Academic Journal
Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.
| العنوان: | Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose. |
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| المؤلفون: | Racané, Livio, Ptiček, Lucija, Kostrun, Sanja, Raić-Malić, Silvana, Taylor, Martin Craig, Delves, Michael, Alsford, Sam, Olmo, Francisco, Francisco, Amanda Fortes, Kelly, John M |
| بيانات النشر: | American Chemical Society |
| سنة النشر: | 2023 |
| المجموعة: | London School of Hygiene & Tropical Medicine: LSHTM Research Online |
| الوصف: | We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg-1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text |
| اللغة: | English |
| Relation: | https://researchonline.lshtm.ac.uk/id/eprint/4671102/9/Racane-etal-2023-Bis-6-amidino-benzothiazoleDerivative.pdf; Racané, Livio; Ptiček, Lucija; Kostrun, Sanja; Raić-Malić, Silvana; Taylor, Martin Craig ; Delves, Michael ; Alsford, Sam ; Olmo, Francisco; Francisco, Amanda Fortes ; Kelly, John M ; (2023) Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose. Journal of medicinal chemistry, 66 (18). pp. 13043-13057. ISSN 0022-2623 DOI: https://doi.org/10.1021/acs.jmedchem.3c01051 |
| DOI: | 10.1021/acs.jmedchem.3c01051 |
| الاتاحة: | https://researchonline.lshtm.ac.uk/id/eprint/4671102/ https://researchonline.lshtm.ac.uk/id/eprint/4671102/9/Racane-etal-2023-Bis-6-amidino-benzothiazoleDerivative.pdf https://doi.org/10.1021/acs.jmedchem.3c01051 |
| Rights: | cc_by_nc_nd_4 |
| رقم الانضمام: | edsbas.1EBDDFCA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.3c01051 |
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