An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

Abstract

Currently there is only one method of treatment for human schistosomiasis, the drug praziquantel. Strong selective pressure has caused a serious concern for a rise in resistance to praziquantel leading to the necessity for additional pharmaceuticals, with a distinctly different mechanism of action, to be used in combination therapy with praziquantel. Previous treatment of Schistosoma mansoni included the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The oxamniquine activating enzyme was identified as a S. mansoni sulfotransferase (SmSULT-OR). Structural data have allowed for directed drug development in reengineering oxamniquine to be effective against S. haematobium and S. japonicum. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxamniquine, our structure-based drug design approach produced a robust SAR program that tested over 300 derivatives and identified several new lead compounds with effective worm killing in vitro. Previous studies resulted in the discovery of compound CIDD-0066790, which demonstrated broad-species activity in killing of schistosome species. As these compounds are racemic mixtures, we tested and demonstrate that the R enantiomer CIDD-007229 kills S. mansoni, S. haematobium and S. japonicum better than the parent drug (CIDD-0066790). The search for derivatives that kill better than CIDD-0066790 has resulted in a derivative (CIDD-149830

Rational approach to drug discovery for human schistosomiasis

“…This affects both adult sexes but mainly the males, causing the parasites to detach from hepatoportal circulation and move into the liver where they are eliminated, in part, by the formation of an adduct on DNA thus blocking DNA replication and transcription ( Pica-Mattoccia et al, 1989 , 2006 ; Valentim et al, 2013 ; Taylor et al, 2017 ). Males express 5X more SmSULT- OR than females which may account for the sex difference in killing ( Guzman et al, 2020 ). If the female worms are not killed, the lack of male worms causes the female worms to revert to an immature state and cease producing eggs ( LoVerde et al, 2004 ).…”

“…If the female worms are not killed, the lack of male worms causes the female worms to revert to an immature state and cease producing eggs ( LoVerde et al, 2004 ). However, male and female worms are both killed by the OXA derivatives ( Guzman et al, 2020 ).

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“…Those derivatives that show the most potent activity are soaked into new crystals and the process repeated ( Fig. 6 ) ( Rugel et al, 2018 ; Guzman et al, 2020 ).

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“…The project team designed, synthesized and screened >300 novel compounds in two, structurally distinct chemical series. From these, several derivatives stand out, such as CIDD–0072229 and CIDD-149830 ( Guzman et al, 2020 ). All of the drugs synthesized are racemic mixtures.…”

“…These efforts culminated in the discovery of CIDD-0072229 and CIDD-0149830, which show varying degrees of pan-anti-schistosome activity across all three species ( Fig. 8 , Rugel et al, 2018 ; Guzman et al, 2020 ). To support these efforts, efficient syntheses were developed, allowing manipulation of multiple functional groups to synergize schistosome SAR with optimization of “drug-like” physicochemical property calculations and in silico molecular modeling and docking studies to aid in compound design cycles.…”