{"doi":"10.1371/journal.pntd.0008517","title":"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) that kills 100% of S. mansoni, S. haematobium and S. japonicum adult worms within 7 days. We hypothesize that the difference in activation and thus killing by the derivatives is due to the ability of the derivative to fit in the binding pocket of each sulfotransferase (SmSULT-OR, ShSULT-OR, SjSULT-OR) and to be efficiently sulfated. The purpose of this research is to develop a second drug to be used in conjunction with praziquantel to treat the major human species of Schistosoma. Collectively, our findings show that CIDD-00149830 and CIDD-0072229 are promising novel drugs for the treatment of human schistosomiasis and strongly support further development and in vivo testing.","journal":"PLoS neglected tropical diseases","year":2020,"id":85935,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":396734,"name":"Anastasia R. Rugel","orcid":null,"position":1,"is_corresponding":false},{"id":396029,"name":"Reid S. Tarpley","orcid":"0000-0003-2431-0831","position":2,"is_corresponding":false},{"id":438439,"name":"Sevan N. Alwan","orcid":"0000-0001-8701-4859","position":3,"is_corresponding":false},{"id":396028,"name":"Frédéric D. Chevalier","orcid":"0000-0003-2611-8106","position":4,"is_corresponding":false},{"id":240059,"name":"Dmytro Kovalskyy","orcid":"0000-0002-1143-8724","position":5,"is_corresponding":false},{"id":396736,"name":"Xiaohang Cao","orcid":null,"position":6,"is_corresponding":false},{"id":396737,"name":"S. Holloway","orcid":null,"position":7,"is_corresponding":false},{"id":245285,"name":"Timothy J. C. Anderson","orcid":"0000-0002-0191-0204","position":8,"is_corresponding":false},{"id":396027,"name":"Alexander B. Taylor","orcid":"0000-0003-3517-6033","position":9,"is_corresponding":false},{"id":396030,"name":"Stanton F. McHardy","orcid":"0000-0003-0070-4924","position":10,"is_corresponding":false},{"id":396032,"name":"Philip T. LoVerde","orcid":"0000-0002-8316-8559","position":11,"is_corresponding":false},{"id":396735,"name":"Meghan A. Guzman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T21:58:16.217017Z","pmid":"32810153","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}