Identification of an orally active carbazole aminoalcohol derivative with broad-spectrum anti-animal trypanosomiasis activity

Cai, X-L; Wang, W; Lai, D-H; Zhang, X; Yao, J; Yu, Y; Li, S; Hide, G; Bai, H; Duan, L; Lun, Z-R

Abstract

Animal trypanosomiasis, caused by the members of subgenus Trypanozoon (Trypanosoma brucei brucei, T. evansi and T. equiperdum), has reduced animal productivity leading to significant negative economic impacts in endemic regions. Due to limited drug discovery and the emergence of drug-resistance over many recent decades, novel and effective compounds against animal trypanosomiasis are urgently required. This study was conducted to evaluate the antitrypanosomal potential of a batch of carbazole aminoalcohol derivatives. Among them, we found that the most effective compound was H1402, which exhibited potent trypanocidal efficacy against the bloodstream-form of T. b. brucei (EC  = 0.73 ± 0.05 µM) and presented low cytotoxicity against two mammalian cell lines with CC > 30 µM. Using a murine model of acute infection, oral administration with H1402 demonstrated a complete clearance of T. b. brucei and all the infected mice were cured when they were treated twice daily for 5 days at a dose of 100 mg/kg. Furthermore, parasites were not detected in mice infected with T. evansi and T. equiperdum (the causative agents of surra and dourine, respectively, in animals) within 30 days following the same regimen with H1402. In addition, H1402 caused severe morphological and ultrastructural destruction to trypanosomes, as well as causing phosphatidylserine externalization, which are suggested to be the most likely cause of cell death. Overall, the present data demonstrated that H1402 could be promising as a rapid, safe and orally active lead compound for the development of new chemotherapeutics for animal trypanosomiasis. [Abstract copyright: Copyright © 2021 Elsevier B.V. All rights reserved.]

Citation

Cai, X., Wang, W., Lai, D., Zhang, X., Yao, J., Yu, Y., …Lun, Z. (2021). Identification of an orally active carbazole aminoalcohol derivative with broad-spectrum anti-animal trypanosomiasis activity. Acta tropica, 219, 105919. https://doi.org/10.1016/j.actatropica.2021.105919

• Journal Article Type: Article
• Acceptance Date: Apr 7, 2021
• Online Publication Date: Apr 20, 2021
• Publication Date: Jul 1, 2021
• Deposit Date: May 17, 2021
• Publicly Available Date: Apr 20, 2022
• Journal: Acta Tropica
• Print ISSN: 0001-706X
• Publisher: Elsevier
• Volume: 219
• Pages: 105919
• DOI: https://doi.org/10.1016/j.actatropica.2021.105919
• Publisher URL: https://doi.org/10.1016/j.actatropica.2021.105919
• Related Public URLs: http://www.journals.elsevier.com/acta-tropica/
• Additional Information: Additional Information : ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1873-6254 **Article IDs: pubmed: 33861972; pii: S0001-706X(21)00098-X **History: accepted 07-04-2021; revised 18-03-2021; submitted 22-05-2020; Funders : National Natural Science Foundation of China;Open Project of Xinjiang Production & Construction Crops Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin; Projects : Unknown; Grant Number: #31720103918, #U1803282; Grant Number: BRZD1503