Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities

Abstract

Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity. Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds’ activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1’s homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.

Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni

“…Comparatively, although amiodarone was less potent than praziquantel, few other studies have described compounds with schistosomicidal activity at a concentration below 10 µM (for review, see [9,16]), which highlights the importance of amiodarone as an anthelmintic agent. Indeed, the 10 µM concentration defines a cut-off value for the selection of drugs for further exploration in an animal model, whereas the 50 µM screening was included to avoid the loss of chemical information for exploring the structure-activity relationship and/or medicinal chemical optimization [12,17].…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…WormAssay quantified the effect of several compounds on worm motility, including neuromodulatory drugs (79), phenylpyrimidines (80) and inhibitors of S. mansoni cyclic nucleotide phosphodiesterase 4 (SmPDE4) (81) and proteasome (82). Recently, a modified version of WormAssay software, named WormAssayGP2, was released by Padalino and colleagues (83,84) and contains minor modifications related to the source code and user interface (85). To date, WormAssayGP2 has been used to detect the schistomicidal activity of putative inhibitors of S. mansoni lysine specific demethylase 1 (SmLSD1) (86) and histone methyltransferase mixed lineage leukemia-1 (SmMLL-1) (84), as well as human ubiquitin-proteasome system (85) inhibitors.…”

“…This assay was able to detect the anti-worm effect of known schistosomicidal drugs (oltipraz and dihydroartemisinin) (70), several drug candidates from small (93,94) and large (70, 95) chemical libraries, as well FDA-approved drugs (e.g., kinase inhibitors) (96). This analysis has also been employed by Hoffmann and colleagues (84,86,(97)(98)(99)(100) who measured the schistosomicidal activity of plant-derived compounds [e.g., diterpenoids (97,99) and triterpenoids (100)] and of potential inhibitors of S. mansoni histone-modifying enzymes (40,84,86,98).…”

First In Silico Screening of Insect Molecules for Identification of Novel Anti-Parasitic Compounds

“…Virtual screenings of compound libraries to identify compounds with activity against schistosomes have received attention in recent years [44][45][46][47]. Moreover, against SmTGR, such screenings have been successful in identifying active molecules [22,48].…”