2. Academic Validation
  3. Restructuring Antiviral Quinazolinone Frameworks to Derive and Optimize Inhibitors of Chikungunya Virus

Restructuring Antiviral Quinazolinone Frameworks to Derive and Optimize Inhibitors of Chikungunya Virus

  • ACS Med Chem Lett. 2025 Oct 24;16(11):2320-2327. doi: 10.1021/acsmedchemlett.5c00515.
Caroline M Roach 1,  Zachary J Streblow 2,  Yuting Zhang 3,  Tyler J Ogorek 4,  Alejandro Ponce-Flores 5,  Colleen B Jonsson 3 5 6,  Daniel N Streblow 2 7,  Jennifer E Golden 1 4
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
  • 2 Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon 97006, United States.
  • 3 Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 4 Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
  • 5 Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 7 Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, Oregon 97006, United States.
PMID: 41257010 DOI: 10.1021/acsmedchemlett.5c00515
Abstract

Chikungunya virus (CHIKV) results in debilitating chronic pain in nearly half of those infected. With no FDA approved small molecule-based therapeutics available, we screened compounds to reveal quinazolinone (S)-1a with a modest 0.3 log reduction of CHIKV titer and no significant toxicity (CC50 > 40 μM). Five scaffold regions were surveyed to improve the titer reduction efficiency. Chemistry was established to preserve the enantiopurity of 2-piperidinyl-containing analogues, affording (R)-1h (BDGR-651) which reduced CHIKV titer in normal human dermal fibroblasts by 4.1 log at 10 μM (EC50 = 0.86 μM). Excellent solubility and mouse microsomal and plasma stabilities were observed, and confocal microscopy of infected Vero E6 cells treated with (R)-1h showed a dose-dependent protective effect. A narrow selectivity index prevented in vivo evaluation, but the study showed that antiencephalitic alphavirus quinazolinones could be reengineered to inhibit CHIKV, an arthritogenic virus, against which previous analogues showed no significant activity.

Keywords

alphavirus; chikungunya; inhibitor; quinazolinone.

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