Design, synthesis, and biological evaluation of N-arylpiperazine derivatives as interferon inducers

Yeonjeong Chu; B Raja Sekhara Reddy; V Pratap Reddy Gajulapalli; K Sudhakar Babu; Eunha Kim; Sanghee Lee

doi:10.1016/j.bmcl.2020.127613

Design, synthesis, and biological evaluation of N-arylpiperazine derivatives as interferon inducers

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127613. doi: 10.1016/j.bmcl.2020.127613. Epub 2020 Oct 16.

Authors

Yeonjeong Chu¹, B Raja Sekhara Reddy², V Pratap Reddy Gajulapalli³, K Sudhakar Babu⁴, Eunha Kim⁵, Sanghee Lee⁶

Affiliations

¹ Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea; Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
² Department of Chemistry, Sri Krishnadevaraya University, Anantapur, India.
³ Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
⁴ Department of Chemistry, Sri Krishnadevaraya University, Anantapur, India. Electronic address: drksbabu9@gmail.com.
⁵ Department of Molecular Science and Technology, Ajou University, Suwon, South Korea. Electronic address: ehkim01@ajou.ac.kr.
⁶ Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul, South Korea. Electronic address: slee19@kist.re.kr.

Abstract

Type I Interferon (IFN) signaling plays an important role in the immune defense system against virus infection and in the innate immune response, thus IFNs are widely used as anti-viral agents and treatment for immune disorder or cancer. However, there is a growing demand for novel small-molecule IFN inducer due to tolerance, toxicity, or short duration of action following direct administration of IFNs. In this study, we assessed arylpiperazine (ARP) as a new core skeleton of IFN inducer. To investigate structure-activity relationship, we designed and synthesized a series of ARP analogues and evaluated the ability to stimulate IFN response in THP-1 human monocyte cells. Compound 5i was identified as a potent type I IFN inducer as it significantly increased cytokine secretion and increased expression of various IFN-stimulating genes which are representative biomarkers of type I IFN pathway. Our results suggested a beneficial therapeutic potential of 5i as an anti-viral agent.

Keywords: Anti-viral agent; Arylpiperazine; Innate immunity; Interferon inducer; type I Interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
Humans
Immunity, Innate / drug effects
Interferon Inducers / chemical synthesis
Interferon Inducers / chemistry*
Interferon Inducers / pharmacology*
Interferon Type I / agonists
Interferon Type I / immunology
Monocytes / drug effects*
Monocytes / immunology
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology*
THP-1 Cells

Substances

Interferon Inducers
Interferon Type I
Piperazines