American Chemical Society
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Identification of 2‑(4-(Phenylsulfonyl)piperazine-1-yl)pyrimidine Analogues as Novel Inhibitors of Chikungunya Virus

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journal contribution
posted on 2020-03-16, 16:13 authored by Julia Moesslacher, Verena Battisti, Leen Delang, Johan Neyts, Rana Abdelnabi, Gerhard Pürstinger, Ernst Urban, Thierry Langer
The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus, and it is the causative agent of chikungunya fever (CHIKF). Although it has re-emerged as an epidemic threat, so far there are neither vaccines nor pharmacotherapy available to prevent or treat an infection. Herein, we describe the synthesis and structure–activity relationship studies of a class of novel small molecule inhibitors against CHIKV and the discovery of a new potent inhibitor (compound 6a). The starting point of the optimization process was N-ethyl-6-methyl-2-(4-(4-fluorophenylsulfonyl)­piperazine-1-yl)­pyrimidine-4-amine (1) with an EC50 of 8.68 μM, a CC50 of 122 μM, and therefore a resulting selectivity index (SI) of 14.2. The optimized compound 6a, however, displays a much lower micromolar antiviral activity (EC50 value of 3.95 μM), considerably better cytotoxic liability (CC50 value of 260 μM) and consequently an improved SI of greater than 61. Therefore, we report the identification of a promising novel compound class that has the potential for further development of antiviral drugs against the CHIKV.