Piperazine-Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Antifungal agents, Aspergillus, Ketoconazole, Trypanosoma,
- MeSH
- Antifungal Agents * pharmacology chemistry MeSH
- Azoles MeSH
- Ketoconazole * pharmacology chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antifungal Agents * MeSH
- Azoles MeSH
- Ketoconazole * MeSH
Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine-modified KTZ derivatives and we evaluated their in vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24 times more potent against Aspergillus flavus and 8 times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100 μM. Derivative 6 had 9- and 7-fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine-modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.
See more in PubMed
M. Shafiei, L. Peyton, M. Hashemzadeh, A. Foroumadi, Bioorg. Chem. 2020, 104, 104240.
L. Ostrosky-Zeichner, A. Casadevall, J. N. Galgiani, F. C. Odds, J. H. Rex, Nat. Rev. Drug Discovery 2010, 9, 719-727.
M. K. Kathiravan, A. B. Salake, A. S. Chothe, P. B. Dudhe, R. P. Watode, M. S. Mukta, S. Gadhwe, Bioorg. Med. Chem. 2012, 20, 5678-5698.
E. B. Smith, J. Am. Acad. Dermatol. 1990, 23, 776-778.
J. Heeres, Pestic. Sci. 1984, 15, 268-279.
K. M. Jørgensen, M. Helleberg, R. K. Hare, L. N. Jørgensen, M. C. Arendrup, J. Fungi 2021, 7, 1-12.
F. Saccoliti, V. N. Madia, V. Tudino, A. De Leo, L. Pescatori, A. Messore, D. De Vita, L. Scipione, R. Brun, M. Kaiser, P. Mäser, C. M. Calvet, G. K. Jennings, L. M. Podust, G. Pepe, R. Cirilli, C. Faggi, A. Di Marco, M. R. Battista, V. Summa, R. Costi, R. Di Santo, J. Med. Chem. 2019, 62, 1330-1347.
J. M. Kratz, Acta Trop. 2019, 198, 105107.
J. A. Urbina, K. Lazardi, E. Marchan, G. Visbal, T. Aguirre, M. M. Piras, R. Piras, R. A. Maldonado, G. Payares, W. De Souza, Antimicrob. Agents Chemother. 1993, 37, 580-591.
P. C. Dumoulin, J. Vollrath, S. S. Tomko, J. X. Wang, B. Burleigh, eLife 2020, 9, 1-19.
F. Hulpia, D. Mabille, G. D. Campagnaro, G. Schumann, L. Maes, I. Roditi, A. Hofer, H. P. de Koning, G. Caljon, S. Van Calenbergh, Nat. Commun. 2019, 10, 5564.
S. Veraldi, M. Romagnuolo, M. Cusini, C. A. Maronese, Dermatol. Ther. 2021, 34, e15060.
Elston, D.M., Gibson, L.E., Kutzner, H. (2022). Infectious Diseases. In: Lin, F., Prichard, J.W., Liu, H., Wilkerson, M.L. (eds) Handbook of Practical Immunohistochemistry. Springer, Cham. https://doi.org/10.1007/978-3-030-83328-2 34.
M. P. Barrett, S. L. Croft, Br. Med. Bull. 2012, 104, 175-196.
M. Ilkit, M. Durdu, Crit. Rev. Microbiol. 2015, 41, 374-388.
D. Nowicka, U. Nawrot, Mycoses 2021, 64, 1140-1150.
J. Heeres, L. J. J. Backx, J. Van Cutsem, J. Med. Chem. 1984, 27, 894-900.
J. D. Sobel, R. Sobel, Expert Opin. Pharmacother. 2018, 19, 971-977.
Y. Xu, C. Sheng, W. Wang, X. Che, Y. Cao, G. Dong, S. Wang, H. Ji, Z. Miao, J. Yao, W. Zhang, Bioorg. Med. Chem. Lett. 2010, 20, 2942-2945.
T. Y. Hargrove, L. Friggeri, Z. Wawrzak, A. Qi, W. J. Hoekstra, R. J. Schotzinger, J. D. York, F. Peter Guengerich, G. I. Lepesheva, J. Biol. Chem. 2017, 292, 6728-6743.
P. K. Shukla, P. Singh, R. K. Yadav, S. Pandey, Top. Med. Chem. 2018, 29, 125-168, ISBN 978-3-319-78252-2.
H. Yang, J. Tong, C. W. Lee, S. Ha, S. H. Eom, Y. J. Im, Nat. Commun. 2015, 6, 6129.
T. M. Joffrion, M. T. Cushion, FEMS Microbiol. Lett. 2010, 311, 1-9.
N. Jacquier, R. Schneiter, J. Steroid Biochem. Mol. Biol. 2012, 129, 70-78.
E. Dannaoui, Int. J. Antimicrob. Agents 2017, 50, 617-621.
W. Liu, L. Yuan, S. Wang, J. Med. Chem. 2020, 63, 21, 12429-12459.
N. P. Wiederhold, Infect. Drug Resist. 2017, 10, 249-259.
K. Pianalto, J. Alspaugh, J. Fungi 2016, 2, 26.
J. A. McBride, G. M. Gauthier, B. S. Klein, Clin. Chest Med. 2017, 38, 435-449.
J. Wheat, Clin. Infect. Dis. 1994, 19, S19-S27.
E. A. McAninch, C. Xu, V. S. Lagari, B. W. Kim, J. Clin. Endocrinol. Metab. 2014, 99, 1537-1542.
Y. Bin Bai, Y. Q. Gao, X. Di Nie, T. M. L. Tuong, D. Li, J. M. Gao, J. Agric. Food Chem. 2019, 67, 6125-6132.
T. J. Gintjee, M. A. Donnelley, G. R. Thompson, J. Fungi 2020, 6, 28.
C. Galiger, M. Brock, G. Jouvion, A. Savers, M. Parlato, O. Ibrahim-Granet, Antimicrob. Agents Chemother. 2013, 57, 3046-3059.
H. Jin, T. Wang, B. A. Falcione, K. M. Olsen, K. Chen, H. Tang, J. Hui, S. Zhai, J. Antimicrob. Chemother. 2016, 71, 1772-1785.
S. Comte-Perret, A. Zanchi, F. Gomez, Endocrinol. Diabetes Metab. Case Reports 2014, 2014, 140083.
P. S. Banankhah, K. A. Garnick, D. J. Greenblatt, J. Clin. Pharmacol. 2016, 56, 1196-1202.
A. K. Gupta, D. C. A. Lyons, J. Cutan. Med. Surg. 2015, 19, 352-357.
N. Thamban Chandrika, S. K. Shrestha, H. X. Ngo, O. V. Tsodikov, K. C. Howard, S. Garneau-Tsodikova, J. Med. Chem. 2018, 61, 158-173.
J. Konter, U. Möllmann, J. Lehmann, Bioorg. Med. Chem. 2008, 16, 8294-8300.
S. Louzoun-Zada, Q. Z. Jaber, M. Fridman, Angew. Chem. Int. Ed. 2019, 58, 15584-15594;
Angew. Chem. 2019, 131, 15730-15740.
R. Elias, R. I. Benhamou, Q. Z. Jaber, O. Dorot, S. L. Zada, K. Oved, E. Pichinuk, M. Fridman, Eur. J. Med. Chem. 2019, 179, 779-790.
X. Wang, J. Liu, J. Chen, M. Zhang, C. Tian, X. Peng, G. Li, W. Chang, H. Lou, Bioorg. Chem. 2021, 110, 104771.
W. Chang, J. Liu, M. Zhang, H. Shi, S. Zheng, X. Jin, Y. Gao, S. Wang, A. Ji, H. Lou, Nat. Commun. 2018, 9, 5102.
A. Kane, D. A. Carter, Pharm. 2022, 15, 4, 482.
M. C. Arendrup, N. Friberg, M. Mares, G. Kahlmeter, J. Meletiadis, J. Guinea, C. T. Andersen, S. Arikan-Akdagli, F. Barchiesi, E. Chryssanthou, P. Hamal, H. Järv, N. Klimko, O. Kurzai, K. Lagrou, C. Lass-Flörl, T. Matos, K. Muehlethaler, T. R. Rogers, A. Velegraki, Clin. Microbiol. Infect. 2020, 26, 1464-1472.
C. M. Gabriel, M. Keener, F. Gallou, B. H. Lipshutz, Org. Lett. 2015, 17, 3968-3971.
E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606-631.
E. E. Seagle, S. L. Williams, T. M. Chiller, Infect. Dis. Clin. North Am. 2021, 35, 237-260.
S. A. Davis, B. M. Vincent, M. M. Endo, L. Whitesell, K. Marchillo, D. R. Andes, S. Lindquist, M. D. Burke, Nat. Chem. Biol. 2015, 11, 481-487.
M. H. Rønnest, M. S. Raab, S. Anderhub, S. Boesen, A. Krämer, T. O. Larsen, M. H. Clausen, J. Med. Chem. 2012, 55, 652-660.
M. A. Ghannoum, Y. Fu, A. S. Ibrahim, L. A. Mortara, M. C. Shafiq, J. E. Edwards, R. S. Criddle, Antimicrob. Agents Chemother. 1995, 39, 2459-2465.
N. Robbins, G. D. Wright, L. E. Cowen, Microbiol. Spectr. 2016, 4(5), 903-922.
B. E. Blass, P. Iyer, M. Abou-Gharbia, W. E. Childers, J. C. Gordon, M. Ramanjulu, G. Morton, P. Arumugam, J. Boruwa, J. Ellingboe, S. Mitra, R. R. Nimmareddy, S. Paliwal, J. Rajasekhar, S. Shivakumar, P. Srivastava, R. S. Tangirala, K. Venkataramanaiah, M. Yanamandra, Bioorg. Med. Chem. Lett. 2016, 26, 5825-5829.
C. C. Tsang, J. Y. M. Tang, S. K. P. Lau, P. C. Y. Woo, Comput. Struct. Biotechnol. J. 2018, 16, 197-210.
F. Yan Guo, C. Ji Zheng, M. Wang, J. Ai, L. Ying Han, L. Yang, Y. Fang Lu, Y. Xuan Yang, M. Guan Piao, H. R. Piao, C. M. Jin, C. H. Jin, ChemMedChem 2021, 16, 2354-2365.
İ. Esentürk, T. Balkan, G. Özhan, S. Döşler, S. Güngör, M. S. Erdal, A. S. Sarac, Pharm. Dev. Technol. 2020, 25, 440-453.
B. Westermann, Biochim. Biophys. Acta Bioenerg. 2012, 1817, 1833-1838.
C.-H. Yao, R. Wang, Y. Wang, C.-P. Kung, J. D. Weber, G. J. Patti, eLife 2019, 8, e41351.
V. Grobárová, K. Vališ, P. Talacko, B. Pavlů, L. Hernychová, J. Nováková, E. Stodůlková, M. Flieger, P. Novák, J. Černý, J. Nat. Prod. 2016, 79, 2304-2314.
K. Vališ, V. Grobárová, L. Hernychová, M. Bugáňová, D. Kavan, M. Kalous, J. Černý, E. Stodůlková, M. Kuzma, M. Flieger, J. Černý, P. Novák, Oncotarget 2017, 8, 103137-103153.
M. Gardes, T. D. Bruns, Mol. Ecol. 1993, 2, 113-118.
B. Räz, M. Iten, Y. Grether-Bühler, R. Kaminsky, R. Brun, Acta Trop. 1997, 68, 139-147.
Amesia hispanica sp. nov., Producer of the Antifungal Class of Antibiotics Dactylfungins
