Figure 1.
Representative structures of small-molecule CCR5 antagonists.
Figure 2.
The binding models for maraviroc and TAK-220.
Figure 3.
Proposed ‘Y shape’pharmacophore model of CCR5 antagonists.
Figure 4.
Synthesis of target piperazine derivatives 9a–h.
Reagents and conditions: a) CH3COONH4, CH2(COOH)2, C2H5OH, reflux, 12 h; b) LiAlH4, THF, 65°C, 3 h; c) corresponding benzoyl chlorides, Et3N, CH2Cl2, 0°C, 4 h; d) (COCl)2, DMSO, CH2Cl2, −78°C, 2 h; e) NaBH(OAc)3, Et3N, CH2Cl2, rt, 8 h.
Figure 5.
Synthesis of target piperazine derivatives 13a–d and 17.
Reagents and conditions: a) 2-(4-chlorophenyl)acetonitrile, K2CO3, DMSO, reflux, 18 h; b) 4-cyanobenzoyl chloride, Et3N, CH2Cl2, rt, 3 h; c) 4-(chloromethyl)benzonitrile, THF, reflux, 2.5 h; d) NaBH(OAc)3, CH2Cl2, rt, 12 h; e) 4-fluorobenzoyl chloride, Et3N, CH2Cl2, rt, 3 h; f) EDC.HCl, CH2Cl2, rt, 8 h; g) 1-bromo-3-chloropropane, KI, CH3CN, MWI, 15 min; h) 4-fluorobenzoyl chloride, Et3N, CH2Cl2, 0°C, 5 h; i) KI, K2CO3, CH3CN, reflux, 24 h.
Figure 6.
Synthesis of target piperazine derivatives 23a–h.
Reagents and conditions: a) SOCl2, EtOH, 0°C, 0.5 h, rt, 3 h, reflux, 1 h; b) (Boc)2O, NaOH, H2O, Dioxane, rt, 12 h; c) DIBAL-H, CH2Cl2, −78°C, 3 h; d) NaBH(OAc)3, CH2Cl2, rt, 8 h; e) 6NHCl, EtOAc, rt, 3 h; f) EDC.HCl, CH2Cl2, rt, 6 h.
Table 1.
Effects of different substituents R1–R4 and link between ring 2 and 3 on CCR5 fusion activity.
Table 2.
Modification of the p-fluorophenyl moiety of 9e.
Table 3.
Antiviral activity of 9e–g, 23a–c, and 23h.