Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis**

Abstract

Schistosomiasis is ad iseaseo fp overty affecting millionso fp eople. Praziquantel (PZQ),w ith its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derivedfrom oxamniquine (OXA), an old antischistosomald rug:f errocene-containing (Fc-CH 2-OXA),r uthenocene-containing (Rc-CH 2-OXA) and benzene-containing (Ph-CH 2-OXA) OXA derivatives. These derivatives showed excellent in vitro activity againstb oth Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducteda dditional in-depthp reclinical studiesa nd report in this investigation on metabolic stability studies, in vivos tudies on S. haematobium and juvenile S. mansoni,c omputational simulations,a nd formulation development. Molecular dynamicss imulations supportedt he in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reasonw hy the promising in vitro activity did not translate into in vivo activityo nS. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as aw ay to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability,t or each an active concentration in the microenvironment of the parasite.

Recent Advances in Anti-Schistosomiasis Drug Discovery

“…Notably, this work also found a benzylated OXA, 11, to be effective against all three parasites in vitro [37]. However, the in vivo efficacy against the parasites was limited, in part due to their instability in acidic media [39].…”

“…Ferrocenyl and ruthenocenyl derivatives of OXA (9-10) were also synthesized and found to be roughly as active as the parent OXA against S. mansoni, but significantly more active in in vitro testing than OXA against S. haematobium and S. japonicum [37][38][39]. Notably, this work also found a benzylated OXA, 11, to be effective against all three parasites in vitro [37].…”

Rational approach to drug discovery for human schistosomiasis

“…Efficacy trials did not demonstrate better effects on reducing worm burden than OXA. A series of studies ( Hess et al, 2017 ; Buchter et al, 2018 , 2020 ) has demonstrated excellent efficacy of OXA derivatives against S . mansoni both in vitro (100% killing) and in vivo (100% killing with a 200 mg/kg dose) and S .…”

“… Hess et al (2017) synthesized ruthenocenyl- and ferrocenyl- and benzyl-derivatives-based organometallic OXA conjugates to improve ADME and physicochemical properties. Current studies focus on increasing bioavailability to improve in vivo activity ( Buchter et al, 2020 ).…”

Dynamics of Schistosoma Mansoni Development in The Intermediate Host, Biomphalaria Glabrata, A Freshwater Snail

“…A large number of studies have been reported about schistosomiasis, including case reports and developments of new drugs and vaccination methods [9][10][11][12][13][14]. On the other hand, few studies that focused on intermediate hosts have been presented [15][16][17].…”