stirring for 1 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 88%; Rf = 0.50 (toluene:cyclohexane = 15:1); m.p.: 104–106 °C (lit [28] m.p. 105–106 °C). The spectroscopic data were found to be identical to the ones described in [28]. Although 2a 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 = 8.09 (m, 2H, H-8, H-5), 7.69 (m, 2H, H-6, H-7), 7.26 (m, 4H, H-2′, H-3′, H-5′, H-6′), 7.19 (m, 1H, H-4′), 4.03 (s, 2H, H-9), 2.25 (s, 3H, H-10) ppm; 13C NMR (100 MHz, CDCl3): δ = 185.4 (C-4), 184.7 (C-1), 145.3 (C-3), 144.4 (C-2), 138.0 (C-1′), 133.5 (C-6, C-7), 132.1 (C-4a), 132.0 (C-8a), 128.6 (C-2′, C-3′, C-5′, C-6′), 126.5 (C-5), 126.4 (C-4′), 126.3 (C-8), 32.4 (C-9), 13.3 (C-10) ppm.
2-Methyl-3-{[4-(trifluoromethyl)phenyl]methyl}-1,4-naphthoquinone (2b). Compound 2b was obtained after stirring for 1.5 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 83%; Rf = 0.42 (toluene:cyclohexane = 15:1); m.p.: 70–71 °C (lit [28] m.p. 70–71 °C). The spectroscopic data were found to be identical to the ones described in [28]. Although 2b 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, DMSO-d6) δ = 7.98 (m, 2H, H-5, H-8), 7.82 (m, 2H, H-6, H-7), 7.60 (d, J = 7.8 Hz, 2H, H-3′, H-5′), 7.45 (d, J = 7.8 Hz, 2H, H-2′, H-6′), 4.06 (s, 2H, H-9), 2.14 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.4 (C-4), 183.9 (C-1), 144.8* (C-2), 143.4* (C-3), 143.2 (C-1′), 133.9* (C-6), 133.8* (C-7), 131.6* (C-4a), 131.3* (C-8a), 129.2 (C-2′, C-6′), 126.9 (q, 2JC,F = 31.8 Hz, C-4′), 125.9* (C-5), 125.8* (C-8), 125.2 (q, 3JC,F = 3.9 Hz, C-3′, C-5′), 124.2 (q, 1JC,F = 271.9 Hz, CF3), 31.6 (C-9), 13.0 (C-10) ppm.
2-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-methyl-1,4-naphthoquinone (2c). Compound 2c was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 69%; Rf = 0.48 (toluene:cyclohexane = 15:1); m.p.: 86–87 °C. 1H NMR (400 MHz, CDCl3) δ = 8.10 (m, 2H, H-5, H-8), 7.72 (m, 2H, H-6, H-7), 7.31 (m, 3H, H-3′, H-5′, H-6′), 4.09 (s, 2H, H-9), 2.23 (s, 3H, H-10) ppm; 13C NMR (100 MHz, CDCl3) δ = 184.9 (C-4), 184.3 (C-1), 160.4 (d, 1JC,F = 248.2 Hz, C-2′), 145.6 (C-3), 143.2 (C-2), 133.7 (C-6, C-7), 132.1 (C-4a), 131.9 (C-8a), 131.1 (d, 3JC,F = 4.4 Hz, C-6′), 130.7 (qd, 2JC,F = 33.4, 3JC,F = 8.0 Hz, C-4′), 129.2 (d, 2JC,F = 15.5 Hz, C-1′), 126.5 (C-5, C-8), 123.7 (qd, 1JC,F = 272.1, 4JC,F = 2.5 Hz, CF3), 121.1 (C-5′), 112.9 (dq, 2JC,F = 25.7, 3JC,F = 3.8 Hz, C-3′), 25.7 (C-9), 13.1 (C-10) ppm; HRMS (APCI) calcd. for C19H12F4O2 [M]− = 348.0773; found: 348.0783.
2-{[4-Fluoro-2-(trifluoromethyl)phenyl]methyl}-3-methyl-1,4-naphthoquinone (2d). Compound 2d was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 66%; Rf = 0.50 (toluene:cyclohexane = 15:1); m.p.: 86–87 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.06 (m, 1H, H-5), 7.98 (m, 1H, H-8), 7.85 (m, 2H, H-6, H-7), 7.64 (dd, J = 9.3, 2.7 Hz, 1H, H-3′), 7.33 (td, J = 8.4, 2.7 Hz, 1H, H-5′), 7.28 (m, 1H, H-6′), 4.07 (s, 2H, H-9), 2.05 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.3 (C-4), 183.8 (C-1), 160.1 (d, 1JC,F = 244.8 Hz, C-4′), 146.1 (C-3), 142.3 (C-2), 133.9 (C-6), 133.8 (C-7), 132.5 (C-1′), 131.9 (C-4a), 131.5 (C-8a), 131.1 (d, 3JC,F = 8.0 Hz, C-6′), 128.5 (qd, 2JC,F = 30.6, 3JC,F = 7.6 Hz, C-2′), 125.9 (C-5, C-8), 123.6 (qd, 1JC,F = 274.3, 4JC,F = 2.8 Hz, CF3), 119.4 (d, 2JC,F = 20.3 Hz, C-5′), 113.7 (dq, 2JC,F = 25.4, 3JC,F = 6.0 Hz, C-3′), 27.8 (C-9), 12.8 (C-10) ppm; HRMS (APCI) calcd. for C19H12F4O2 [M]− = 348.0773; found: 348.0784.
2-{[2-Fluoro-5-(trifluoromethyl)phenyl]methyl}-3-methyl-1,4-naphthoquinone (2e). Compound 2e was obtained after stirring for 3.5 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 63%; Rf = 0.44 (toluene:cyclohexane = 15:1); m.p.: 88–89 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.02 (m, 1H, H-5), 7.98 (m, 1H, H-8), 7.84 (m, 2H, H-6, H-7), 7.66 (m, 2H, H-4′, H-6′), 7.42 (t, J = 9.2 Hz, 1H, H-3′), 4.05 (s, 2H, H-9), 2.14 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.4 (C-4), 183.8 (C-1), 162.3 (dq, 1JC,F = 250.4, 1.5 Hz, C-2′), 145.4* (C-3), 142.1* (C-2), 133.7 (C-6, C-7), 131.8* (C-4a), 131.5* (C-8a), 127.7 (C-6′), 127.1 (C-1′), 125.9 (C-4′), 125.8 (C-5, C-8), 125.3 (qd, 2JC,F = 32.3, 4JC,F = 3.3 Hz, C-5′), 123.7 (q, 1JC,F = 271.1 Hz, CF3), 116.3 (d, 2JC,F = 23.8 Hz, C-3′), 25.4 (C-9), 12.9 (C-10) ppm; HRMS (ESI) calcd. for C19H11F4O2 [M-H]− = 347.0695; found: 347.0703.
2-[(6-Chloropyridin-3-yl)methyl]-3-methyl-1,4-naphthoquinone (2f). Compound 2f was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 60%; Rf = 0.48 (toluene:cyclohexane = 15:1); m.p.: 159–160 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.35 (dd, J = 2.5, 0.8 Hz, 1H, H-2′), 8.00 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.71 (dd, J = 8.3, 2.6 Hz, 1H, H-4′), 7.40 (dd, J = 8.3, 0.7 Hz, 1H, H-5′), 4.00 (s, 2H, H-9), 2.18 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.4 (C-4), 184.0 (C-1), 149.7 (C-2′), 148.0 (C-6′), 145.0 (C-3), 142.9 (C-2), 139.6 (C-4′), 133.9* (C-7), 133.8* (C-6), 133.7 (C-3′), 131.7 (C-8a), 131.4 (C-4a), 125.9* (C-5), 125.8* (C-8), 124.0 (C-5′), 28.5 (C-9), 13.0 (C-10) ppm; HRMS (ESI) calcd. for C17H13ClNO2 [M+H]+ = 298.0635; found: 298.0627.
2-Methyl-3-[(4-nitrophenyl)methyl]-1,4-naphthoquinone (2g). Compound 2g was obtained after stirring for 2.5 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 66%; Rf = 0.40 (toluene:cyclohexane = 15:1); m.p.: 160–161 °C (lit [18] m.p. 156–157 °C). The spectroscopic data were found to be identical to the ones described in [18,28]. Although 2g 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, DMSO-d6) δ = 8.13 (d, J = 8.8 Hz, 2H, H-2′, H-6′), 8.02 (m, 2H, H-5, H-8), 7.85 (m, 2H, H-6, H-7), 7.53 (d, J = 8.8 Hz, 2H, H-3′, H-5′), 4.13 (s, 2H, H-9), 2.16 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.5 (C-4), 183.9 (C-1), 146.6 (C-4′), 145.9 (C-1′), 145.2 (C-3), 143.1 (C-2), 133.9 (C-6, C-7), 131.7*(C-4a), 131.4*(C-8a), 129.5 (C-3′, C-5′), 125.9 (C-5, C-8), 123.5 (C-2′, C-6′), 31.7 (C-9), 13.1 (C-10) ppm.
2-[(2-Fluoro-4-nitrophenyl)methyl]-3-methyl-1,4-naphthoquinone (2h). Compound 2h was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 58%; Rf = 0.48 (toluene:cyclohexane = 15:1); m.p.: 170–171 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.10 (dd, J = 9.9, 2.4 Hz, 1H, H-3′), 8.04 (m, 1H, H-5), 7.98 (m, 1H, H-8), 7.95 (m, 1H, H-5′), 7.85 (m, 2H, H-6, H-7), 7.53 (dd, J = 8.5, 7.7 Hz, 1H, H-6′), 4.09 (s, 2H, H-9), 2.15 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.3 (C-4), 183.6 (C-1), 159.4 (d, 1JC,F = 248.7 Hz, C-2′), 146.8 (d, 3JC,F = 9.1 Hz, C-4′), 145.8 (C-3), 141.9 (C-2), 134.0 (C-7), 133.9 (C-6), 133.5 (d, 2JC,F = 15.8 Hz, C-1′), 131.7 (C-4a), 131.4 (C-8a), 131.0 (d, 3JC,F = 4.6 Hz, C-6′), 125.9 (C-5, C-8), 119.5 (d, 4JC,F = 3.4 Hz, C-5′), 110.9 (d, 2JC,F = 27.6 Hz, C-3′), 25.6 (d, 3JC,F = 2.8 Hz, C-9), 13.0 (C-10) ppm; HRMS (ESI) calcd. for C18H11FNO4 [M-H]− = 324.0672; found: 324.0680.
2-Methyl-3-[(2,4,5-trifluorophenyl)methyl]-1,4-naphthoquinone (2i). Compound 2i was obtained after stirring for 4 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 55%; Rf = 0.39 (toluene:cyclohexane = 15:1); m.p.: 159–160 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.02 (m, 1H, H-5), 7.97 (m, 1H, H-8), 7.84 (m, 2H, H-6, H-7), 7.51 (ddd, J = 10.9, 9.7, 6.9 Hz, 1H, H-3′), 7.36 (ddd, J = 11.5, 9.0, 7.1 Hz, 1H, H-6′) 3.92 (s, 2H, H-9), 2.11 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.3 (C-4), 183.7 (C-1), 155.2 (ddd, 1JC,F = 243.2, 3JC,F = 9.8, 4JC,F = 2.3 Hz, C-2′), 147.8 (ddd, 1JC,F = 246.7, 2JC,F = 14.3, 3JC,F = 13.0 Hz, C-4′), 146.0 (ddd, 1JC,F = 241.6, 2JC,F = 12.4, 4JC,F = 3.5 Hz, C-5′), 145.6 (C-3), 141.9 (C-2), 133.8* (C-6), 133.7* (C-7), 131.8 (C-4a), 131.5 (C-8a), 125.9* (C-5), 125.8* (C-8), 122.2 (ddd, 2JC,F = 18.1, 3JC,F = 5.9, 4JC,F = 4.0 Hz, C-1′), 117.8 (dd, 2JC,F = 19.8, 3JC,F = 5.7 Hz, C-6′), 105.6 (dd, 2JC,F = 29.1, 3JC,F = 21.3 Hz, C-3′), 24.7 (d, 3JC,F = 2.9 Hz, C-9), 12.8 (C-10) ppm; HRMS (APCI) calcd. for C18H11F3O2 [M]− = 316.0711; found: 316.0721.

3.1.3. General Synthetic Procedure for Acetamidobenzylmenadiones 2j,k (Route C)

The respective aminophenylacetic acid (200 mg) was added to glacial acetic acid (3 mL) and subjected to microwave irradiation (180 W, 150 °C) for 40 min. The reaction mixture was poured into EtOAc (50 mL) and washed with H2O (15 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield the crude products as orange solids, which were used without further purification.
As described in the Section 3.1.2, menadione (1 equiv.) was then added to a stirred solution of the above acetaminophenylacetic acid (2 equiv.) and treated with AgNO3 and (NH4)2S2O8 to give the corresponding acetamidobenzylmenadiones.
2-[(4-Acetamidophenyl)methyl]-3-methyl-1,4-naphthoquinone (2j). Compound 2j was obtained after stirring for 1.5 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 94%; Rf = 0.41 (toluene:cyclohexane = 15:1); m.p.: 196–197 °C (lit [35] m.p. 198–200 °C). The spectroscopic data were found to be identical to the ones described in [35]. Although 2j 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, DMSO-d6) δ = 9.85 (s, 1H, NH), 8.00 (m, 2H, H-5, H-8), 7.83 (m, 2H, H-6, H-7), 7.45 (d, J = 8.6 Hz, 2H, H-3′, H-5′), 7.13 (d, J = 8.6 Hz, 2H, H-2′, H-6′), 3.92 (s, 2H, H-9), 2.14 (s, 3H, H-10, 1.99 (s, 3H, CH3-CO) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.7 (C-4), 184.1 (C-1), 168.0 (CO-CH3), 144.5* (C-2), 144.1* (C-3), 137.4 (C-4′), 133.9* (C-6), 133.8* (C-7), 132.5 (C-1′), 131.6* (C-4a), 131.4* (C-8a), 128.5 (C-2′, C-6′), 125.9* (C-5), 125.8* (C-8), 119.1 (C-3′, C-5′), 31.0 (C-9), 23.8 (CH3-CO), 12.9 (C-10) ppm.
2-[(3-Acetamidophenyl)methyl]-3-methyl-1,4-naphthoquinone (2k). Compound 2k was obtained after stirring for 1.5 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 90%; Rf = 0.41 (toluene:cyclohexane = 15:1); m.p.: 188–189 °C (lit [35] m.p. 163–165 °C). The spectroscopic data were found to be identical to the ones described in [35]. Although 2k 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, DMSO-d6) δ = 9.81 (s, 1H, NH), 8.01 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.49 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H, H-4′), 7.31 (t, J = 1.9 Hz, 1H, H-2′), 7.18 (t, J = 7.8 Hz, 1H, H-5′), 6.91 (m, 1H, H-6′), 3.95 (s, 2H, H-9), 2.15 (s, 3H, H-10), 1.98 (s, 3H, CH3-CO) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.6 (C-4), 183.9 (C-1), 168.1 (CO-CH3), 144.4* (C-2), 144.3* (C-3), 139.5 (C-3′), 138.5 (C-1′), 133.9 (C-6, C-7), 131.6* (C-4a), 131.4* (C-8a), 128.7 (C- 5′), 126.0* (C-5), 125.8* (C-8), 118.4 (C-2′), 116.8 (C-4′), 123.1 (C-6′), 31.6 (C-9), 23.9 (CH3-CO), 12.9 (C-10) ppm.

3.1.4. General Synthetic Procedure for Amidobenzylmenadiones 2l–o (Route C)

The acetamido derivatives 2j resp. 2k (200 mg) were added to a mixture of HCl conc. (0.5 mL) and MeOH (4 mL) and subjected to microwave irradiation (250 W, 150 °C) for 30 min. The reaction mixture was poured into EtOAc (50 mL) and washed with sat. aq Na2CO3 (15 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain crude products as orange solids, which were used without further purification.
The above prepared unprotected aminobenzyl derivative (1 equiv.) and dicyclohexyl-carbodiimide (DCC, 1.2 equiv.) were added in sequence to a stirred solution of the corresponding carboxylic acid (1.25 mmol, 1 equiv.) in anhydrous DMF (4 mL) under exclusion of air or humidity. The reaction mixture was stirred at rt until TLC showed complete consumption of the starting material (3–4 h). The mixture was then filtered and the residue extracted with MTBE (20 mL). The combined organic layers were washed successively with H2O, 1M HCl, and sat. aq Na2CO3, dried over Na2SO4, and concentrated in vacuo to give a residue, which was purified by flash chromatography as detailed below.
2-Methyl-3-{[4-(2,2,2-trifluoroacetamido)phenyl]methyl}-1,4-naphthoquinone (2l). Compound 2l was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 71%; Rf = 0.51 (toluene:cyclohexane = 15:1); m.p.: 194–195 °C. 1H NMR (400 MHz, DMSO-d6) δ = 11.19 (s, 1H, NH), 8.01 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.56 (m, 2H, H-3′, H-5′), 7.27 (m, 2H, H-2′, H-6′), 3.98 (s, 2H, H-9), 2.16 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.6 (C-4), 184.0 (C-1), 154.3 (q, 2JC,F = 36.8 Hz, CO-CF3), 144.4* (C-3), 144.1* (C-2), 135.6 (C-1′), 134.3 (C-4′), 133.9* (C-6), 133.8* (C-7), 131.7* (C-4a), 131.4* (C-8a), 128.8 (C-2′, C-6′), 125.9* (C-5), 125.8* (C-8), 121.2 (C-3′, C-5′), 115.7 (q, 1JC,F = 288.9 Hz, CF3), 31.2 (C-9), 12.9 (C-10) ppm; HRMS (ESI) calcd. for C20H13F3NO3 [M-H]− = 372.0848; found: 372.0854.
2-Methyl-3-{[3-(2,2,2-trifluoroacetamido)phenyl]methyl}-1,4-naphthoquinone (2m). Compound 2m was obtained after stirring for 3 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 31%; Rf = 0.53 (toluene:cyclohexane = 15:1); m.p.: 194–195 °C. 1H NMR (400 MHz, DMSO-d6) δ = 11.12 (s, 1H, NH), 8.01 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.57 (ddd, J = 7.9, 2.2, 1.1 Hz, 1H, H-4′), 7.45 (t, J = 1.9 Hz, 1H, H-2′), 7.31 (t, J = 7.9 Hz, 1H, H-5′), 7.13 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H, H-6′), 4.00 (s, 2H, H-9), 2.17 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.6 (C-4), 183.9 (C-1), 154.3 (q, 2JC,F = 37.0 Hz, CO-CF3), 144.5* (C-2), 144.1* (C-3), 139.1 (C-1′), 136.5 (C-3′), 133.9 (C-6, C-7), 131.6* (C-4a), 131.4* (C-8a), 129.0 (C-5′), 126.0* (C-5), 125.9* (C-8), 125.8 (C-6′), 118.7 (C-4′), 120.4 (C-2′), 115.6 (q, 1JC,F = 288.8 Hz, CF3), 31.6 (C-9), 13.0 (C-10) ppm; HRMS (ESI) calcd. for C20H13F3NO3 [M-H]− = 372.0848; found: 372.0855.
2-Methyl-2-{[4-(4,4,4-trifluorobutanamido)phenyl]methyl}-1,4-naphthoquinone (2n). Compound 2n was obtained after stirring for 4 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 70%; Rf = 0.40 (toluene:cyclohexane = 15:1); m.p.: 180–181 °C. 1H NMR (400 MHz, DMSO-d6) δ = 10.00 (s, 1H, NH), 8.01 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.46 (d, J = 8.4 Hz, 2H, H-3′, H-5′), 7.16 (d, J = 8.4 Hz, 2H, H-2′, H-6′), 3.93 (s, 2H, H-9), 2.57 (m, 4H, H-2″, H-3″), 2.15 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.7 (C-4), 184.1 (C-1), 168.0 (C-1″), 144.5* (C-2), 144.1* (C-3), 137.1 (C-4′), 133.9* (C-6), 133.8* (C-7), 132.9 (C-1′), 131.6* (C-4a), 131.4* (C-8a), 128.6 (C-2′, C-6′), 127.4 (q, 1JC,F = 276.2 Hz, C-4″), 125.9 (C-5, C-8), 119.2 (C-3′, C-5′), 31.1 (C-9), 28.5 (C-2″), 28.4 (q, 2JC,F = 28.7 Hz, C-3″), 12.9 (C-10) ppm; HRMS (ESI) calcd. for C22H17F3NO3 [M-H]− = 400.1161; found: 400.1168.
2-Methyl-3-{[3-(4,4,4-trifluorobutanamido)phenyl]methyl}-1,4-naphthoquinone (2o). Compound 2o was obtained after stirring for 4 h, then purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 16%; Rf = 0.42 (toluene:cyclohexane = 15:1); m.p.: 180–181 °C. 1H NMR (400 MHz, DMSO-d6) δ = 9.97 (s, 1H, NH), 8.01 (m, 2H, H-5, H-8), 7.85 (m, 2H, H-6, H-7), 7.50 (dt, J = 7.9, 1.3 Hz, 1H, H-4′), 7.33 (t, J = 1.3 Hz, 1H, H-2′), 7.21 (t, J = 7.9 Hz, 1H, H-5′), 6.95 (dt, J = 7.9, 1.3 Hz, 1H, H-6′), 3.96 (s, 2H, H-9), 2.54 (m, 2H, H-2″), 2.51 (m, 2H, H-3″), 2.16 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.6 (C-4), 183.9 (C-1), 168.1 (C-1″), 144.4* (C-2), 144.3* (C-3), 139.1 (C-3′), 138.7 (C-1′), 134.0* (C-6), 133.9* (C-7), 131.6* (C-4a), 131.4* (C-8a), 128.8 (C-5′), 127.4 (q, 1JC,F = 276.2 Hz, C-4″), 126.0* (C-5), 125.9* (C-8), 123.4 (C-6′), 118.5 (C-2′), 116.9 (C-4′), 31.6 (C-9), 28.6 (q, 3JC,F = 2.9 Hz, C-2″), 28.3 (q, 2JC,F = 28.4 Hz, C-3″), 12.9 (C-10) ppm; HRMS (ESI) calcd. for C22H19F3NO3 [M+H]+ = 402.1317; found: 402.1305.

3.1.5. General Synthetic Procedure for Benzylmenadiones 2p–s (Route D)

Tetralone (200 mg, 1 equiv.) and the respective aldehyde (1.1 equiv.) were added successively to a stirred solution of KOH (1.2 equiv.) in EtOH (5 mL) at rt. The stirring was continued until the TLC showed complete consumption of the starting material (2.5–4 h). The mixture was poured into 30 mL of ice-cold water, and a white precipitate was formed. The product was filtered, washed with ice-cold water and concentrated in vacuo to give a beige solid, which was used without further purification.
Trichlororhodium trihydrate (0.1 equiv.) was added to a stirred solution of the benzylidene derivative prepared above (200 mg, 1 equiv.) in well-degassed EtOH (5 mL) under strict exclusion of air or moisture. The mixture was refluxed until the TLC showed complete consumption of the starting material (24 h). After concentration, the residue was partitioned between H2O (15 mL) and EtOAC (50 mL) and the aqueous layer was extracted again with EtOAc (30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the crude product, which was used without further purification.
(Diacetoxyiodo)benzene (PIDA) (2.1 equiv.) was added in portions to a stirred solution of above prepared naphthol (200 mg, 1 equiv.) in acetonitrile (5 mL) and water (2 mL) at −5 °C for 20–30 min. The reaction mixture was allowed to reach ambient temperature and stirred until the TLC showed complete consumption of the starting material (1 h). After removal of CH3CN under reduced pressure, the resulting residue was extracted three times with CH2Cl2 (20 mL). The combined organic phases were washed with a 1M aqueous solution of triethylammonium acetate, dried over Na2SO4 and concentrated in vacuo to give a yellow solid, which was used without further purification.
The above-prepared 2-benzyl naphthoquinone derivative (200 mg, 1 equiv.) and acetic acid (5 equiv.) were added to a stirred solution of CH3CN/H2O (3:1, 12 mL) and heated to 85 °C. AgNO3 (0.35 equiv.) was added first and then (NH4)2S2O8 (1.3 equiv.) dissolved in 4 mL CH3CN/H2O (3:1) dropwise over a period of 5 min. Stirring at 85 °C was continued until TLC showed complete consumption of the starting material (3–4 h). After cooling to ambient temperature, the mixture was extracted three times with CH2Cl2 (20 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography as detailed below.
2-[(4-Fluorophenyl)methyl]-3-methyl-1,4-naphthoquinone (2p). Compound 2p was purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 17%; Rf = 0.52 (toluene:cyclohexane = 15:1); m.p.: 108–109 °C (lit [28] m.p. 114–115 °C). The spectroscopic data were found to be identical to the ones described in [28]. Although 2p 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, DMSO-d6) δ = 7.26 (m, 2H, H-2′, H-6′), 7.08 (t, J = 8.9 Hz, 2H, H-3′, H-5′), 3.96 (s, 2H, H-9), 2.15 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.6 (C-4), 184.0 (C-1), 160.7 (d, 1JC,F = 242.0 Hz, C-4′), 144.3* (C-2), 144.2* (C-3), 134.2 (d, 4JC,F = 2.9 Hz, C-1′), 133.9* (C-6), 133.8* (C-7), 131.6* (C-4a), 131.4* (C-8a), 130.1 (d, 3JC,F = 8.0 Hz, C-2′, C-6′), 125.9* (C-5), 125.8* (C-8), 115.1 (d, 2JC,F = 21.1 Hz, C-3′, C-5′), 30.8 (C-9), 12.9 (C-10) ppm.
2-Methyl-3-{[4-(trifluoromethoxy)phenyl]methyl}-1,4-naphthoquinone (2q). Compound 2q was purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: <5%; Rf = 0.59 (toluene:cyclohexane = 15:1); m.p.: 72–73 °C (lit [28] m.p. 65–66 °C). The spectroscopic data were found to be identical to the ones described in [28]. Although 2p 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, DMSO-d6) δ = 8.01 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.36 (d, J = 8.8 Hz, 2H, H-2′, H-6′), 7.25 (d, J = 8.2 Hz, 2H, H-3′, H-5′), 4.01 (s, 2H, H-9), 2.16 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.5 (C-4), 184.0 (C-1), 146.6 (q, 3JC,F = 1.8 Hz, C-4′), 144.6* (C-2), 143.8* (C-3), 137.7 (C-1′), 133.9* (C-6), 133.8* (C-7), 131.7* (C-4a), 131.4* (C-8a), 130.1 (C-2′, C-6′), 125.9* (C-5), 125.8* (C-8), 121.1 (C-3′, C-5′), 120.0 (q, 1JC,F = 255.8 Hz, CF3), 30.9 (C-9), 12.9 (C-10) ppm.
2-Methyl-3-{[3-(trifluoromethoxy)phenyl]methyl}-1,4-naphthoquinone (2r). Compound 2r was purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: <5%; Rf = 0.59 (toluene:cyclohexane = 15:1); m.p.: 70–71 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.00 (m, 2H, H-5, H-8), 7.84 (m, 2H, H-6, H-7), 7.40 (t, J = 8.1 Hz, 1H, H-5′), 7.25 (m, 2H, H-2′, H-6′), 7.18 (ddt, J = 8.1, 2.4, 1.1 Hz, 1H, H-4′), 4.04 (s, 2H, H-9), 2.14 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.5 (C-4), 184.0 (C-1), 148.4 (q, 3JC,F = 1.6 Hz, C-3′), 144.8* (C-2), 143.4* (C-3), 141.0 (C-1′), 133.9* (C-6), 133.8* (C-7), 131.7* (C-4a), 131.4* (C-8a), 130.3 (C-5′), 125.9* (C-5), 125.8* (C-8), 127.3 (C-6′), 120.9 (C-2′), 120.0 (q, 1JC,F = 256.1 Hz, CF3), 118.5 (C-4′), 31.3 (C-9), 12.9 (C-10) ppm; HRMS (APCI) calcd. for C19H13F3O3 [M]− = 346.0817; found: 346.0829.
2-{[2-Fluoro-5-(trifluoromethoxy)phenyl]methyl}-3-methyl-1,4-naphthoquinone (2s). Compound 2s was purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: <5%; Rf = 0.58 (toluene:cyclohexane = 15:1); m.p.: 78–79 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.03 (m, 1H, H-5), 7.99 (m, 1H, H-8), 7.84 (m, 2H, H-6, H-7), 7.33 (t, J = 9.1 Hz, 1H, H-3′), 7.29 (d, J = 5.4 Hz, 1H, H-6′), 7.28 (m, 1H, H-4′), 4.01 (s, 2H, H-9), 2.12 (s, 3H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 184.3 (C-4), 183.7 (C-1), 158.6 (d, 1JC,F = 244.5 Hz, C-2′), 145.6* (C-2), 144.2 (C-5′), 142.0* (C-3), 133.9* (C-6), 133.8* (C-7), 131.8 (C-4a), 131.5 (C-8a), 127.3 (d, 2JC,F = 18.1 Hz, C-1′), 125.9 (C-5), 125.8 (C-8), 123.2 (d, 3JC,F = 5.1 Hz, C-6′), 120.9 (d, 3JC,F = 9.1 Hz, C-4′), 119.9 (q, 1JC,F = 256.1 Hz, CF3), 116.7 (d, 2JC,F = 24.8 Hz, C-3′), 25.3 (d, 3JC,F = 2.9 Hz, C-9), 12.8 (C-10) ppm; HRMS (APCI) calcd. for C19H12F4O3 [M]− = 364.0723; found: 364.0736.

3.1.6. General Synthetic Procedure for Benzylnaphthoquinones 4a–e (Route B)

AgNO3 (0.1 equiv.) and (NH4)2S2O8 (2 equiv.) were dissolved in water (4 mL) and a solution of 1,4-naphthoquinone (200 mg, 1 equiv.) and the respective phenylacetic acid derivative (1.4 equiv.) in a 1:1 mixture of CH3CN/CH2Cl2 (4 mL) was quickly added. The two-phase mixture was heated to 80 °C and stirred until the TLC showed complete consumption of the starting material (1.5–2.5 h). After cooling to ambient temperature, the mixture was extracted three times with CH2Cl2 (20 mL). The combined organic layers were washed three times with H2O, dried over Na2SO4, and concentrated in vacuo to give a residue, which was purified by flash chromatography as detailed below.
2-Benzyl-1,4-naphthoquinone (4a). Compound 4a was obtained after stirring for 1.5 h and purified by flash chromatography using toluene/cyclohexane (15:1). Amber solid; yield: 75%; Rf = 0.41 (toluene:cyclohexane = 15:1); m.p.: 92–93 °C (lit [70] m.p. 85–86 °C). The spectroscopic data were found to be identical to the ones described in [70]. 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 = 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 (s, 2H, H-9) 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), 133.7* (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 (C-9) ppm.
2-{[4-(Trifluoromethyl)phenyl]methyl}-1,4-naphthoquinone (4b). Compound 4b was obtained after stirring for 2 h and purified by flash chromatography using toluene/cyclohexane (15:1). Amber solid; yield: 66%; Rf = 0.36 (toluene:cyclohexane = 15:1); m.p.: 99–100 °C (lit [26] m.p. 98–100 °C). The spectroscopic data were found to be identical to the ones described in [26]. Although 4b 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, DMSO-d6) δ = 7.99 (m, 1H, H-8), 7.95 (m, 1H, H-5), 7.84 (m, 2H, H-6, H-7), 7.67 (d, J = 7.9 Hz, 2H, H-3′, H-5′), 7.55 (d, J = 7.9 Hz, 2H, H-2′, H-6′), 6.85 (s, 1H, H-3), 3.96 (s, 2H, H-9) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 184.5 (C-4), 184.2 (C-1), 149.3 (C-2), 142.6 (C-1′), 135.8 (C-3), 134.1* (C-6), 134.0* (C-7), 131.6 (C-4a, C-8a), 129.9 (C-2′, C-6′), 127.2 (q, 2JC,F = 31.8 Hz, C-4′), 126.1 (C-8), 125.6 (C-5), 125.3 (q, 3JC,F = 3.9 Hz, C-3′, C-5′), 124.2 (q, 1JC,F = 272.1 Hz, CF3), 34.7 (C-9) ppm.
2-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-1,4-naphthoquinone (4c). Compound 4c was obtained after stirring for 2.5 h and purified by flash chromatography using toluene/cyclohexane (15:1). Amber solid; yield: 58%; Rf = 0.58 (toluene:cyclohexane = 15:1); m.p.: 130–131 °C. 1H NMR (400 MHz, CDCl3) δ = 8.12 (m, 1H, H-5), 8.05 (m, 1H, H-8), 7.75 (m, 2H, H-6, H-7), 7.45 (m, 1H, H-6′), 7.41 (m, 1H, H-5′), 7.35 (d, J = 9.7 Hz, 1H, H-3′), 6.62 (d, J = 1.6 Hz, 1H, H-3), 3.99 (s, 2H, H-9) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.8 (C-4), 184.5 (C-1), 160.8 (d, 1JC,F = 249.2 Hz, C-2′), 148.1 (C-2), 135.8 (d, 5JC,F = 1.1 Hz, C-3), 134.0 (C-7), 133.9 (C-6), 132.4 (d, 3JC,F = 4.6 Hz, C-6′), 132.0 (C-4a, C-8a), 131.6 (qd, 2JC,F = 33.5, 3JC,F = 8.0 Hz, C-4′), 128.2 (dq, 2JC,F = 15.7, 5JC,F = 1.0 Hz, C- 1′), 126.7 (C-5), 126.2 (C-8), 123.2 (qd, 1JC,F = 272.5, 4JC,F = 2.3 Hz, CF3), 121.6 (C-5′), 113.2 (dq, 2JC,F = 25.1, 3JC,F = 3.7 Hz, C-3′), 29.2 (C-9) ppm; HRMS (ESI) calcd. for C18H9F4O2 [M-H]− = 333.0544; found: 333.0550.
2-{[4-Fluoro-2-(trifluoromethyl)phenyl]methyl}-1,4-naphthoquinone (4d). Compound 4d was obtained after stirring for 2.5 h and purified by flash chromatography using toluene/cyclohexane (15:1). Amber solid; yield: 61%; Rf = 0.43 (toluene:cyclohexane = 15:1); m.p.: 132–133 °C. 1H NMR (400 MHz, CDCl3) δ = 8.15 (m, 1H, H-5), 8.05 (m, 1H, H-8), 7.76 (m, 2H, H-6, H-7), 7.44 (dd, J = 9.0, 2.6 Hz, 1H, H-3′), 7.29 (m, 1H, H-6′), 7.25 (td, J = 8.4, 2.6 Hz, 1H, H-5′), 6.27 (s, 1H, H-3), 4.08 (s, 2H, H-9) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.7 (C-4), 184.6 (C-1), 161.3 (d, 1JC,F = 248.7 Hz, C-4′), 150.1 (C-2), 135.8 (C-3), 134.3 (d, 3JC,F = 7.7 Hz, C-6′), 133.9 (C-6, C-7), 132.0 (C-4a, C-8a), 131.2 (qd, 2JC,F = 31.4, 3JC,F = 7.4 Hz, C-2′), 130.8 (C-1′), 126.8 (C-5), 126.2 (C-8), 123.3 (qd, 1JC,F = 274.1, 4JC,F = 2.7 Hz, CF3), 119.3 (dq, 2JC,F = 20.7, 5JC,F = 1.1 Hz, C-5′), 114.3 (dq, 2JC,F = 25.0, 3JC,F = 5.7 Hz, C-3′) 31.7 (C-9) ppm; HRMS (ESI) calcd. for C18H9F4O2 [M-H]− = 333.0544; found: 333.0549.
2-[(6-Chloropyridin-3-yl)methyl]-1,4-naphthoquinone (4e). Compound 4e was obtained after stirring for 2 h and purified by flash chromatography using toluene/cyclohexane (15:1). Amber solid; yield: 55%; Rf = 0.57 (toluene:cyclohexane = 15:1); m.p.: 154–155 °C. 1H NMR (400 MHz, CDCl3) δ = 8.34 (d, J = 2.5 Hz, 1H, H-2′), 8.09 (dd, J = 5.8, 3.4 Hz, 1H, H-8), 8.06 (dd, J = 5.7, 3.4 Hz, 1H, H-5), 7.75 (m, 2H, H-6, H-7), 7.58 (dd, J = 8.2, 2.5 Hz, 1H, H-4′), 7.30 (d, 8.2 Hz, 1H, H-5′), 6.68 (s, 1H, H-3), 3.88 (s, 2H, H-9) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.7 (C-4), 184.6 (C-1), 150.3 (C-2′, C-6′), 149.0 (C-2), 139.7 (C- 4′), 135.9 (C-3), 134.1* (C-6), 134.0* (C-7), 132.0* (C-4a), 131.9* (C-8a), 131.6 (C-3′), 126.8 (C-8), 126.3 (C-5), 124.4 (C-5′), 32.6 (C-9) ppm; HRMS (APCI) calcd. for C16H11ClNO2 [M+H]+ = 284.0473; found: 284.0465.

3.1.7. General Synthetic Procedure for Trifluoromenadiones 5a–c (Route B)

CuI (0.5 equiv.), bis(pinacolato)diboron (B2pin2, 0.01 equiv.), and Togni reagent (2 equiv.) were dissolved in CHCl3 (3 mL) in the strict exclusion of air or moisture, and the mixture was refluxed in an oil bath at 85 °C. The corresponding benzylnaphthoquinone derivative (200 mg. 1 equiv.) dissolved in 5 mL of CHCl3 was then added, and stirring was continued at 85 °C until TLC showed complete consumption of the starting material (20–26 h). After cooling to ambient temperature, the mixture was diluted with CHCl3 (20 mL) and washed with H2O (15 mL) three times. The organic layer was dried over Na2SO4 and then concentrated in vacuo to give a residue, which was purified by flash chromatography as detailed below.
2-Benzyl-3-(trifluoromethyl)-1,4-naphthoquinone (5a). Compound 5a was obtained from 4a after stirring for 20 h and purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 60%; Rf = 0.49 (toluene:cyclohexane = 15:1); m.p.: 72–73 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.06 (m, 1H, H-5), 8.03 (m, 1H, H-8), 7.93 (m, 1H, H-6), 7.89 (m, 1H, H-7), 7.28 (m, 2H, H-3′, H-5′), 7.20 (dd, J = 7.5, 1.8 Hz, 2H, H-2′, H-6′), 7.18 (m, 1H, H-4′), 4.18 (s, 2H, H-9) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 183.3 (C-1), 180.3 (C-4), 149.2 (q, 3JC,F = 1.8 Hz, C-2), 137.5 (C-1′), 134.7 (C-6), 134.4 (C-7), 132.4 (q, 2JC,F = 27.0 Hz, C-3), 131.6 (q, 4JC,F = 1.5 Hz, C-4a), 131.0 (C-8a), 128.4 (C-3′, C-5′), 127.9 (C-2′, C-6′), 126.4 (C-8), 126.2 (C-4′), 125.9 (C-5), 122.4 (q, 1JC,F = 278.1 Hz, C-10), 31.7 (q, 4JC,F = 3.3 Hz, C-9) ppm; HRMS (APCI) calcd. for C18H11F3O2 [M]− = 316.0711; found: 316.0719.
2-(Trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]methyl}-1,4-naphthoquinone (5b). Compound 5b was obtained from 4b after stirring for 24 h and purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 57%; Rf = 0.32 (toluene:cyclohexane = 15:1); m.p.: 83–84 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.07 (m, 1H, H-5), 8.03 (m, 1H, H-8), 7.94 (td, J = 7.4, 1.7 Hz, 1H, H-6), 7.90 (td, J = 7.4, 1.6 Hz, 1H, H-7), 7.63 (d, J = 8.2 Hz, 2H, H-3′, H-5′), 7.46 (d, J = 8.2 Hz, 2H, H-2′, H-6′), 4.26 (s, 2H, H-9) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 183.2 (C-1), 180.2 (C-4), 148.4 (q, 3JC,F = 1.8 Hz, C-2), 142.6 (C-1′), 134.7 (C-6), 134.4 (C-7), 132.9 (q, 2JC,F = 27.1 Hz, C-3), 131.7 (q, 4JC,F = 1.5 Hz, C-4a), 131.1 (C-8a), 128.8 (C-2′, C-6′), 127.0 (q, 2JC,F = 31.9 Hz, C-4′), 126.4 (C-8), 125.9 (C-5), 125.2 (q, 3JC,F = 3.9 Hz, C-3′, C-5′), 124.2 (q, 1JC,F = 278.1 Hz, 4′-CF3), 122.3 (q, 1JC,F = 278.3 Hz, C-10), 31.7 (q, 4JC,F = 3.2 Hz, C-9) ppm; HRMS (APCI) calcd. for C19H10F6O2 [M]− = 384.0585; found: 384.0584.
2-{[2-Fluoro-4-(trifluoromethyl)phenyl]methyl}-3-(trifluoromethyl)-1,4-naphthoquinone (5c). Compound 5c was obtained from 4c after stirring for 26 h and purified by flash chromatography using toluene/cyclohexane (15:1). Yellow solid; yield: 40%; Rf = 0.30 (toluene:cyclohexane = 15:1); m.p.: 75–76 °C. 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (m, 1H, H-5), 8.04 (m, 1H, H-8), 7.95 (td, J = 7.5, 1.7 Hz, 1H, H-6), 7.92 (td, J = 7.4, 1.6 Hz, 1H, H-7), 7.69 (m, 1H, H-3′), 7.47 (m, 2H, H-5′, H-6′), 4.21 (s, 2H, H-9) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 182.9 (C-1), 180.1 (C-4), 159.5 (d, 1JC,F = 247.4 Hz, C-2′), 147.6 (q, 3JC,F = 2.8 Hz, C-2), 134.8 (C-6), 134.5 (C-7), 133.3 (q, 2JC,F = 27.2 Hz, C-3), 131.6 (C-4a), 131.1 (C-8a), 130.8 (qd, 2JC,F = 33.2, 3JC,F = 8.0 Hz, C-4′, C-6′), 129.6 (d, 2JC,F = 32.2 Hz, C-1′), 126.4 (C-8), 126.0 (C-5), 123.3 (qd, 1JC,F = 272.0, 4JC,F = 2.5 Hz, 4′-CF3), 122.3 (q, 1JC,F = 278.1 Hz, C-10), 121.4 (C-5′), 112.6 (dq, 2JC,F = 25.6, 3JC,F = 3.8 Hz, C-3′), 25.4 (dq, 3JC,F = 6.1, 4JC,F = 3.1 Hz, C-9) ppm; HRMS (APCI) calcd. for C19H9F7O2 [M]− = 402.0498; found: 402.0501.

4. Conclusions

In this study, we present the synthesis of 27 plasmodione-like benzylnaphthoquinone derivatives together with their antiprotozoal activities and physicochemical parameters. The antiplasmodial potential was found highly promising, which was also confirmed by remarkably high selectivities. Ligand efficiency metrics, specifically size-independent ligand efficiency (SILE), correlated strongly with antiplasmodial activity, thus guiding drug optimization.
The four-fold fluorinated benzylmenadione 2e showed the lowest IC50 of all prepared compounds against the P. falciparum NF54 strain at 0.006 μM along with very good selectivity (SI = 7495). The trypanocidal effect among the synthesized compounds was also assessed. It was found strongest in benzyl-NQ, 4a, albeit much less pronounced.
The findings presented in this work demonstrate the potential of benzylmenadiones as promising chemical leads in the development of new antiplasmodial drugs.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26052114/s1.

Author Contributions

Conceptualization, A.P.; methodology, A.P.; software, A.P.; validation, A.P. and W.S.; formal analysis, A.P.; investigation, A.P., G.B., E.-M.P.-W., M.K. and P.M.; resources, A.P., E.-M.P.-W., M.K. and P.M.; data curation, A.P., E.-M.P.-W., M.K., P.M. and W.S.; writing—original draft preparation, A.P. and W.S.; writing—review and editing, A.P., E.-M.P.-W., M.K., P.M. and W.S.; visualization, A.P.; supervision, A.P.; project administration, A.P.; funding acquisition, 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 for discussions and to the University of Graz for Open Access Funding. NAWI Graz is acknowledged for supporting the Graz Central Lab Environmental, Plant, and Microbial Metabolomics.

Conflicts of Interest

The authors declare no conflicts of interest.

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Ijms 26 02114 g001
Figure 1. 1,4-Naphthoquinones with remarkable biological activity.
Figure 1. 1,4-Naphthoquinones with remarkable biological activity.
Ijms 26 02114 g001
Ijms 26 02114 sch001
Scheme 1. Synthesis of benzyl-substituted naphthoquinone and menadione derivatives via Kochi–Anderson reaction (A–C) or an alternative tetralone route (D). Reagents and conditions: (A): (a) phenylacetic acid derivative (1.4 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 1–4 h. (B): (a) phenylacetic acid derivative (1.4 equiv.), AgNO3 (0.1 equiv.), (NH4)2S2O8 (2 equiv.), CH3CN/CH2Cl2, 80 °C, 1.5–2.5 h; (b). CuI (0.5 equiv.), B2pin2 (0.01 equiv.), Togni reagent (2 equiv.), CHCl3, 85 °C, 20–26 h. (C): (a) AcOH, mw, 150 °C, 40 min; (b) acetaminophenylacetic acid (2 equiv.), menadione (1 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 1.5 h; (c) MeOH/HCl conc., mw, 150 °C, 30 min; (d) carboxylic acid (1 equiv.), DCC (1.2 equiv.), DMF, rt, 3–4 h. (D): (a) benzaldehyde derivative (1.1 equiv.), KOH/EtOH, rt, 2.5–4 h; (b) RhCl3 (0.1 equiv.), EtOH, 85 °C, 24 h; (c) PIDA (2.1 equiv.), CH3CN/H2O, −5 °C → rt, 1.5 h; (d) AcOH (5 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 3 h.
Scheme 1. Synthesis of benzyl-substituted naphthoquinone and menadione derivatives via Kochi–Anderson reaction (A–C) or an alternative tetralone route (D). Reagents and conditions: (A): (a) phenylacetic acid derivative (1.4 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 1–4 h. (B): (a) phenylacetic acid derivative (1.4 equiv.), AgNO3 (0.1 equiv.), (NH4)2S2O8 (2 equiv.), CH3CN/CH2Cl2, 80 °C, 1.5–2.5 h; (b). CuI (0.5 equiv.), B2pin2 (0.01 equiv.), Togni reagent (2 equiv.), CHCl3, 85 °C, 20–26 h. (C): (a) AcOH, mw, 150 °C, 40 min; (b) acetaminophenylacetic acid (2 equiv.), menadione (1 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 1.5 h; (c) MeOH/HCl conc., mw, 150 °C, 30 min; (d) carboxylic acid (1 equiv.), DCC (1.2 equiv.), DMF, rt, 3–4 h. (D): (a) benzaldehyde derivative (1.1 equiv.), KOH/EtOH, rt, 2.5–4 h; (b) RhCl3 (0.1 equiv.), EtOH, 85 °C, 24 h; (c) PIDA (2.1 equiv.), CH3CN/H2O, −5 °C → rt, 1.5 h; (d) AcOH (5 equiv.), AgNO3 (0.35 equiv.), (NH4)2S2O8 (1.3 equiv.), CH3CN/H2O, 85 °C, 3 h.
Ijms 26 02114 sch001
Ijms 26 02114 g002
Figure 2. Scatterplot of lipophilic ligand efficiency (LLE) vs. size-independent ligand efficiency (SILE) for the synthesized compounds including some optimization trajectories; the colors are assigned according to their respective pIC50.
Figure 2. Scatterplot of lipophilic ligand efficiency (LLE) vs. size-independent ligand efficiency (SILE) for the synthesized compounds including some optimization trajectories; the colors are assigned according to their respective pIC50.
Ijms 26 02114 g002
Ijms 26 02114 g003
Figure 3. Application of the AtlasCBS concept using a schematic NSEI-nBEI plane analysis of the synthesized benzyl-naphthoquinones including optimization trajectories; the colors are assigned according to their respective pIC50.
Figure 3. Application of the AtlasCBS concept using a schematic NSEI-nBEI plane analysis of the synthesized benzyl-naphthoquinones including optimization trajectories; the colors are assigned according to their respective pIC50.
Ijms 26 02114 g003
Ijms 26 02114 g004
Figure 4. Plot of SILE (P. falciparum) data obtained in this study (x) vs. calculated log SI (P. falciparum) (y); the colors are assigned according to their respective pIC50. Substances that lie in the yellow shaded area combined high selectivity with acceptable size-independent ligand efficiency values.
Figure 4. Plot of SILE (P. falciparum) data obtained in this study (x) vs. calculated log SI (P. falciparum) (y); the colors are assigned according to their respective pIC50. Substances that lie in the yellow shaded area combined high selectivity with acceptable size-independent ligand efficiency values.
Ijms 26 02114 g004
Table 1. Synthesis of benzyl-substituted naphthoquinone and menadione derivatives (overall yields calculated from NQ, MD, and tetralone).
Table 1. Synthesis of benzyl-substituted naphthoquinone and menadione derivatives (overall yields calculated from NQ, MD, and tetralone).
CompdStructureRouteYield (%)CompdStructureRouteYield (%)
2aIjms 26 02114 i001A882oIjms 26 02114 i002C14
2bIjms 26 02114 i003A832pIjms 26 02114 i004D17
2cIjms 26 02114 i005A692qIjms 26 02114 i006D<5
2dIjms 26 02114 i007A662rIjms 26 02114 i008D<5
2eIjms 26 02114 i009A632sIjms 26 02114 i010D<5
2fIjms 26 02114 i011A604aIjms 26 02114 i012B75
2gIjms 26 02114 i013A664bIjms 26 02114 i014B66
2hIjms 26 02114 i015A584cIjms 26 02114 i016B58
2iIjms 26 02114 i017A554dIjms 26 02114 i018B61
2jIjms 26 02114 i019C944eIjms 26 02114 i020B55
2kIjms 26 02114 i021C905aIjms 26 02114 i022B45
2lIjms 26 02114 i023C675bIjms 26 02114 i024B38
2mIjms 26 02114 i025C285cIjms 26 02114 i026B23
2nIjms 26 02114 i027C66
Table 2. In vitro antiparasitic activity, mammalian cell toxicity, and predicted oral toxicity of the synthesized compounds.
Table 2. In vitro antiparasitic activity, mammalian cell toxicity, and predicted oral toxicity of the synthesized compounds.
CompdP. falc. 1SI 2P. falc. 1T. b. rhod. 3SI 2T. b. rhod. 3Cyt L6 4Oral Toxicity 6
IC50 μM pIC50 5IC50 μM pIC50 5IC50 μMLD50 mg/kg
Chl.0.003303678.52 91.1
Mel. 0.00640338.2224.2
Pod. 0.024
2a0.3581266.4562.79314.2045.023500
2b0.0489947.3165.27614.1948.152500
2c0.01153777.9481.39614.0961.746500
2d0.02030997.7023.21034.6362.274500
2e0.00674958.2493.02104.0343.0382000
2f0.0376547.438.26935.0824,1722000
2g0.1111726.9628.03414.5519.069500
2h0.0228107.6725.54314.5917.427500
2i0.04412317.3530.35324.5254.509500
2j0.695246.1628.88614.5416.317500
2k0.758226.1239.45704.4016.5681000
2l0.1471096.8323.38414.6316.1091033
2m0.321436.4924.26514.6213.706948
2n0.159926.8072.25004.1414.6871000
2o0.6701316.1750.79924.2987.5471000
2p0.04311947.3733.22524.4851.124500
2q0.02942507.5481.57524.09122.724500
2r0.04916417.3126.06434.5880.536500
2s0.03821667.4275.76314.1283.2291000
4a2.755225.560.3181936.5061.551500
4b0.686286.160.503386.3019.189500
4c1.762215.750.790476.1036.997500
4d2.307175.641.744225.7638.379500
4e2.00625.700.52286.283.9442000
5a3.80435.421.88465.7210.769500
5b1.45715.841.96215.712.004500
5c2.31405.649.41405.030.805500
1 P. falciparum, strain NF54, erythrocytic stages; 2 SI is defined as the ratio: IC50 in L6 cells/IC50 in each parasite; 3 T. brucei rhodesiense, strain STIB900 trypomastigote bloodstream forms; 4 cytotoxicity L6 cells rat skeletal myoblasts; 5 pIC50 = −log10 IC50 (M); 6 The oral toxicity was calculated using the ProTox 3.0 software (https://tox.charite.de/protox3/, accessed on 25 October 2024), and the calculated median lethal dose (LD50) is given in mg/kg body weight. Reference drugs: chloroquine (chl.), melarsoprol (mel.), podophyllotoxin (pod.). Values in bold highlight the most striking results.
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Presser, A.; Blaser, G.; Pferschy-Wenzig, E.-M.; Kaiser, M.; Mäser, P.; Schuehly, W. Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties. Int. J. Mol. Sci. 2025, 26, 2114. https://doi.org/10.3390/ijms26052114

AMA Style

Presser A, Blaser G, Pferschy-Wenzig E-M, Kaiser M, Mäser P, Schuehly W. Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties. International Journal of Molecular Sciences. 2025; 26(5):2114. https://doi.org/10.3390/ijms26052114

Chicago/Turabian Style

Presser, Armin, Gregor Blaser, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Mäser, and Wolfgang Schuehly. 2025. "Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties" International Journal of Molecular Sciences 26, no. 5: 2114. https://doi.org/10.3390/ijms26052114

APA Style

Presser, A., Blaser, G., Pferschy-Wenzig, E.-M., Kaiser, M., Mäser, P., & Schuehly, W. (2025). Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties. International Journal of Molecular Sciences, 26(5), 2114. https://doi.org/10.3390/ijms26052114

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