cn0c00339_si_001.pdf (4.07 MB)
Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury
journal contribution
posted on 2020-07-23, 09:43 authored by Junfeng Lu, Chen Chen, Xiaobing Deng, Marvin SH Mak, Zeyu Zhu, Xixin He, Jinhao Liang, Swetha K. Maddili, Karl W. K. Tsim, Yifan Han, Rongbiao PiTraumatic
brain injury (TBI) is a prevalent public healthcare concern
frequently instigated by mechanical shock, traffic, or violence incidents,
leading to permanent nerve damage, and there is no ideal treatment
for it yet. In this study, a series of Rolipram–Tranilast hybrids
were designed and synthesized. The neuroprotective activities of the
Rolipram–Tranilast hybrids were evaluated both in vitro and
in vivo. Compound 5 has been identified as the strongest
neuroprotective molecule among the series with robust anti-oxidant
and anti-inflammatory potentials. Compound 5 significantly
increased the heme oxygenase-1 (HO-1) levels and the phosphorylated
cAMP response elements binding protein (p-CREB) while it down-regulated
phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile
in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment
of TBI and other central nervous system (CNS) diseases associated
with PDE4B and oxidative stress.