Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

• Published in: ACS chemical neuroscience Vol. 11; no. 15; pp. 2348 - 2360
• Main Authors: Lu, Junfeng, Chen, Chen, Deng, Xiaobing, Mak, Marvin SH, Zhu, Zeyu, He, Xixin, Liang, Jinhao, Maddili, Swetha K, Tsim, Karl W. K, Han, Yifan, Pi, Rongbiao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05-08-2020
• Subjects: Animals; Brain Injuries, Traumatic - drug therapy; Cyclic Nucleotide Phosphodiesterases, Type 4; Mice; ortho-Aminobenzoates; Rolipram - pharmacology; Tranilast; Rolipram; CREB; inflammation; neuroprotection; traumatic brain injury; oxidative stress
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.0c00339

Traumatic 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.