Revisiting 2-Substituted-4(1 H)-Quinolones for Targeting the Plasmodium falciparum Cytochrome bc1 Complex

  • J Med Chem. 2026 Jun 25;69(12):14114-14139. doi: 10.1021/acs.jmedchem.5c03295.
Sovitj Pou  1 ,  Katherine M Liebman  1 ,  Rolf W Winter  1 ,  Aaron Nilsen  1  2 ,  Yuexin Li  1 ,  Isaiah N Lyche  1 ,  Teresa M Riscoe  1  3 ,  Jemma Montgomery  1 ,  Max J Gramelspacher  1 ,  Rozalia A Dodean  1 ,  Lev N Zakharov  4 ,  Binod Nepal  5 ,  Jane X Kelly  1 ,  Martin J Smilkstein  1 ,  Sandhya Kortagere  5 ,  Akhil B Vaidya  5 ,  P Holland Alday  1  6 ,  J Stone Doggett  1  6 ,  Karl Kudyba  7  8 ,  Norma Roncal  7  8 ,  Kutub Ashraf  7  8 ,  Susan Leed  7  8 ,  Patricia J Lee  7 ,  Michael S Madejczyk  7 ,  Alison Roth  7  8 ,  Michael K Riscoe  1  3
Affiliations
  • 1. VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.
  • 2. Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
  • 3. Department of Microbiology and Molecular Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
  • 4. Center for Advanced Materials Characterization in Oregon (CAMCOR), Eugene, Oregon 97403, United States.
  • 5. Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, United States.
  • 6. School of Medicine Division of Infectious Diseases, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
  • 7. Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
  • 8. Integrated Pathogen Therapeutics Department, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
PMID: 42266065 DOI: 10.1021/acs.jmedchem.5c03295
Abstract

Quinolones substituted at the 2- and 3-positions with biaryl and diphenylether groups have been investigated for their antimalarial potential. ELQ-300, with a 3-position diphenyl ether, is at an advanced stage of preclinical development. Here, we synthesize the 2-position isomer of ELQ-300, i.e., HLQ-102, and describe synthetic procedures for preparing it that avoid the use of expensive catalysts and afford access to substituted quinolones bearing substituents in the 2-position as well as the benzenoid ring and with the critical 3-position CH3 group. We profile HLQ analogs for their antimalarial activity along with pharmacokinetics of the selected lead molecule. Cross-resistance patterns indicate that, like its predecessor, HLQ-102 targets the Qi site of the Parasite cytochrome bc1 complex. This finding suggests the existence of two separate troughs in the target protein capable of accommodating such large structural features regardless of whether it is placed at the 2- or 3-positon of the Quinolone ring.

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