Expanding the Activity Profile of Pyrido[1,2-a]benzimidazoles: Synthesis and Evaluation of Novel N1-1-Phenylethanamine Derivatives against Schistosoma mansoni
| Autor: | Kelly Chibale, Alexandra Probst, Jennifer Keiser, Kelly Chisanga, Godwin Akpeko Dziwornu, Cécile Haeberli |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug Benzimidazole biology Chemistry media_common.quotation_subject 030106 microbiology Schistosomiasis Pharmacology medicine.disease biology.organism_classification Chinese hamster 3. Good health Praziquantel 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Infectious Diseases Drug development In vivo parasitic diseases medicine Schistosoma mansoni media_common medicine.drug |
| Zdroj: | ACS Infectious Diseases. 7:1032-1043 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.0c00278 |
| Popis: | Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 μM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice. |
| Databáze: | OpenAIRE |
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