< em > In vitro < /em > , < em > in vivo < /em > , and ADME evaluation of SF < sub > 5 < /sub > -containing < em > N,N' < /em > -diarylureas as antischistosomal agents

Antimicrob Agents Chemother. 2021 Jul 26:AAC0061521. doi: 10.1128/AAC.00615-21. Online ahead of print.ABSTRACTIn recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group. Low IC50 values for Schistosoma mansoni newly transformed schistosomula (0.6 - 7.7 μM) and adult worms (0.1 - 1.6 μM) were observed. Four selected compounds, highly active in presence of albumin (>70% at 10 μM), endowed with decent cytotoxicity profile (SI against L6 cells >8.5) and good microsomal hepatic stability (>62.5% of drug remaining after 60 min), were tested in S. mansoni infected mice. Despite the promising in vitro worm killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.PMID:34310210 | DOI:10.1128/AAC.00615-21

Source: Antimicrobial Agents and Chemotherapy - July 26, 2021 Category: Microbiology Authors: Alexandra Probst Eug ènia Pujol C écile Häberli Jennifer Keiser Santiago V ázquez Source Type: research