Activity of N-phenylbenzamide analogs against the neglected disease pathogen, Schistosoma mansoni.

For the Schistosoma mansoni flatworm pathogen, we report a structure-activity relationship of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross-screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast-acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h. Against HEK 293 mammalian cells, both compounds exhibited high CC50 values (9.8 ± 1.6 and 11.1 ± 0.2 µM respectively) which could translate to comfortable selectivity. When evaluated in a concentration-response format, compound 9 was active in the nanomolar range (EC50 = 80 nM), translating to a selectivity index of 123 over HEK 293 cells. The data encourage the further investigation of N-phenylbenzamides as antischistosomals.

Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei.

Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure-activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.