{"doi":"10.1002/cmdc.202300128","title":"Scalable and Chromatography‐Free Synthesis of Efflux Pump Inhibitor Phenylalanine Arginine β‐Naphthylamide for Its Validation in Wild‐Type Bacterial Strains","abstract":"Phenylalanine arginine β-naphthylamine, or PAβN, is a C-terminus capped dipeptide discovered in 1999 as an RND-type efflux pump inhibitor (EPI). Since then, PAβN has become a standard tool compound in EPI research and development. Despite this, PAβN lacks a detailed or efficient synthesis, and standard parameters for its use in wild-type bacterial strains are inconsistent or non-existent. Therefore, a scalable and chromatography-free synthesis of PAβN was developed using streamlined traditional solution-phase peptide coupling chemistry. With this procedure, gram scale quantities of PAβN were synthesized alongside analogues and stereoisomers to build a focused library to evaluate simple structure activity relationships. While most analogues were less active than the broadly utilized L,L-PAβN itself, we identified that its enantiomer, D,D-PAβN, also provided 8- to 16-fold potentiation of the antibiotic levofloxacin at 40 to 50 μg/mL concentrations of EPI in various wild-type Pseudomonas aeruginosa strains. Additionally, D,D-PAβN was shown to be significantly more hydrolytically stable than L,L-PAβN, indicating that it may be a useful, and now readily synthesized, tool compound facilitating future EPI research.","journal":"ChemMedChem","year":2023,"id":406823,"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":0.9601,"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":1186143,"name":"Kelsey G. Howey","orcid":null,"position":1,"is_corresponding":false},{"id":913507,"name":"Matthew C. O’Reilly","orcid":"0000-0002-9175-4179","position":2,"is_corresponding":false},{"id":1185921,"name":"Christopher M. Russo","orcid":"0000-0001-5594-9000","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T01:21:07.213041Z","pmid":"37126222","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":[]}