In the present study, we synthesized and evaluated the anti-inflammatory effects of the two component hybrids, caffeic acid (CA)-ferulic acid (FA), FA-Tryptamine (Trm), CA-Piperonyl Triazol (PT) and FA-PT. Of these five hybrids, CA-FA had the most potent inhibitory effect on butyrylcholinesterase (BuChE) activity. The CA containing hybrids, CA-FA, CA-Trm, and CA-PT, dose-dependently inhibited LPS-induced nitric oxide (NO) generation in BV2 cells, whereas FA-PT, FA-Trm, CA, FA, Trm, and PT did not. Although CA-FA, CA-Trm and CA-PT had similar inhibitory effects on LPS-induced NO generation, CA-FA best protected BV2 cells from LPS-induced cell death. CA-FA, but not CA or FA, dose-dependently inhibited LPS-induced up-regulations of NO synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in BV2 and RAW264.7 cells. Furthermore, CA-FA inhibited LPS-induced iNOS, COX-2, interleukin-6, and interleukin-1 beta mRNA expressions in BV2 cells. CA-FA also inhibited the LPS-induced phosphorylations of STAT3, Akt, and I kappa B and selectively inhibited LPS-induced NF-kappa B activation. Overall, our data suggest that CA-FA has BuChE inhibitory effects and down-regulates inflammatory responses by inhibiting NF-kappa B, which indicates CA-FA be viewed as a potential therapeutic agent for the treatment of inflammatory diseases of the peripheral system and central nervous systems. (C) 2019 Elsevier Inc. All rights reserved.