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Communication

Probing Adamantane Arylhydroxamic Acids against Trypanosoma brucei and Trypanosoma cruzi

by
Angeliki Sofia Foscolos
1,
Andrew Tsotinis
1,
Martin C. Taylor
2,
John M. Kelly
2 and
Ioannis P. Papanastasiou
1,*
1
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens Panepistimioupoli-Zografou, 15784 Athens, Greece
2
Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1 E7HT, UK
*
Author to whom correspondence should be addressed.
Molbank 2022, 2022(2), M1363; https://doi.org/10.3390/M1363
Submission received: 30 March 2022 / Revised: 12 May 2022 / Accepted: 13 May 2022 / Published: 15 May 2022
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Versions Notes

Abstract

:
In this work, we present the synthesis and the anti-trypanosomal activity of the 2-(4-(adamant-1-yl)phenyl)-N-hydroxyarylamides, 1a,b and the 2-(4-(adamant-1-yl)phenoxy)-N-hydroxyacetamide, 1c. The 4-(adamant-1-yl)phenyl- and 4-(adamant-1-yl)phenoxy- moieties, which are endowed with promising drug-like properties, are functionalized at the side chain termini as hydroxamic acids. The phenoxy acetohydroxamic derivative, 1c, shows the most interesting profile in terms of activity and toxicity against trypanosomes and merits further investigation.

1. Introduction

One-sixth of the global population, more than 1 billion, is infected with one or more neglected tropical diseases (NTDs) and an additional 2 billion are at risk [1]. Among the “most neglected” NTDs are the two types of trypanosomiasis: human African trypanosomiasis (HAT) and Chagas disease (CD) [2]. Public–private consortia bridge the gap between research and the current therapeutic regimens against these diseases [3,4]. Large-scale phenotypic screening has identified many drug candidates that are active against the kinetoplastid protozoa. However, validated targets against the parasitic diseases are fewer because of the complexities of pathogen biology and, in some cases, insufficiently robust genetic approaches [5]. The challenge for new classes of effective therapeutic agents involves investigation of target-based approaches of drug design [6].
The current drugs used against HAT and CD are suboptimal. The approved regimen presents many restrictions, such as serious adverse side effects, excessive toxicity, limited efficacy and increasing resistance [3,4]. The older therapeutical arsenal consists of pentamidine, eflornithine, suramin, melarsoprol and nifurtimox, while newer agents are benznidazole and the latter fexinidazole and acoziborole [5]. Over the last decade, the scientific community has made tremendous efforts toward NTD control and many more late-stage candidates will be generated in the pipeline, in due course [7,8,9].
We have been exploring the chemical space of structurally different adamantane derivatives and their biological role against trypanosomes [10,11,12,13,14,15]. Recently, we published the promising drug-like properties of 4-(adamant-1-yl)phenyl- and 4-(adamant-1-yl)phenoxy- moieties in various scaffolds with trypanocidal activity [16,17,18]. In the current work, we present the synthesis and the anti-trypanosomal activity of 2-(4-(adamant-1-yl)phenyl)-N-hydroxyarylamides 1a,b and the 2-(4-(adamant-1-yl)phenoxy)-N-hydroxyacetamide 1c (Figure 1). The new derivatives exhibit the 4-(adamant-1-yl)phenyl- and 4-(adamant-1-yl)phenoxy- cores, which are functionalized as hydroxamic acids. Hydroxamic acids exhibit metal-chelating properties and act as inhibitors of metalloproteins with a wide spectrum of therapeutic roles [19]. Acetohydroxamic adamantane derivatives have shown significant activity against T. brucei [20] (Figure 1). We now explore the role of the phenyl or phenoxy substitution at the C1 position of the adamantane cage regarding the functional hydroxamic end of the side chain in the 1a,b and c derivatives and their activity against trypanosomes.

2. Results and Discussion

2.1. Chemistry

The synthesis of the hydroxamic acids 1a–c was accomplished by the reactions shown in Scheme 1. Carboxylic acids 3–5 were coupled with O-benzylhydroxylamine in the presence of 1,1′-carbonyldiimidazole (CDI) in THF to give the corresponding O-benzyl hydroxamates 2a–c, in yields of 68–74%. Subsequent O-benzyl deprotection by hydrogenolysis in the presence of Pd/C in ethanol afforded the target hydroxamic acids, 1a–c, in high yield (90–95%). The synthesis of the carboxylic acids 3 and 4 (Scheme 1) has been described in our previously published protocols [18,21], while the preparation of the 2-(4-(adamantan-1-yl)phenoxy)acetic acid 5 was reported by Lee et al. [22].

2.2. Biological Evaluation

The new hydroxamic acid analogues 1a–c were tested for their activity against the bloodstream form Trypanosoma brucei and Trypanosoma cruzi epimastigotes and the results are presented in Table 1 and Table 2.
We found that the acetohydroxamide 1b was more potent than the benzohydroxamide 1a, which had little activity against trypanosomes. Of the three derivatives tested, the phenoxy acetamide 1c was the most active. Insertion of the oxygen atom of the phenoxy group enhanced activity against T. brucei more than ninefold compared with 1b (IC50 of 1c versus IC50 of 1b, Table 1). For comparison purposes, the phenoxy acetamide 1c was 12-fold more potent against T. cruzi epimastigotes and more than eight times more potent against the T. brucei bloodstream forms than benznidazole and fexinidazole, two heterocyclic nitro-drugs that are used to treat T. cruzi and T. brucei, respectively. The activity of both compounds against T. cruzi followed the same pattern. These results have prompted us to further investigate these structure-activity relationships and pursue in the future the synthesis of related structures.

3. Materials and Methods

3.1. Chemistry

All chemicals and solvents were obtained from commercial suppliers and used without further purification. Concentrated refers to the removal of solvents with a rotary evaporator at normal water aspirator pressure, followed by further evacuation on a high-vacuum line. Reactions were monitored by thin-layer chromatography. Thin-layer chromatography was performed using E. Merck precoated silica gel 60 F254 plates. Developed TLC plates were visualized with UV light (254 nm) and iodine. The chromatographic purification of the products was carried out using Silica gel 60 (40–63 μm, 230–400 mesh ASTM, Silica flash). Melting points were determined on a Büchi 530 apparatus and are uncorrected.
1H-NMR and 13C-NMR spectra (Supplementary Materials) were taken in CDCl3 or DMSO-d6 at 298 K (25 °C) and recorded on a Bruker Ultrashiel™ Plus Avance III 600 spectrometer (Bruker, Billerica, Massachusetts, U.S.) and a Bruker DRX400 spectrometer.The measured chemical shifts are reported in δ (ppm), and the residual solvent signal was used as the internal calibration standard (CDCl3): 1H = 7.26 ppm, 13C = 77.0 ppm; (DMSO-d6): 1H = 2.50 ppm; and 13C = 39.52 ppm. Splitting patterns are designated as follows: s, singlet; br. s, broad singlet; d, doublet; t, triplet; q, quartet; multiplet; and complex m, complex multiplet. Coupling constants (J) are expressed in units of Hertz (Hz). IR spectra were recorded by using the attenuated total reflection (ATR) method on a FTIR Bruker Tensor 27. Microanalyses were carried out by the NCSR Demokritos, Greece, and the results obtained had a maximum deviation of ±0.4% from the theoretical value.
The 1H and 13C NMR spectra for the hydroxamic acid derivatives described in this report (compounds 1a–c), are consistent with a Z/E conformation of these molecules in solution. The detected double set of characteristic peaks in the 1H and 13C NMR spectra confirm the presence of the two carbonyl rotamers. The assignment of the Z or E rotamers was based on literature data concerning Z/E geometry studies in simple hydroxamate structures (Figure 2) [23,24,25,26,27].

3.2. Synthesis

3.2.1. 4-(Adamant-1-yl)-N-(benzyloxy)benzamide 2a

To a solution of the carboxylic acid 3 [18] (400 mg, 1.56 mmol) in dry THF (20 mL) was added 1,1′-carbonyldiimidazole (304 mg, 1.87 mmol), and the mixture was stirred at ambient temperature for 1 h under argon. Then, O-benzylhydroxylamine hydrochloride (299 mg, 1.87 mmol) and triethylamine (284 mg, 2.81 mmol) were successively added, and the stirring was continued at room temperature for 24 h and then at 50 °C for 1 h under argon. After removal of the solvent in vacuo, water was added, and the mixture was extracted with ethyl acetate (×3). The combined extracts were washed with brine (×2), water (×2), dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography, using as eluent a mixture of DCM:MeOH, 95:5 to give O-benzyl hydroxamate 2a as a white solid. Yield 420 mg (74%). M.p.: 137–138 °C.
Mixture of two rotamers E and Z. E/Z ≈ 1.8.
1H-NMR (400 MHz, CDCl3), δ (ppm): (Rotamer E): 1.63–1.73 (~q, 6H, 4,6,10-H), 1.79 (s, 6H,2,8,9-H), 2.01 (br. s, 3H, 3,5,7-H), 4.94 (s, 2H, OCH2), 7.26–7.30 (complex m, 9H, Har), 8.58 (s, 1 H, NH); 13C-NMR (50 MHz, CDCl3), δ (ppm): 27.81 (3,5,7-C), 33.62 (1-C), 35.66 (4,6,10-C), 41.94 (2,8,9-C), 77.79 (OCH2), 124.26 (3,5-Car), 126.85, 127.04, 127.24, 127.39, 127.69 (2′,3′,4′,5′,6′-Car), 127.64 (2,6-Car), 127.86 (1-Car), 128.33 (1′-Car), 150.62 (4-Car), 158.68 (C=O).
1H-NMR (400 MHz, CDCl3), δ (ppm): (Rotamer Z): 1.63–1.73 (~q, 6H, 4,6,10-H), 1.75 (s, 6H,2,8,9-H), 1.84 (br. s, 3H, 3,5,7-H), 4.96 (s, 2H, OCH2), 7.26–7.30 (complex m, 9H, Har), 8.58 (s, 1 H, NH); 13C-NMR (50 MHz, CDCl3), δ (ppm): 27.99 (3,5,7-C), 33.62 (1-C), 35.66 (4,6,10-C), 40.18 (2,8,9-C), 74.61 (OCH2), 124.26 (3,5-Car), 126.85, 127.04, 127.24, 127.39, 127.69 (2′,3′,4′,5′,6′-Car), 127.64 (2,6-Car), 127.86 (1-Car), 128.21 (1′-Car), 149.94 (4-Car), 158.68 (C=O).
Anal Calcd. for C24H27NO2 (%): C, 79.74; H, 7.53; N, 3.87; found (%) C, 79.62; H, 7.47; N, 3.77.

3.2.2. 2-(4-(Adamantan-1-yl)phenyl)-N-(benzyloxy)acetamide 2b

Prepared from the carboxylic acid 4 [21] in a similar manner to benzamide 2a. Yield 68%. M.p.: 81–83 °C.
Mixture of two rotamers E and Z. E/Z ≈ 1.5.
1H-NMR (600 MHz, CDCl3), δ (ppm): (Rotamer Ε): 1.73–1.79 (~d, 6H, 4,6,10-H), 1.89 (br. s, 6H,2,8,9-H), 2.09 (s, 3H, 3,5,7-H), 3.76 (s, 2H, CH2CO), 4.97 (s, 2H, OCH2Ph), 7.29–7.41 (complex m, 9H, Har), 7.53 (s, 1 H, NH); 13C-NMR (150 MHz, CDCl3), δ (ppm): 29.10 (3,5,7-C), 36.20 (1-C), 36.94 (4,6,10-C), 40.97 (CH2CO), 43.33 (2,8,9-C), 79.27 (OCH2Ph), 125.37 (3,5-Car), 128.75, 128.86, 128.96, 129.38, 129.45 (2′,3′,4′,5′,6′-Car), 130.19 (2,6-Car), 133.67 (1′-Car), 135.23 (1-Car), 152.36 (4-Car), 159.60 (C=O).
1H-NMR (600 MHz, CDCl3), δ (ppm): (Rotamer Ζ): 1.73–1.79 (~d, 6H, 4,6,10-H), 1.89 (br. s, 6H,2,8,9-H), 2.09 (s, 3H, 3,5,7-H), 3.47 (s, 2H, CH2CO), 4.99 (s, 2H, OCH2Ph), 7.29–7.41 (complex m, 9H, Har), 7.81 (s, 1 H, NH); 13C-NMR (150 MHz, CDCl3), δ (ppm): 29.10 (3,5,7-C), 36.20 (1-C), 36.94 (4,6,10-C), 40.97 (CH2CO), 43.33 (2,8,9-C), 78.95 (OCH2Ph), 125.37 (3,5-Car), 128.75, 128.86, 128.96, 129.38, 129.45 (2′,3′,4′,5′,6′-Car), 130.19 (2,6-Car), 133.67 (1′-Car), 135.27(1-Car), 150.76 (4-Car), 159.67 (C=O).
Anal Calcd. for C25H29NO2 (%): C, 79.96; H, 7.78; N, 3.73; found (%) C, 80.10; H, 7.96; N, 3.77.

3.2.3. 2-(4-(Adamant-1-yl)phenoxy)-N-(benzyloxy)acetamide 2c

Prepared from the carboxylic acid 5 [22] in a similar manner to benzamide 2a. Yield 71%. M.p.: 104–105 °C.
1H-NMR (400 MHz, CDCl3), δ (ppm): 1.62–1.70 (~q, 6H, 4,6,10-H), 1.77 (br. s, 6H,2,8,9-H), 1.99 (s, 3H, 3,5,7-H), 4.45 (s, 2H, OCH2CO), 4.85 (s, 2H, OCH2Ph), 6.68–6.70 (d, 2H, J ≈ 8.2 Hz, 2,6-Har) 7.17–7.22 (m, 7H, Har), 7.49 (s, 1 H, NH).
Anal Calcd. for C25H29NO3 (%): C, 76.70; H, 7.47; N, 3.58; found (%) C, 76.63; H, 7.41; N, 3.78.

3.2.4. 4-(Adamant-1-yl)-N-hydroxybenzamide 1a

O-benzyl hydroxamate 2a (350 mg, 0.97 mmol) in absolute EtOH (30 mL) was hydrogenated (Pd/C 10%, 35 mg) for 3 h at room temperature and 55 psi pressure. The catalyst was filtered off, washed with EtOH (×3), and the combined filtrates were evaporated in vacuo. The residue was purified by flash column chromatography, using as eluent a mixture of n-hexanes/AcOEt, 50:50, increasing to 20:80 to afford the title compound 1a as a white crystalline solid. Yield 250 mg (95%). M.p.: 144–145 °C; IR, v(NH): 3415–3362 cm−1, v(C=O): 3201 cm−1. v(C=O): 1650 cm−1.
Mixture of two rotamers E and Z. Z > E.
1H-NMR (400 MHz, CDCl3), δ (ppm): (Rotamer Z): 1.63–1.72 (m, 6H, 4,6,10-H), 1.75–1.77 (~d, 6H,2,8,9-H), 1.98 (s, 3H, 3,5,7-H), 5.99 (br. s, 1H, OH), 7.16–7.36 (m, 4H, Har) 7.58 (s, 1 H, NH); 13C-NMR (50 MHz, CDCl3), δ (ppm): 27.82 (3,5,7-C), 33.63 (1-C), 35.67 (4,6,10-C), 41.96 (2,8,9-C), 125.98 (3,5-Car), 127.52 (2,6-Car), 139.98 (1-Car), 154.23 (4-Car), 168.43 (C=O).
1H-NMR (400 MHz, CDCl3), δ (ppm): (Rotamer E): 1.63–1.72 (m, 6H, 4,6,10-H), 1.79–1.82 (~d, 6H,2,8,9-H), 2.01 (s, 3H, 3,5,7-H), 6.16 (br. s, 1H, OH), 7.16–7.36 (m, 4H, Har), 7.57 (s, 1H, NH); 13C-NMR (50 MHz, CDCl3), δ (ppm): 30.74 (3,5,7-C), 33.63 (1-C), 35.67 (4,6,10-C), 45.75 (2,8,9-C), 126.31 (3,5-Car), 126.57 (2,6-Car), 139.98 (1-Car), 154.71 (4-Car), 168.69 (C=O).
Anal Calcd. for C17H21NO2 (%): C, 75.25; H, 7.80; N, 5.16; found (%) C, 75.43; H, 7.84; N, 5.36.

3.2.5. 2-(4-(Adamantan-1-yl)phenyl)-N-hydroxyacetamide 1b

Prepared from O-benzyl hydroxamate 2b in a similar manner to N-hydroxybenzamide 1a. Yield 90%. M.p.: 93–95 °C; IR, v(NH): 3400 cm−1, v(OH): 3273 cm−1, v(C=O): 1650 cm−1.
Mixture of two rotamers E and Z. Z/E ≈ 9.2
1H-NMR (600 MHz, DMSO-d6), δ (ppm): (Rotamer Z): 1.71–10.76 (~q, 6H, 4,6,10-H), 1.85 (s, 6H,2,8,9-H), 2.05 (s, 3H, 3,5,7-H), 3.43 (s, 2H, CH2CO), 6.11 (s, 1H, OH), 7.16–7.17 (d, 2H, J ≈ 8.2 Hz, 3,5-Har), 7.25–7.27 (d, 2H, J ≈ 8.2 Hz, 2,6-Har), 8.19 (s, 1H, NH); 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 28.26 (3,5,7-C), 35.38 (1-C), 36.15 (4,6,10-C), 41.30 (CH2CO), 42.62 (2,8,9-C), 124.26 (3,5-Car), 128.90 (2,6-Car), 132.99 (1-Car), 148.64 (4-Car), 167.10 (C=O).
1H-NMR (600 MHz, DMSO-d6), δ (ppm): (Rotamer E): 1.71–1.76 (~q, 6H, 4,6,10-H), 1.80–1.85 (s, 6H,2,8,9-H), 2.05 (s, 3H, 3,5,7-H), 3.72 (s, 2H, CH2CO), 6.11 (s, 1H, OH), 7.19–7.20 (d, 2H, J ≈ 8.2 Hz, 3,5-Har), 7.29–7.30 (d, 2H, J ≈ 8.2 Hz, 2,6-Har), 7.37 (s, 1H, NH); 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 28.26 (3,5,7-C), 35.38 (1-C), 36.15 (4,6,10-C), 42.55 (CH2CO), 42.62 (2,8,9-C), 124.36 (3,5-Car), 128.55 (2,6-Car), 132.99 (1-Car), 148.64 (4-Car), 173.00 (C=O).
Anal Calcd. for C18H23NO2 (%): C, 75.76; H, 8.12; N, 4.91; found (%) C, 75.68; H, 7.93; N, 4.87.

3.2.6. 2-(4-(Adamantan-1-yl)phenoxy)-N-hydroxyacetamide 1c

Prepared from O-benzyl hydroxamate 2c in a similar manner to N-hydroxybenzamide 1a. Yield 90%. M.p.: 104–105 °C; IR, v(NH): 3396 cm−1, v(OH): 3150 cm−1, v(C=O): 1655 cm−1.
Mixture of two rotamers E and Z. E/Z ≈ 5.3.
1H-NMR (600 MHz, DMSO-d6), δ (ppm): (Rotamer Z): 1.69–1.74 (~q, 6H, 4,6,10-H), 1.82 (s, 6H,2,8,9-H), 2.03 (s, 3H, 3,5,7-H), 4.39 (s, 2H, OCH2CO), 6.17 (s, 1H, OH), 6.88–6.99 (d, 2H, J ≈ 8 Hz, 2,6-Har), 7.24–7.2 (d, 2H, J ≈ 8 Hz, 3,5-Har), 8.27 (s, 1 H, NH); 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 28.43 (3,5,7-C), 35.14 (1-C), 36.25 (4,6,10-C), 42.87 (2,8,9-C), 65.94 (OCH2), 114.22 (2,6-Car), 125.53 (3,5-Car), 143.73 (4-Car), 155.67 (1-Car), 164.50 (C=O).
1H-NMR (600 MHz, DMSO-d6), δ (ppm): (Rotamer E): 1.69–1.74 (~q, 6H, 4,6,10-H), 1.82 (s, 6H,2,8,9-H), 2.08 (s, 3H, 3,5,7-H), 4.43 (s, 2H, OCH2CO), 6.81 (s, 1H, OH), 6.88–6.99 (d, 2H, J ≈ 8 Hz, 2,6-Har), 7.24–7.26 (d, 2H, J ≈ 8 Hz, 3,5-Har), 7.46 (s, 1 H, NH); 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 30.62 (3,5,7-C), 35.14 (1-C), 36.25 (4,6,10-C), 42.87 (2,8,9-C), 66.85 (OCH2), 114.22 (2,6-Car), 125.53 (3,5-Car), 143.73 (4-Car), 162.64 (1-Car), 170.53 (C=O).

3.3. Biological Assays

3.3.1. Cytotoxic Activity against Rat Skeletal Myoblast L6 Cells

Cytotoxicity against mammalian cells was assessed using microtitre plates. Briefly, L6 cells (a rat skeletal muscle line) were seeded at 1 × 104 mL−1 in 200 μL of RPMI-1640 growth medium containing seven different compound concentrations in a range previously established to encompass both the IC50 and IC90 values. The plates were incubated for 6 days at 37 °C and 20 μL Alamar Blue (Biosource Ltd, Wilton, North Yorkshire England.) was then added to each well. After an additional 8 h incubation, the fluorescence was determined using a Gemini fluorescent plate reader (Molecular Devices). Inhibition of growth was calculated by comparison with control values and IC50 and IC90 values were determined in triplicate using linear regression analysis.

3.3.2. Trypanosoma brucei Culturing and Drug Testing

Bloodstream form T. brucei (strain 427) were cultured at 37 °C in modified Iscove’s medium. Trypanocidal activity was assessed by growing parasites in microtiter plates in the presence of various drug concentrations. Parasites were seeded at 0.25 × 10−5 mL−1 in 200 μL of growth medium containing seven different compound concentrations in a range previously established to encompass both the IC50 and IC90 values. The plates were incubated for 48 h at 37 °C and 20 μL Alamar Blue was then added to each well. After an additional overnight incubation, the fluorescence was determined using a Gemini fluorescent plate reader (Molecular Devices).

3.3.3. Trypanosoma cruzi Culturing and Drug Testing

T. cruzi epimastigotes (strain CL Brener) were cultured at 28 °C in supplemented RPMI-1640 medium. Trypanocidal activity was assessed by growing parasites in microtiter plates in the presence of various drug concentrations. Parasites were seeded at 2.5 × 10−5 mL−1 in 200 μL of growth medium containing 7 different compound concentrations in a range previously established to encompass both the IC50 and IC90 values. The plates were incubated for 4 days at 28 °C and 20 μL Alamar Blue was then added to each well. After an additional 3 days incubation, the fluorescence was determined using a Gemini fluorescent plate reader (Molecular Devices).

Supplementary Materials

The following material is available online. Figure S1: 1H-NMR spectrum of compound 2a; Figure S2: 13C-NMR spectrum of compound 2a; Figure S3: 1H-NMR spectrum of compound 2b; Figure S4: 13C-NMR spectrum of compound 2b; Figure S5: 1H-NMR spectrum of compound 2c; Figure S6: 1H-NMR spectrum of compound 1a; Figure S7: 13C-NMR spectrum of compound 1a; Figure S8: IR Spectrum of compound 1a; Figure S9: 1H-NMR spectrum of compound 1b; Figure S10: 13C-NMR spectrum of compound 1b; Figure S11: IR Spectrum of compound 1b; Figure S12: 1H-NMR spectrum of compound 1c; Figure S13: 13C-NMR spectrum of compound 1c; Figure S14: IR Spectrum of compound 1c.

Author Contributions

Conceptualization, I.P.P.; methodology, A.S.F.; validation, A.S.F., investigation, M.C.T. and J.M.K.; data curation, M.C.T. and J.M.K.; writing—original draft preparation, A.S.F. and I.P.P.; writing—review and editing, I.P.P., A.T. and J.M.K.; supervision, I.P.P.; All authors have read and agreed to the published version of the manuscript.

Funding

A.S.F. was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the HFRI PhD Fellowship grant (Fellowship Number: 1539).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

A.S.F acknowledges the support of the research work by the Hellenic Foundation for Research and Innovation (HFRI) under the HFRI PhD Fellowship grant (Fellowship Number: 1539).

Conflicts of Interest

The authors declare no conflict of interest.

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Molbank 2022 m1363 g001 550
Figure 1. Adamantane hydroxamic derivatives with anti-trypanosomal activity.
Figure 1. Adamantane hydroxamic derivatives with anti-trypanosomal activity.
Molbank 2022 m1363 g001
Molbank 2022 m1363 sch001 550
Scheme 1. Synthesis of the hydroxamic acid analogues 1a–c.
Scheme 1. Synthesis of the hydroxamic acid analogues 1a–c.
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Figure 2. Tautomers of hydroxamic acids 1a–c.
Figure 2. Tautomers of hydroxamic acids 1a–c.
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Table
Table 1. Anti-T. brucei screening of derivatives 1a–c.
Table 1. Anti-T. brucei screening of derivatives 1a–c.
CmpdT. brucei
IC50 (μM) a		T. brucei
IC90 (μM) a		L6 Cells
IC50 (μM) a		S.I.
L6/Tb IC50 b
1a19.1 ± 0.326.4 ± 0.223.0 ± 0.51.2
1b2.70 ± 0.184.14 ± 0.2815.7 ± 1.35.8
1c0.286 ± 0.0070.631 ± 0.0204.85 ± 0.5017
Fexinidazole c2.40 ± 0.184.51 ± 0.57
a IC50 and IC90; concentration that inhibits growth by 50% and 90%, respectively. b S.I.; selectivity index, the ratio of IC50 values obtained with the rat myoblast L6 cell line and T. brucei. c Fexinidazole was tested under the same conditions as for the reported derivatives.
Table
Table 2. Anti-T. cruzi screening of derivatives 1a–c.
Table 2. Anti-T. cruzi screening of derivatives 1a–c.
CmpdT. cruzi
IC50 (μM) a		T. cruzi
IC90 (μM) a		L6 Cells
IC50 (μM) a		S.I.
L6/Tc IC50 b
1a8.81 ± 0.3317.8 ± 0.423.0 ± 0.52.6
1b2.25 ± 0.064.25 ± 0.0815.7 ± 1.37.0
1c0.432 ± 0.0370.737 ± 0.0834.85 ± 0.5011
Benznidazole d5.39 ± 0.199.74 ± 0.88
a IC50 and IC90; concentration that inhibits growth by 50% and 90%, respectively. b S.I.; selectivity index, the ratio of IC50 values obtained with the rat myoblast L6 line and T. cruzi. d Benznidazole was tested under the same conditions as for the reported derivatives.
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Foscolos, A.S.; Tsotinis, A.; Taylor, M.C.; Kelly, J.M.; Papanastasiou, I.P. Probing Adamantane Arylhydroxamic Acids against Trypanosoma brucei and Trypanosoma cruzi. Molbank 2022, 2022, M1363. https://doi.org/10.3390/M1363

AMA Style

Foscolos AS, Tsotinis A, Taylor MC, Kelly JM, Papanastasiou IP. Probing Adamantane Arylhydroxamic Acids against Trypanosoma brucei and Trypanosoma cruzi. Molbank. 2022; 2022(2):M1363. https://doi.org/10.3390/M1363

Chicago/Turabian Style

Foscolos, Angeliki Sofia, Andrew Tsotinis, Martin C. Taylor, John M. Kelly, and Ioannis P. Papanastasiou. 2022. "Probing Adamantane Arylhydroxamic Acids against Trypanosoma brucei and Trypanosoma cruzi" Molbank 2022, no. 2: M1363. https://doi.org/10.3390/M1363

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