Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles
Copyright © 2016 Elsevier Masson SAS. All rights reserved..
Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.58-4.19 μM for epimastigotes; compounds 6, 19-21 and 24: IC50 = 0.22-0.54 μM for amastigotes) being as potent as the reference drug benznidazole. SAR analysis suggests that electron-donating groups at position 1 of indazolinone ring are associated with an improved antichagasic activity. Moreover, compounds of series A displayed low unspecific toxicities against an in vitro model of mammalian cells (fibroblasts), which were reflected in high values of the selectivity indexes (SI). Compound 20 was also very efficient against amastigotes from Tulahuen and Y strains of T. cruzi (IC50 = 0.81 and 0.60 μM, respectively), showing low toxicity towards cardiac cells (LC50 > 100 μM). In what concerns compounds of series B, some of them displayed moderate activity against trophozoites of a metronidazole-sensitive isolate of T. vaginalis (35 and 36: IC50 = 9.82 and 7.25 μM, respectively), with low unspecific toxicity towards Vero cells. Compound 36 was also active against a metronidazole-resistant isolate (IC50 = 9.11 μM) and can thus be considered a good prototype for the development of drugs directed to T. vaginalis resistant to 5-nitroimidazoles.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2016 |
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Erschienen: |
2016 |
Enthalten in: |
Zur Gesamtaufnahme - volume:115 |
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Enthalten in: |
European journal of medicinal chemistry - 115(2016) vom: 10. Juni, Seite 295-310 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Fonseca-Berzal, Cristina [VerfasserIn] |
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Links: |
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Themen: |
Antiprotozoal drug |
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Anmerkungen: |
Date Completed 09.01.2017 Date Revised 10.01.2017 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.ejmech.2016.03.036 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM258813326 |
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520 | |a Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.58-4.19 μM for epimastigotes; compounds 6, 19-21 and 24: IC50 = 0.22-0.54 μM for amastigotes) being as potent as the reference drug benznidazole. SAR analysis suggests that electron-donating groups at position 1 of indazolinone ring are associated with an improved antichagasic activity. Moreover, compounds of series A displayed low unspecific toxicities against an in vitro model of mammalian cells (fibroblasts), which were reflected in high values of the selectivity indexes (SI). Compound 20 was also very efficient against amastigotes from Tulahuen and Y strains of T. cruzi (IC50 = 0.81 and 0.60 μM, respectively), showing low toxicity towards cardiac cells (LC50 > 100 μM). In what concerns compounds of series B, some of them displayed moderate activity against trophozoites of a metronidazole-sensitive isolate of T. vaginalis (35 and 36: IC50 = 9.82 and 7.25 μM, respectively), with low unspecific toxicity towards Vero cells. Compound 36 was also active against a metronidazole-resistant isolate (IC50 = 9.11 μM) and can thus be considered a good prototype for the development of drugs directed to T. vaginalis resistant to 5-nitroimidazoles | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Antiprotozoal drug | |
650 | 4 | |a Indazole | |
650 | 4 | |a Nitroheterocycle | |
650 | 4 | |a Trichomonas vaginalis | |
650 | 4 | |a Trypanosoma cruzi | |
650 | 7 | |a Indazoles |2 NLM | |
700 | 1 | |a Ibáñez-Escribano, Alexandra |e verfasserin |4 aut | |
700 | 1 | |a Reviriego, Felipe |e verfasserin |4 aut | |
700 | 1 | |a Cumella, José |e verfasserin |4 aut | |
700 | 1 | |a Morales, Paula |e verfasserin |4 aut | |
700 | 1 | |a Jagerovic, Nadine |e verfasserin |4 aut | |
700 | 1 | |a Nogal-Ruiz, Juan José |e verfasserin |4 aut | |
700 | 1 | |a Escario, José Antonio |e verfasserin |4 aut | |
700 | 1 | |a da Silva, Patricia Bernardino |e verfasserin |4 aut | |
700 | 1 | |a Soeiro, Maria de Nazaré C |e verfasserin |4 aut | |
700 | 1 | |a Gómez-Barrio, Alicia |e verfasserin |4 aut | |
700 | 1 | |a Arán, Vicente J |e verfasserin |4 aut | |
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