{"doi":"10.1101/2023.03.11.532093","title":"Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5- <i>a</i> ]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis","abstract":"ABSTRACT Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei -infected mice with tolerable doses of TPDs 3 and 4 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of 4 at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398701,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":712491,"name":"Lawrence J. Liu","orcid":null,"position":1,"is_corresponding":false},{"id":667818,"name":"Carmine Varricchio","orcid":"0000-0002-1673-4768","position":2,"is_corresponding":false},{"id":1124303,"name":"Bobby Lucero","orcid":"0000-0001-5070-3458","position":3,"is_corresponding":false},{"id":554452,"name":"Thibault Alle","orcid":"0000-0001-8459-6443","position":4,"is_corresponding":false},{"id":1062599,"name":"Wenqian Yang","orcid":"0009-0003-7283-4565","position":5,"is_corresponding":false},{"id":1174974,"name":"Ido Bem‐Shalom","orcid":null,"position":6,"is_corresponding":false},{"id":263938,"name":"Michael K. Gilson","orcid":"0000-0002-3375-1738","position":7,"is_corresponding":false},{"id":357077,"name":"Kurt R. Brunden","orcid":"0000-0002-9732-134X","position":8,"is_corresponding":false},{"id":519666,"name":"Andrea Brancale","orcid":"0000-0002-9728-3419","position":9,"is_corresponding":false},{"id":241386,"name":"Conor R. Caffrey","orcid":"0000-0003-3048-8572","position":10,"is_corresponding":false},{"id":554454,"name":"Carlo Ballatore","orcid":"0000-0002-2718-3850","position":11,"is_corresponding":false},{"id":392200,"name":"Ludovica Monti","orcid":"0000-0001-8468-8073","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T01:19:47.744358Z","pmid":"36945407","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":[]}