{"doi":"10.1016/j.ejmech.2025.117572","title":"Discovery and optimization of a novel carboxamide scaffold with selective antimalarial activity","abstract":"Artemisinin combination therapies (ACTs) are critical components of malaria control worldwide. Alarmingly, ACTs have begun to fail, owing to the rise in artemisinin resistance. Thus, there is an urgent need for an expanded set of novel antimalarials to generate new combination therapies. Herein, we have identified a 1,2,4-triazole-containing carboxamide scaffold that, through scaffold hopping efforts, resulted in a nanomolar potent deuterated picolinamide ( 110 ). The lead compound of this class ( 110 ) displays moderate aqueous solubility (13.4 μM) and metabolic stability (CLint app HLM 17.3 μL/min/mg) in vitro , as well as moderate oral bioavailability (%F 16.2) in in vivo pharmacokinetic studies. Compound 110 also displayed activity against various P. falciparum isolates with different genetic backgrounds and a slow-to-moderate rate of killing (average parasite reduction ratio 2.4), making the series appealing for further development. • 96 analogs were synthesized and tested in vitro against Plasmodium falciparum. • The scaffold is P. falciparum -selective with no cytotoxicity against HepG2 cells. • A deuteromethyl isotopologue improves aqueous solubility and metabolic stability. • The lead picolinamide ( 110 ) exhibits an EC 50 < 200 nM against P. falciparum. • 110 displays a slow-to-moderate rate of killing, similar to pyrimethamine.","journal":"European Journal of Medicinal Chemistry","year":2025,"id":520831,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1359934,"name":"Roger Trombley","orcid":null,"position":1,"is_corresponding":false},{"id":1359935,"name":"Maris Podgurski","orcid":null,"position":2,"is_corresponding":false},{"id":1148971,"name":"Anthony A. Ruberto","orcid":"0000-0002-3215-9484","position":3,"is_corresponding":false},{"id":409994,"name":"Meng Cui","orcid":"0000-0002-3895-135X","position":4,"is_corresponding":false},{"id":829216,"name":"Caitlin Cooper","orcid":"0000-0002-9994-0291","position":5,"is_corresponding":false},{"id":1359630,"name":"William E. Long","orcid":"0009-0006-8333-0604","position":6,"is_corresponding":false},{"id":1303981,"name":"Gia-Bao Nguyen","orcid":null,"position":7,"is_corresponding":false},{"id":953192,"name":"Adriana A. Marin","orcid":"0000-0001-5841-9486","position":8,"is_corresponding":false},{"id":792326,"name":"Sarah Lee","orcid":"0000-0002-2781-3082","position":9,"is_corresponding":false},{"id":71987,"name":"Franco Lombardo","orcid":"0000-0002-0875-1664","position":10,"is_corresponding":false},{"id":355427,"name":"Steven P. Maher","orcid":"0000-0002-9560-5656","position":11,"is_corresponding":false},{"id":355429,"name":"Dennis E. Kyle","orcid":"0000-0002-0238-965X","position":12,"is_corresponding":false},{"id":488062,"name":"Roman Manetsch","orcid":"0000-0001-7038-6867","position":13,"is_corresponding":false},{"id":1310424,"name":"Alicia Wagner","orcid":"0000-0003-1782-1721","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40199028","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":[]}