Sponsor
This project was supported with funds from the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Program, with additional supplemental funding from VA Technology Transfer, Merit Review Grant award numbers 1I01 BX005674 (J.X.K.), I01 BX003312 (M.K.R.), and 2I01 BX003312-10 (M.K.R.). Research reported in this publication was also supported by the US National Institutes of Health award numbers R01 AI 158533 (J.X.K.), R01 AI 182513 (M.K.R.), R01 AI 141412 (M.K.R.), R56 AI 182513 (M.K.R.), and R01 AI 100569 (M.K.R.), the US Department of Defense Peer Reviewed Medical Research Program (log number PR181134); and Department of Defense, U.S. Army under award numbers W81XWH2210494 (J.X.K.) and HT94252410473 (M.K.R.). Additional support for this research was provided by the Open Philanthropy Project (M.K.R.) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number F31 AI 174772 (M.J.H). The Murdock Charitable Trust provided instrument funding for the BSR/PK Core Facility at Oregon Health & Science University.
Published In
Antimicrobial Agents and Chemotherapy
Document Type
Article
Publication Date
3-2-2026
Subjects
Plasmodium falciparum -- malaria, Ultidrug-resistant malaria, 4-aminoquinoline, Antimalarial agents
Abstract
Plasmodium falciparum, the deadliest causative agent of malaria, continues to evade eradication efforts through widespread drug resistance. The recent development of ADC-028, a 4-aminoquinoline antimalarial with excellent activity and pharmacokinetic properties, prompted the investigation of bisquinoline analogs featuring similar structural motifs. Here, we describe a structure-activity relationship study that guided the optimization of compounds with key features, including the 4-anilinoquinoline core and diverse bridging linkers. Several analogs exhibited potent in vitro activity (IC50 < 20 nM) against both drug-sensitive and multidrug-resistant P. falciparum strains, while maintaining favorable cytotoxicity profiles. Among them, 25 demonstrated improved intrinsic metabolic stability (t1/2 = 121 min) and potent in vivo efficacy (ED50 = 0.32 mg/kg/day), achieving complete curative protection at a reduced dose compared to ADC-028. While 25 showed moderately reduced oral bioavailability (F = 43%) and a shorter half-life (T1/2 = 27.2 h) relative to ADC-028, its enhanced in vivo efficacy underscores its therapeutic potential. This work highlights a promising path forward in developing antimalarials that retain the efficacy of legacy compounds while overcoming modern resistance mechanisms.
Rights
Copyright (c) 2026 The Authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
Locate the Document
DOI
10.1128/aac.01300-25
Persistent Identifier
https://archives.pdx.edu/ds/psu/44541
Citation Details
Handford, M. J., Li, Y., Riscoe, T., Zhang, X., Kelly, J. X., & Riscoe, M. K. (2026). Designing novel bisquinoline antimalarials from historical 4-aminoquinolines to combat drug-resistant malaria. Antimicrobial Agents and Chemotherapy.