Schistosomiasis caused by Schistosoma spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against Plasmodium falciparum, motivating further investigation into their efficacy against Schistosoma mansoni, due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult Schistosoma mansoni yielded 11 candidates with low EC50 values for newly transformed schistosomula (1.12–4.63 μM) and adults (2.78–9.47 μM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of Schistosoma mansoni. The two compounds 2,2′-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride (1) and 2,2′-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride (19), were selected for an in vivo study in Schistosoma mansoni-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction
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