Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents
A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive str...
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| Format: | Article |
| Language: | English |
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MDPI AG
2016-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | http://www.mdpi.com/1424-8247/9/2/20 |
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| author | Jean J. Vanden Eynde Annie Mayence Madhusoodanan Mottamal Cyrus J. Bacchi Nigel Yarlett Marcel Kaiser Reto Brun Tien L. Huang |
| author_facet | Jean J. Vanden Eynde Annie Mayence Madhusoodanan Mottamal Cyrus J. Bacchi Nigel Yarlett Marcel Kaiser Reto Brun Tien L. Huang |
| author_sort | Jean J. Vanden Eynde |
| collection | DOAJ |
| description | A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents. |
| first_indexed | 2024-04-13T02:47:35Z |
| format | Article |
| id | doaj.art-5058fb26228c47a4bb981b2eea64d1b9 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-04-13T02:47:35Z |
| publishDate | 2016-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-5058fb26228c47a4bb981b2eea64d1b92022-12-22T03:05:57ZengMDPI AGPharmaceuticals1424-82472016-04-01922010.3390/ph9020020ph9020020Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic AgentsJean J. Vanden Eynde0Annie Mayence1Madhusoodanan Mottamal2Cyrus J. Bacchi3Nigel Yarlett4Marcel Kaiser5Reto Brun6Tien L. Huang7College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USACollege of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USARCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USAHaskins Laboratories and Department of Biological and Health Sciences, Pace University, 1 Pace Plaza, New York, NY 10038, USAHaskins Laboratories and Department of Chemistry and Physical Sciences, Pace University, 1 Pace Plaza, New York, NY 10038, USASwiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, SwitzerlandSwiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, SwitzerlandCollege of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USAA series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.http://www.mdpi.com/1424-8247/9/2/20antiparasiticsbisbenzamidinesDNA bindingPlasmodium falciparumTrypanosoma brucei |
| spellingShingle | Jean J. Vanden Eynde Annie Mayence Madhusoodanan Mottamal Cyrus J. Bacchi Nigel Yarlett Marcel Kaiser Reto Brun Tien L. Huang Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents Pharmaceuticals antiparasitics bisbenzamidines DNA binding Plasmodium falciparum Trypanosoma brucei |
| title | Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents |
| title_full | Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents |
| title_fullStr | Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents |
| title_full_unstemmed | Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents |
| title_short | Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents |
| title_sort | alkanediamide linked bisbenzamidines are promising antiparasitic agents |
| topic | antiparasitics bisbenzamidines DNA binding Plasmodium falciparum Trypanosoma brucei |
| url | http://www.mdpi.com/1424-8247/9/2/20 |
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