Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose
Posted on 2023-09-18 - 19:35
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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Racané, Livio; Ptiček, Lucija; Kostrun, Sanja; Raić-Malić, Silvana; Taylor, Martin Craig; Delves, Michael; et al. (2023). Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.3c01051
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (10)
LR
Livio Racané
LP
Lucija Ptiček
SK
Sanja Kostrun
SR
Silvana Raić-Malić
MT
Martin Craig Taylor
MD
Michael Delves
SA
Sam Alsford
FO
Francisco Olmo
AF
Amanda Fortes Francisco
JK
John M. Kelly
KEYWORDS
stage 1 trypanosomiasislow membrane permeabilityconsiderable therapeutic potentialaliphatic central units20 mg kgvitro adme profilecultured asexual formslow nanomolar concentrations9a bvitro potencybloodstream formsunsubstituted 5trypanocidal activitysingle doseremarkable selectivitymice treatedlysosomal sequestrationfound evidencefold ).exquisite crosscyclohexyl spacercrucial determinantsbenzothiazole derivativesbenzothiazole derivativeamidine groupsalso active