2. Academic Validation
  3. Enteroviral replication inhibition by N-Alkyl triazolopyrimidinone derivatives through a non-capsid binding mode

Enteroviral replication inhibition by N-Alkyl triazolopyrimidinone derivatives through a non-capsid binding mode

  • Bioorg Med Chem Lett. 2022 May 15:64:128673. doi: 10.1016/j.bmcl.2022.128673.
Bishyajit Kumar Biswas 1,  Jin Soo Shin 2,  Yashwardhan R Malpani 1,  Dasom Hwang 2,  Eunhye Jung 2,  Soo Bong Han 1,  Avinash G Vishakantegowda 1,  Young-Sik Jung 3
Affiliations

Affiliations

  • 1 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
  • 3 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea. Electronic address: ysjung@krict.re.kr.
PMID: 35292344 DOI: 10.1016/j.bmcl.2022.128673
Abstract

Small-molecule inhibitors exhibiting broad-spectrum enteroviral inhibition by targeting viral replication proteins are highly desirable in Antiviral drug discovery. We used the previously identified Antiviral compound 1 as the starting material to develop a novel compound series with high efficacy against human rhinovirus (hRV). Further optimization of N-substituted triazolopyrimidinone derivatives revealed that the N-alkyl triazolopyrimidinone derivatives (2) had more potent Antiviral activity against hRVs than compound 1. The new compounds showed improved selectivity index values, and compound 2c (KR-25210) displayed broad anti-hRV activity, with half-maximal effective concentration values ≤ 2 µM against all tested hRVs. In addition, 2c showed notable activity against Other enteroviruses. Drug-likeness elucidation showed that 2c exhibited reasonable human and rat liver microsomal phase-I stability and safe CYP inhibition. Replication studies revealed that 2c is not a capsid inhibitor, and a time-of-addition assay indicated that 2c targets the virus replication stages.

Keywords

Antiviral compound; Enterovirus; Human rhinovirus; N-Alkyl-triazolopyrimidinone.

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