In Vitro , In Vivo , and Absorption, Distribution, Metabolism, and Excretion Evaluation of SF ₅ -Containing N,N’ -Diarylureas as Antischistosomal Agents

Abstract

In 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 IC 50 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 SF 5 -containing N,N’ -diarylureas.

Recent Advances in Anti-Schistosomiasis Drug Discovery

“…Pharmacokinetic data suggest that 31 has significantly higher overall systemic exposure than the other two, perhaps due to the pyridine substituent. N,N′-diarylureas bearing pentafluorosulfanyl (▬SF 5 ) groups, such as 32, have also been synthesized and assessed; like the other ureas tested, they demonstrated excellent activity in vitro (IC 50 's as low as 0.6 μM against S. mansoni NTS) but marginal efficacy in vivo [65].…”

“…Leads resulting from a high throughput screen using ATP quantitation (60)(61)(62)(63)(64)(65)(66)(67).…”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…Scheme 59 Synthesis and antibacterial activity of an SF 5 containing triclocarban analogue 51 The same SF 5 -N,N′-diphenylurea 15 -and three other structurally related SF 5 -substituted compounds -were found to have interesting in vitro activity against schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. 52 These four compounds were highly active in the presence of albumin, had decent cytotoxicity profiles and good microsomal hepatic stability. Unfortunately, despite the promising in vitro worm-killing potency, none of them showed significant activity in vivo in S. mansoni-infected mice.…”

Chemistry of Pentafluorosulfanyl Derivatives and Related Analogs: From Synthesis to Applications

“…The same class of compounds has been recently repurposed as antischistosomal agents. [130] Despite the promising in vitro activity towards worms and high selectivity index, they lack anti-worm activity and harbour potential toxicity in vivo. Other SF 5 -containing scaffolds with antimicrobial activity have been reported by the group of Sintim.…”

“…The novel diarylurea 159 (Scheme 50, A) showed higher potency and a broader spectrum of activity towards Gram‐positive bacteria compared to TCC. The same class of compounds has been recently repurposed as antischistosomal agents [130] . Despite the promising in vitro activity towards worms and high selectivity index, they lack anti‐worm activity and harbour potential toxicity in vivo.…”