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

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.

Figure 1

For optimization, we divided the initial hit 1 into five parts. Compounds with modifications at the same part of the molecule are summarized to “Groups”.

Scheme 1. Synthesis of the Initial Hit 1

Reagents and conditions: (a) EtOH, 24–48 h, rt; (b) EtOH, microwave, 3 min, 155 °C, 250 W, 12 bar, tert-butyl piperazine-1-carboxylate; (c) 4.5 M HCl, dioxane/THF, 24 h rt; (d) DCM, N(CH₂CH₃)₃, 24 h rt, 4-fluorobenzenesulfonyl chloride.

Scheme 2. Synthesis of the Compounds from Group A (5a–5r) and Group B (6a, 6b)

Reagents and condition: (a) DCM, N(CH₂CH₃)₃, 24 h rt.

Scheme 3. Synthesis of the Compounds from Group C (7a, 7b)

Reagents and conditions: (a) EtOH, microwave, 3 min, 155 °C, 250 W, 12 bar; 3b, tert-butyl 1,4-diazepane-1-carboxylate; 4c, 1,2,3,4-tetrahydroquinoxaline; (b) 4b, 4.5 M HCl, dioxane/THF, 24 h rt; (c) DCM, N(CH₂CH₃)₃, 24 h rt, 4-fluorobenzenesulfonyl chloride.

Scheme 4. Synthesis of the Compounds from Group D (8a–8d), from Group E (9a–9d), and 10a, 10b

Reagents and conditions: (a) EtOH, 24–48 h rt; 2b/2j, propan-2-amine; 2c, 2-methylpropan-2-amin; 2d, sodium ethoxide; 2e, pyrrolidine; 2f–i, ethylamine; (b) EtOH, microwave, 3 min, 155 °C, 250 W, 12 bar, tert-butyl piperazine-1-carboxylate; (c) 4.5 M HCl, dioxane/THF, 24 h rt; (d) DCM, N(CH₂CH₃)₃, 24 h rt, 4-fluorobenzenesulfonyl chloride.

Scheme 5. Synthesis of 11a–11c

Reagents and conditions: (a) DCM, N(CH₂CH₃)₃, 24 h rt; 11a/11b, 4-chlorobenzoyl chloride; 11c, 4-fluorobenzoyl chloride.