Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites
The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1H-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1H-imidazol-3-ium (1a). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against Trypanosoma brucei, whereas bisarylimidamides (3) were submicromolar inhibitors of T. brucei, Trypanosoma cruzi, and Leishmania donovani. None of the compounds showed relevant activity against the urogenital, nonkinetoplastid parasite Trichomonas vaginalis. We show that series 1 and 3 bind strongly and selectively to the minor groove of AT DNA, whereas series 2 also binds by intercalation. The measured pKa indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔTm) for series 2 and 3. Compound 3a, which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 19 vom: 12. Okt., Seite 13452-13480 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nué-Martinez, J Jonathan [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 30.10.2023 Date Revised 30.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c00697 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362258902 |
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| 100 | 1 | |a Nué-Martinez, J Jonathan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites |
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| 500 | |a Date Revised 30.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1H-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1H-imidazol-3-ium (1a). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against Trypanosoma brucei, whereas bisarylimidamides (3) were submicromolar inhibitors of T. brucei, Trypanosoma cruzi, and Leishmania donovani. None of the compounds showed relevant activity against the urogenital, nonkinetoplastid parasite Trichomonas vaginalis. We show that series 1 and 3 bind strongly and selectively to the minor groove of AT DNA, whereas series 2 also binds by intercalation. The measured pKa indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔTm) for series 2 and 3. Compound 3a, which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antiprotozoal Agents |2 NLM | |
| 650 | 7 | |a benzylaniline |2 NLM | |
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| 650 | 7 | |a Benzamides |2 NLM | |
| 700 | 1 | |a Cisneros, David |e verfasserin |4 aut | |
| 700 | 1 | |a Moreno-Blázquez, María Del Valle |e verfasserin |4 aut | |
| 700 | 1 | |a Fonseca-Berzal, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Manzano, José Ignacio |e verfasserin |4 aut | |
| 700 | 1 | |a Kraeutler, Damien |e verfasserin |4 aut | |
| 700 | 1 | |a Ungogo, Marzuq A |e verfasserin |4 aut | |
| 700 | 1 | |a Aloraini, Maha A |e verfasserin |4 aut | |
| 700 | 1 | |a Elati, Hamza A A |e verfasserin |4 aut | |
| 700 | 1 | |a Ibáñez-Escribano, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Lagartera, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Herraiz, Tomás |e verfasserin |4 aut | |
| 700 | 1 | |a Gamarro, Francisco |e verfasserin |4 aut | |
| 700 | 1 | |a de Koning, Harry P |e verfasserin |4 aut | |
| 700 | 1 | |a Gómez-Barrio, Alicia |e verfasserin |4 aut | |
| 700 | 1 | |a Dardonville, Christophe |e verfasserin |4 aut | |
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