{"doi":"10.17615/brja-nk18","title":"Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1","abstract":"Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular-target-directed approach involving intervention of hexokinase activity—a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC50=9.1 μm), low mammalian cytotoxicity (IMR90 cells, EC50>25 μm), and no appreciable activity on whole bloodstream-form (BSF) parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50=0.28 μm; BSF, ED50=1.9 μm). Compounds in this series also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency than toward TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple disease-causing trypanosomatid protozoa.","journal":"UNC Libraries","year":2022,"id":311887,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1008812,"name":"S.L. Patrick","orcid":null,"position":1,"is_corresponding":false},{"id":1008813,"name":"D.P. Flaherty","orcid":null,"position":2,"is_corresponding":false},{"id":618572,"name":"H. Khan","orcid":"0000-0001-8220-3765","position":3,"is_corresponding":false},{"id":1008814,"name":"J.C. Morris","orcid":null,"position":4,"is_corresponding":false},{"id":1008815,"name":"E.W. Kahney","orcid":null,"position":5,"is_corresponding":false},{"id":1006302,"name":"W.S. Weiner","orcid":null,"position":6,"is_corresponding":false},{"id":1008816,"name":"A.L. Hackler","orcid":null,"position":7,"is_corresponding":false},{"id":1008817,"name":"M.T. Harris","orcid":null,"position":8,"is_corresponding":false},{"id":1008818,"name":"E.R. Sharlow","orcid":null,"position":9,"is_corresponding":false},{"id":945832,"name":"J.E. Golden","orcid":null,"position":10,"is_corresponding":false},{"id":945836,"name":"C.E. Schroeder","orcid":null,"position":11,"is_corresponding":false},{"id":945840,"name":"J. Aubé","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T00:33:32.327694Z","pmid":null,"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":[]}