Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General
2.1.2. Synthesis of the 2,9-bis(formyl)-4,7-diphenyl-1,10-phenanthroline (2)
2.1.3. General Procedure for the Synthesis of 2,9-Bis[(substituted-iminomethyl)phenyl]-4,7-diphenyl-1,10-phenanthrolines (3a-p)
2,9-Bis[(2-dimethylaminoethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3a)
2,9-Bis[(3-dimethylaminopropyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3b)
2,9-Bis[(4-dimethylaminobutyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3c)
2,9-Bis[(5-dimethylaminopentyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3d)
2,9-Bis [2-(4-methylpiperazin-1-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3e)
2,9-Bis[[(3-(4-methylpiperazin-1-yl)propyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3f)
2,9-Bis[[(4-(4-methylpiperazin-1-yl)butyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3g)
2,9-Bis [2-(morpholin-1-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3h)
2,9-Bis [3-(morpholin-1-yl)propyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3i)
2,9-Bis [2-(piperidin-1-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3j)
2,9-Bis [3-(piperidin-1-yl)propyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3k)
2,9-Bis [3-(pyrrolidin-1-yl)propyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3l)
2,9-Bis [2-(pyridin-2-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3m)
2,9-Bis [2-(pyridin-3-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3n)
2,9-Bis [2-(pyridin-4-yl)ethyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3o)
2,9-Bis [3-(pyridin-4-yl)propyl)iminomethyl]-4,7-diphenyl-1,10-phenanthroline (3p)
2.1.4. General Procedure for the Synthesis of 2,9-Bis[(substituted-aminomethyl)phenyl]-4,7-diphenyl-1,10-phenanthrolines 4a-p
2,9-Bis[(2-dimethylaminoethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4a)
2,9-Bis[(3-dimethylaminopropyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4b)
2,9-Bis[(4-dimethylaminobutyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4c)
2,9-Bis[(5-dimethylaminopentyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4d)
2,9-Bis [2-(4-methylpiperazin-1-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4e)
2,9-Bis[[(3-(4-methylpiperazin-1-yl)propyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4f)
2,9-Bis[[(4-(4-methylpiperazin-1-yl)butyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4g)
2,9-Bis [2-(morpholin-1-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4h)
2,9-Bis [3-(morpholin-1-yl)propyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4i)
2,9-Bis [2-(piperidin-1-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4j)
2,9-Bis [3-(piperidin-1-yl)propyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4k)
2,9-Bis [3-(pyrrolidin-1-yl)propyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4l)
2,9-Bis [2-(pyridin-2-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4m)
2,9-Bis [2-(pyridin-3-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4n)
2,9-Bis [2-(pyridin-4-yl)ethyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4o)
2,9-Bis [3-(pyridin-4-yl)propyl)aminomethyl]-4,7-diphenyl-1,10-phenanthroline (4p)
2.1.5. General procedure for 2,9-bis[(substituted-aminomethyl)phenyl]-4,7-diphenyl-1,10-phenanthrolines 1a-p
2.2. Biological Evaluation
2.2.1. In Vitro Antiplasmodial Activity
2.2.2. In Vitro Antileishmanial Activity
2.2.3. In Vitro Antitrypanosomal Activity
2.2.4. Cytotoxicity Evaluation
2.3. FRET Melting Experiments
2.4. Native Electrospray Mass Spectrometry and Circular Dichroism
2.4.1. Samples
2.4.2. Native Mass Electrospray Spectrometry
2.4.3. Circular Dichroism
3. Results
3.1. Chemistry
3.2. Biological Evaluation
3.2.1. In Vitro Antimalarial Activity
3.2.2. In Vitro Antileishmanial Activity against Promastigote Forms
3.2.3. In Vitro Activity against Trypanosoma Brucei Brucei
3.2.4. Cytotoxicity and Selectivity Index
3.3. FRET Melting Experiments
3.4. Native Electrospray Mass Spectrometry and Circular Dichroism
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Salt a | mp (°C) b | % Yield c | |
---|---|---|---|---|
1a | Orange crystals | 4 (COOH)2 | 179–181 | 64 |
1b | Beige crystals | 4 (COOH)2 | 161–163 | 60 |
1c | Orange crystals | 4 (COOH)2 | 111–113 | 56 |
1d | Beige crystals | 4 (COOH)2 | 119–121 | 57 |
1e | Orange crystals | 6 (COOH)2 | 185–187 | 81 |
1f | Yellow-orange crystals | 6 (COOH)2 | 205–207 | 58 |
1g | Beige crystals | 6 (COOH)2 | 207–209 | 63 |
1h | Beige crystals | 4 (COOH)2 | 194–196 | 73 |
1i | Yellow crystals | 4 (COOH)2 | 174–176 | 61 |
1j | Beige crystals | 4 (COOH)2 | 192–194 | 69 |
1k | Beige crystals | 4 (COOH)2 | 141–143 | 62 |
1l | Beige crystals | 4 (COOH)2 | 145–147 | 61 |
1m | Orange crystals | 2 (COOH)2 | 165–167 | 63 |
1n | Orange crystals | 2 (COOH)2 | 164–166 | 74 |
1o | Beige crystals | 2 (COOH)2 | 147–149 | 66 |
1p | Yellow crystals | 2 (COOH)2 | 99–101 | 83 |
Compound | P. falciparum Strains IC50 Values (μM) a | L. donovani IC50 Values (μM) b | Trypanosoma brucei brucei IC50 Values (μM) c | Cytotoxicity to HepG2 Cells CC50 Values (μM) d | |
---|---|---|---|---|---|
W2 | 3D7 | Trypanos Antat 1.9 | |||
CQ e | 0.40 ± 0.04 | 0.11 ± 0.01 | n.d. h | n.d. h | 30 |
MQ e | 0.016 ± 0.002 | 0.06 ± 0.003 | n.d. h | n.d. h | n.d. h |
Pentamidinef | n.d. h | n.d. h | 5.5 ± 0.80 | 0.0002 ± 0.00006 | 2.3 ± 0.50 |
Amphotericin B f | n.d. h | n.d. h | 0.1 ± 0.04 | n.d. h | 8.8 ± 0.60 |
Suramine g | n.d.h | n.d. h | n.d. h | 0.03 ± 0.003 | n.d. h |
Fexinidazole g | n.d.h | n.d. h | n.d. h | 0.59 ± 0.039 | n.d. h |
Eflornithineg | n.d. h | n.d. h | n.d. h | 15.19 ± 0.64 | n.d. h |
Doxorubicin | n.d. h | n.d. h | n.d. h | n.d. h | 0.06 ± 0.02 |
1a | 1.00 ± 0.34 | 1.80 ± 0.67 | >12.5 i | 0.67 ± 0.03 | 6.52 ± 0.61 |
1b | 6.13 ± 1.63 | 21.19 ± 7.72 | >12.5 i | 0.57 ± 0.07 | 5.96 ± 0.20 |
1c | 0.03 ± 0.003 | 10.31 ± 2.13 | >12.5 i | 0.86 ± 0.16 | 10.43 ± 0.70 |
1d | 3.51 ± 0.52 | 4.79 ± 0.50 | >12.5 i | 1.42 ± 0.10 | 3.35 ± 0.33 |
1e | 0.92 ± 0.18 | 2.16 ± 0.32 | >12.5 i | 0.45 ± 0.03 | 10.54 ± 1.27 |
1f | 11.27 ± 2.93 | 21.54 ± 4.10 | >12.5 i | 0.97 ± 0.11 | 8.62 ± 0.50 |
1g | 2.48 ± 0.49 | 8.19 ± 3.53 | >12.5 i | 0.96 ± 0.13 | 16.75 ± 0.60 |
1h | 0.17 ± 0.05 | 0.67 ± 0.21 | 4.50 ± 2.20 | 0.22 ± 0.06 | 5.89 ± 0.53 |
1i | 0.04 ± 0.01 | 1.45 ± 0.58 | >12.5 i | 0.29 ± 0.02 | 6.29 ± 1.06 |
1j | 2.60 ± 0.55 | 1.59 ± 0.59 | 2.52 ± 0.20 | 0.20 ± 0.02 | 1.64 ± 0.14 |
1k | 1.65 ± 0.36 | 3.18 ± 0.68 | >12.5 i | 0.77 ± 0.10 | 4.29 ± 0.52 |
1l | 0.03 ± 0.01 | 9.91 ± 1.73 | >12.5 i | 1.13 ± 0.06 | 15.17 ± 1.56 |
1m | 0.07 ± 0.01 | 0.47 ± 0.12 | >12.5 i | 0.63 ± 0.01 | 4.34 ± 0.31 |
1n | 2.54 ± 0.36 | 0.71 ± 0.11 | 2.67 ± 0.80 | 0.43 ± 0.03 | 3.10 ± 0.19 |
1o | 1.87 ± 0.58 | 0.73 ± 0.19 | 2.69 ± 0.60 | 0.21 ± 0.01 | 19.11 ± 2.11 |
1p | 0.145 ± 0.04 | 1.02 ± 0.35 | >12.5 i | 0.65 ± 0.05 | 3.04 ± 0.19 |
Compound | Selectivity Index a | |||
---|---|---|---|---|
HepG2/W2 | HepG2/3D7 | HepG2/L. donovani | HepG2/Tryp. | |
CQ | 75 | 272 | n.d. b | n.d. b |
Pentamidine | n.d. b | n.d. b | n.d. b | 11,500 |
Amphotericin B | n.d. b | n.d. b | 88.0 | n.d. b |
1a | 6.52 | 3.62 | n.d. b | 9.73 |
1b | 0.97 | 0.28 | n.d. b | 10.46 |
1c | 347.67 | 1.01 | n.d. b | 12.13 |
1d | 0.95 | 0.70 | n.d. b | 2.36 |
1e | 11.46 | 4.88 | n.d. b | 23.42 |
1f | 0.76 | 0.40 | n.d. b | 8.89 |
1g | 6.75 | 2.04 | n.d. b | 17.45 |
1h | 34.64 | 8.79 | 1.31 | 26.77 |
1i | 157.25 | 4.34 | n.d. b | 21.69 |
1j | 0.63 | 1.03 | 0.65 | 8.20 |
1k | 2.60 | 1.35 | n.d. b | 5.57 |
1l | 505.7 | 1.53 | n.d. b | 13.42 |
1m | 62.0 | 9.23 | n.d. b | 6.89 |
1n | 1.22 | 4.37 | 1.16 | 7.21 |
1o | 10.22 | 26.18 | 7.10 | 91.0 |
1p | 20.97 | 2.98 | n.d. b | 4.68 |
Compound | ΔTm (°C) a | ΔTm (°C) a | ΔTm (°C) a | ΔTm (°C) a | ΔTm (°C) a | |||||
---|---|---|---|---|---|---|---|---|---|---|
FPf1T | FPf8T | FtrypBT | F21T | FdxT | ||||||
PhenDC3 | 24.6 | ±0.1 | 24.7 | ±0.2 | 19.2 | ±0.2 | 26.3 | ±0.1 | 0.1 | ±0.2 |
CQ | 1.9 | ±0.1 | 2.4 | ±1.2 | n.d. b | 2.4 | ±1.1 | n.d. b | ||
MQ | 3.1 | ±0.5 | 6.6 | ±2.3 | n.d. b | 2.6 | ±0.5 | n.d. b | ||
1a | 1.8 | ±0.3 | 1.6 | ±0.2 | 1.9 | ±0.1 | 1.8 | ±0.4 | −0.3 | ±0.2 |
1b | 7.4 | ±0.6 | 7.9 | ±0.3 | 8.7 | ±0.6 | 12.8 | ±1.3 | −0.3 | ±0.2 |
1c | 8.9 | ±0.8 | 10.2 | ±1.0 | 10.6 | ±0.8 | 13.2 | ±0.4 | −0.5 | ±0.4 |
1d | 18.8 | ±0.2 | 20.5 | ±0.2 | 14.7 | ±0.7 | 18.1 | ±0.9 | 1.8 | ±0.2 |
1e | 9.4 | ±1.0 | 10.5 | ±0.1 | 8.0 | ±0.4 | 9.6 | ±0.6 | −1.6 | ±0.2 |
1f | 8.8 | ±0.5 | 10.9 | ±0.9 | 9.1 | ±0.5 | 10.8 | ±0.6 | −0.5 | ±0.1 |
1g | 13.4 | ±0.7 | 14.5 | ±1.2 | 12.2 | ±1.7 | 11.2 | ±0.9 | −0.5 | ±0.1 |
1h | 1.8 | ±0.4 | 1.9 | ±0.2 | 2.2 | ±0.1 | 2.0 | ±0.2 | −0.9 | ±0.4 |
1i | 6.7 | ±0.5 | 6.7 | ±0.6 | 6.0 | ±0.9 | 8.2 | ±0.1 | −1.5 | ±0.4 |
1j | 5.6 | ±0.6 | 7.3 | ±2.4 | 7.2 | ±0.6 | 7.7 | ±2.1 | 0.2 | ±0.1 |
1k | 12.8 | ±0.7 | 14.0 | ±0.3 | 8.3 | ±1.0 | 12.0 | ±0.7 | 0.4 | ±0.3 |
1l | 15.4 | ±0.9 | 14.2 | ±0.9 | 11.6 | ±0.9 | 14.5 | ±0.4 | 0.7 | ±0.2 |
1m | 1.3 | ±0.2 | 1.0 | ±0.2 | 1.8 | ±0.6 | 1.0 | ±0.5 | −0.2 | ±0.1 |
1n | 2.9 | ±0.4 | 5.3 | ±0.4 | 5.2 | ±0.3 | 4.6 | ±0.6 | −0.3 | ±0.1 |
1o | 2.9 | ±0.1 | 5.2 | ±0.1 | 5.3 | ±0.7 | 3.9 | ±0.3 | −0.3 | ±0.2 |
1p | 3.5 | ±0.3 | 3.9 | ±0.7 | 3.7 | ±0.3 | 3.6 | ±0.3 | −1.1 | ±0.2 |
Ligands | Kd (µM) a | |||||
---|---|---|---|---|---|---|
Name | Stoichiometry | Pf1 | Pf8 | 24TTG | 24nonG4 | DK66 |
1c | 1 | 23 | 3 | 44 | 9 | 110 |
1d | 1 | 8 | 3 | 38 | 11 | 53 |
1l | 1 | 10 | 2 | 34 | 8 | 55 |
1m | 1 | n.b. | 83 | n.b. | n.b. | n.b. |
1c | 2 | n.b. | 50 | 28 | <LOQ | n.b. |
1d | 2 | 24 | 16 | 62 | <LOQ | n.b. |
1l | 2 | 37 | 59 | 18 | <LOQ | n.b. |
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Guillon, J.; Cohen, A.; Boudot, C.; Monic, S.; Savrimoutou, S.; Moreau, S.; Albenque-Rubio, S.; Lafon-Schmaltz, C.; Dassonville-Klimpt, A.; Mergny, J.-L.; et al. Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux. Pathogens 2022, 11, 1339. https://doi.org/10.3390/pathogens11111339
Guillon J, Cohen A, Boudot C, Monic S, Savrimoutou S, Moreau S, Albenque-Rubio S, Lafon-Schmaltz C, Dassonville-Klimpt A, Mergny J-L, et al. Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux. Pathogens. 2022; 11(11):1339. https://doi.org/10.3390/pathogens11111339
Chicago/Turabian StyleGuillon, Jean, Anita Cohen, Clotilde Boudot, Sarah Monic, Solène Savrimoutou, Stéphane Moreau, Sandra Albenque-Rubio, Camille Lafon-Schmaltz, Alexandra Dassonville-Klimpt, Jean-Louis Mergny, and et al. 2022. "Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux" Pathogens 11, no. 11: 1339. https://doi.org/10.3390/pathogens11111339