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

Julia Moesslacher; Verena Battisti; Leen Delang; Johan Neyts; Rana Abdelnabi; Gerhard Pürstinger; Ernst Urban; Thierry Langer

doi:10.1021/acsmedchemlett.9b00662

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

ACS Med Chem Lett. 2020 Mar 5;11(5):906-912. doi: 10.1021/acsmedchemlett.9b00662. eCollection 2020 May 14.

Authors

Julia Moesslacher¹, Verena Battisti², Leen Delang³, Johan Neyts³, Rana Abdelnabi³, Gerhard Pürstinger¹, Ernst Urban², Thierry Langer²

Affiliations

¹ University of Innsbruck, Department of Pharmacy, Innrain 80/82, 6020 Innsbruck, Austria.
² University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, A-1090 Vienna, Austria.
³ KU Leuven Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, B-3000 Leuven, Belgium.

Abstract

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.