2. Academic Validation
  3. Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus

Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus

  • J Med Chem. 2017 Apr 13;60(7):3165-3186. doi: 10.1021/acs.jmedchem.7b00180.
Kuan-Chieh Ching 1 2,  Thi Ngoc Quy Tran 2,  Siti Naqiah Amrun 3,  Yiu-Wing Kam 3,  Lisa F P Ng 3 4,  Christina L L Chai 1 2 5
Affiliations

Affiliations

  • 1 NUS Graduate School for Integrative Sciences and Engineering , Centre for Life Sciences, No. 05-01, 28 Medical Drive, 117456, Singapore.
  • 2 Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore.
  • 3 Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, No. 04-06, 138648, Singapore.
  • 4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Block MD6, Centre for Translational Medicine, 14 Medical Drive, No. 14-01T, 117599, Singapore.
  • 5 Institute of Chemical and Engineering Sciences, A*STAR , 8 Biomedical Grove, Neuros Building, No. 07-01/02/03, 138665, Singapore.
PMID: 28350454 DOI: 10.1021/acs.jmedchem.7b00180
Abstract

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus, and there is no approved effective Antiviral treatment currently available for CHIKV. We previously reported the discovery of thieno[3,2-b]pyrrole 1b that displayed good Antiviral activity against CHIKV Infection in vitro. However, it has a short half-life in the presence of human liver microsomes (HLMs) (T1/2 = 2.91 min). Herein, we report further optimization studies in which potential metabolically labile sites on compound 1b were removed or modified, resulting in the identification of thieno[3,2-b]pyrrole 20 and pyrrolo[2,3-d]thiazole 23c possessing up to 17-fold increase in metabolic half-lives in HLMs and good in vivo pharmacokinetic properties. Compound 20 not only attenuated viral RNA production and displayed broad-spectrum Antiviral activity against Other alphaviruses and CHIKV isolates but also exhibited limited cytotoxic liability (CC50 > 100 μM). These studies have identified two compounds that have the potential for further development as Antiviral drugs against CHIKV Infection.

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