Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation
As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synth...
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2000
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v43_n9_p1826_Szajnman http://hdl.handle.net/20.500.12110/paper_00222623_v43_n9_p1826_Szajnman |
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paper:paper_00222623_v43_n9_p1826_Szajnman2025-07-30T17:30:41Z Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation Szajnman, Sergio Hernán Elhalem, Eleonora Rodríguez, Juan Bautista 2 (4 phenoxyphenylthio)ethyl thiocyanic acid 2 bromo 4 phenoxyphenoxyethyl thiocyanic acid 2 iodo 4 phenoxyphenoxyethyl 4 thiocyanic acid 2,4 dichlorophenoxyethyl thiocyanic acid 4 (2 methylphenoxy)phenoxyethyl thiocyanic acid antiprotozoal agent thiocyanic acid derivative unclassified drug antiprotozoal activity article Chagas disease drug potency drug synthesis growth inhibition nonhuman Trypanosoma Trypanosoma cruzi trypanosomiasis Animals Cell Division Drug Design Indicators and Reagents Magnetic Resonance Spectroscopy Mass Spectrometry Spectrophotometry, Ultraviolet Structure-Activity Relationship Thiocyanates Trypanocidal Agents Trypanosoma cruzi As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts. Fil:Szajnman, S.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Elhalem, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2000 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v43_n9_p1826_Szajnman http://hdl.handle.net/20.500.12110/paper_00222623_v43_n9_p1826_Szajnman |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
2 (4 phenoxyphenylthio)ethyl thiocyanic acid 2 bromo 4 phenoxyphenoxyethyl thiocyanic acid 2 iodo 4 phenoxyphenoxyethyl 4 thiocyanic acid 2,4 dichlorophenoxyethyl thiocyanic acid 4 (2 methylphenoxy)phenoxyethyl thiocyanic acid antiprotozoal agent thiocyanic acid derivative unclassified drug antiprotozoal activity article Chagas disease drug potency drug synthesis growth inhibition nonhuman Trypanosoma Trypanosoma cruzi trypanosomiasis Animals Cell Division Drug Design Indicators and Reagents Magnetic Resonance Spectroscopy Mass Spectrometry Spectrophotometry, Ultraviolet Structure-Activity Relationship Thiocyanates Trypanocidal Agents Trypanosoma cruzi |
| spellingShingle |
2 (4 phenoxyphenylthio)ethyl thiocyanic acid 2 bromo 4 phenoxyphenoxyethyl thiocyanic acid 2 iodo 4 phenoxyphenoxyethyl 4 thiocyanic acid 2,4 dichlorophenoxyethyl thiocyanic acid 4 (2 methylphenoxy)phenoxyethyl thiocyanic acid antiprotozoal agent thiocyanic acid derivative unclassified drug antiprotozoal activity article Chagas disease drug potency drug synthesis growth inhibition nonhuman Trypanosoma Trypanosoma cruzi trypanosomiasis Animals Cell Division Drug Design Indicators and Reagents Magnetic Resonance Spectroscopy Mass Spectrometry Spectrophotometry, Ultraviolet Structure-Activity Relationship Thiocyanates Trypanocidal Agents Trypanosoma cruzi Szajnman, Sergio Hernán Elhalem, Eleonora Rodríguez, Juan Bautista Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| topic_facet |
2 (4 phenoxyphenylthio)ethyl thiocyanic acid 2 bromo 4 phenoxyphenoxyethyl thiocyanic acid 2 iodo 4 phenoxyphenoxyethyl 4 thiocyanic acid 2,4 dichlorophenoxyethyl thiocyanic acid 4 (2 methylphenoxy)phenoxyethyl thiocyanic acid antiprotozoal agent thiocyanic acid derivative unclassified drug antiprotozoal activity article Chagas disease drug potency drug synthesis growth inhibition nonhuman Trypanosoma Trypanosoma cruzi trypanosomiasis Animals Cell Division Drug Design Indicators and Reagents Magnetic Resonance Spectroscopy Mass Spectrometry Spectrophotometry, Ultraviolet Structure-Activity Relationship Thiocyanates Trypanocidal Agents Trypanosoma cruzi |
| description |
As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4- phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC50 values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moiety as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts. |
| author |
Szajnman, Sergio Hernán Elhalem, Eleonora Rodríguez, Juan Bautista |
| author_facet |
Szajnman, Sergio Hernán Elhalem, Eleonora Rodríguez, Juan Bautista |
| author_sort |
Szajnman, Sergio Hernán |
| title |
Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| title_short |
Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| title_full |
Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| title_fullStr |
Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| title_full_unstemmed |
Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation |
| title_sort |
design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of trypanosoma cruzi proliferation |
| publishDate |
2000 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v43_n9_p1826_Szajnman http://hdl.handle.net/20.500.12110/paper_00222623_v43_n9_p1826_Szajnman |
| work_keys_str_mv |
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| _version_ |
1840326377281159168 |