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https://doi.org/10.1016/j.ejmech.2022.114110
Title: | Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection | Authors: | Tran, Quy Thi Ngoc Lee, Regina Ching Hua Liu, Hon Jin Ran, Danli Low, Vincent Zhan Lin To, Dong Quang Chu, Justin Jang Hann Chai, Christina Li Lin |
Keywords: | Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy Chikungunya Arbovirus Antiviral Labdane diterpenoid Oxindole |
Issue Date: | 15-Feb-2022 | Publisher: | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Citation: | Tran, Quy Thi Ngoc, Lee, Regina Ching Hua, Liu, Hon Jin, Ran, Danli, Low, Vincent Zhan Lin, To, Dong Quang, Chu, Justin Jang Hann, Chai, Christina Li Lin (2022-02-15). Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 230. ScholarBank@NUS Repository. https://doi.org/10.1016/j.ejmech.2022.114110 | 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. | Source Title: | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | URI: | https://scholarbank.nus.edu.sg/handle/10635/235426 | ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2022.114110 |
Appears in Collections: | Staff Publications Elements |
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1-s2.0-S0223523422000125-main.pdf | Published version | 3.89 MB | Adobe PDF | CLOSED | Published | |
R221208n10_Manuscript.pdf | 2.14 MB | Adobe PDF | OPEN | Pre-print | View/Download |
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