Activities of N , N ′-Diarylurea MMV665852 Analogs against Schistosoma mansoni

Abstract

There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852, N,N=-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult Schistosoma mansoni worms in vitro. Active compounds were evaluated with a cytotoxicity assay, in silico calculations, metabolic stability studies, and an in vivo assay with mice harboring adult S. mansoni worms. Of the 46 compounds tested at 33.3 M, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC 90 s) of <10 M against adult worms, with selectivity indexes of >2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight to S. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of the N,N=-diarylurea MMV665852 had high efficacy against S. mansoni in vitro and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…[133] Subsequently,alibrary of structural analogues of MMV665852 (36)w as screened. [134] All compounds contained similars tructuralm oieties such as N,N'-diarylureas, N-aryl,N'-alkylureas, N-phenyl benzamides, anda ryl N-phenylcarbamates ( Figure 5A). With the exception of N-aryl,N'-alkylureas, compounds with good in vitro activity were identified in all compound classes (IC 50 andI C 90 values were in the low single-digit or sub-micromolar range against S. mansoni).…”

“… A) Development of N , N ′‐diarylureas and analogues as antischistosomal agents . B) Chemical structures of 3‐cyano‐1,2,5‐oxadiazole‐2‐oxides as TGR inhibitors …”

“…Subsequently, a library of structural analogues of MMV665852 ( 36 ) was screened . All compounds contained similar structural moieties such as N , N ′‐diarylureas, N ‐aryl, N ′‐alkylureas, N ‐phenyl benzamides, and aryl N ‐phenylcarbamates (Figure A).…”

“…Another limiting factor of the N , N ′‐diarylurea analogues was their low aqueous solubility. Improvement of bioavailability might be achieved by structural optimization, making the N , N ′‐diarylureas and their analogues a promising starting point for further investigations …”

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

“…Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) in S. mansoni -infected mice. The authors concluded that there is a need to synthesise compounds with improved solubility and pharmacokinetic properties [72]. …”