Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection.

Abstract

Chikungunya virus (CHIKV) infection, a febrile illness caused by a mosquito-transmitted alphavirus, has afflicted millions of people worldwide. There is currently no approved effective antiviral treatment for CHIKV infection. In this study, we report a new class of small-molecule CHIKV inhibitors, the oxindole-labdanes, that potently block the replication of CHIKV with good selectivity. Andrographolide, a previously reported inhibitor of CHIKV infection, was used as the lead compound for our initial structure-activity relationship (SAR) study. From a focused library of 72 andrographolide analogues, we identified the lead compound (E)-2 with improved antiviral activities. Further optimization of (E)-2 led to the discovery of the normal-labdane 7-chloro-oxindole (E)-42 as potent inhibitor against two low-passage CHIKV isolates from human patients with an EC50 of 1.55 μM against CHIKV-122508 and 0.14 μM against CHIKV-6708. Compound (E)-42 displayed minimal cytotoxic liability (CC50 > 100 μM), thus furnishing good selectivity relative to the host cells. Mechanistically, (E)-42 does not inactivate the viral particles but rather acts on the host cells to interfere with the viral replication, demonstrating both prophylactic and therapeutic effects. Our findings open a new avenue for the development of oxindole-labdane compounds as promising antiviral drugs against CHIKV infection.

• Authors: Quy Thi Ngoc Tran, Regina Ching Hua Lee, Hon Jin Liu, Danli Ran, Vincent Zhan Lin Low, Dong Quang To, Justin Jang Hann Chu, Christina Li Lin Chai
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 230 Pg. 114110 (Feb 15 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35085859 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antiviral Agents
• Diterpenes
• Oxindoles
• RNA, Viral
• labdane

Topics

• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Chikungunya Fever (drug therapy)
• Diterpenes (pharmacology, therapeutic use)
• Humans
• Oxindoles (pharmacology)
• RNA, Viral
• Virus Replication