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<p>West Nile Virus (WNV) is a mosquito-borne emerging virus, which can result in the development of meningitis or encephalitis. Our medicinal chemistry effort was initiated to identify potent small-molecule inhibitors of WNV with the potential for lead optimization. The initial hit compound 8-(4-(2,5-dimethylbenzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1<i>H</i>-purine-2,6-dione <b>1</b> was identified from a high-throughput screening (HTS) campaign of 197 K compounds using a cytopathic effect (CPE) cell-based assay against WNV, and showed antiviral inhibition against WNV (EC<sub>90</sub> = 0.93 µM), moderate cytotoxicity (CC<sub>50</sub> = 12 µM), low solubility (solubility = 9.7 µM) and metabolic stability [mouse and human microsomal stability (MLM and HLM) half-lives &lt; 10 min]. To improve the antiviral activity and drug-like properties of this hit compound, a structure-activity relationship (SAR) campaign led to the discovery of a new potent inhibitor, 8-(4-(4-(<i>tert</i>-butyl)benzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1<i>H</i>-purine-2,6-dione <b>21</b>, which retained its potency and efficacy and minimal cytotoxicity (EC<sub>90</sub> = 0.87 μM, CC<sub>50</sub> &gt; 30 μM) as compared to hit compound <b>1</b>. In addition to its desired anti-WNV activity profile, analog <b>21</b> showed improved microsomal stability (MLM t<sub>1/2</sub> = 21 min, HLM t<sub>1/2</sub> = 41 min) with acceptable pharmacokinetic properties for an initial in vivo proof-of-concept (POC) study, though the compound was inactive. Herein, we report the hit-to-lead optimization study that led to the discovery of this xanthine series.</p><p></p>

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Targeting west nile virus replication by xanthine inhibitors

  • 期刊论文

  • 发表日期：

    2025年9月26日

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  • Theresa H. Nguyen,
  • Jessica L. Smith,
  • Shuklendu D. Karyakarte,
  • John P. Tillotson,
  • Sarath C. Sarngadharan,
  • Fuad Al Abir,
  • Jake Y. Chen,
  • Sixue Zhang,
  • Lynn Rasmussen,
  • Robert Bostwick,
  • Alec J. Hirsch,
  • Corinne E. Augelli-Szafran,
  • Ashish K. Pathak,
  • Omar Moukha-Chafiq

摘要

West Nile Virus (WNV) is a mosquito-borne emerging virus, which can result in the development of meningitis or encephalitis. Our medicinal chemistry effort was initiated to identify potent small-molecule inhibitors of WNV with the potential for lead optimization. The initial hit compound 8-(4-(2,5-dimethylbenzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 1 was identified from a high-throughput screening (HTS) campaign of 197 K compounds using a cytopathic effect (CPE) cell-based assay against WNV, and showed antiviral inhibition against WNV (EC90 = 0.93 µM), moderate cytotoxicity (CC50 = 12 µM), low solubility (solubility = 9.7 µM) and metabolic stability [mouse and human microsomal stability (MLM and HLM) half-lives < 10 min]. To improve the antiviral activity and drug-like properties of this hit compound, a structure-activity relationship (SAR) campaign led to the discovery of a new potent inhibitor, 8-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 21, which retained its potency and efficacy and minimal cytotoxicity (EC90 = 0.87 μM, CC50 > 30 μM) as compared to hit compound 1. In addition to its desired anti-WNV activity profile, analog 21 showed improved microsomal stability (MLM t1/2 = 21 min, HLM t1/2 = 41 min) with acceptable pharmacokinetic properties for an initial in vivo proof-of-concept (POC) study, though the compound was inactive. Herein, we report the hit-to-lead optimization study that led to the discovery of this xanthine series.