Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity

Taehun Kim, Woo Seung Son, Mohammad Neaz Morshed, Ashwini M. Londhe, Seo Yun Jung, Jong Hyun Park, Woo Kyu Park, Sang Min Lim, Ki Duk Park, Sung Jin Cho, Kyu-Sung Jeong, Jiyoun Lee, Ae Nim Pae

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.
Original languageEnglish
Pages (from-to)240-256
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume141
DOIs
Publication statusPublished - 2017 Sep 21

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Alzheimer Disease
Mitochondrial Proteins
Derivatives
Adenosine Triphosphate
Lead compounds
Membranes
Proteins
Mitochondrial Membrane Potential
Depolarization
Mitochondrial Membranes
Modulators
Inhibitory Concentration 50
Libraries
Toxicity
Assays
Recovery
Therapeutics
Pharmaceutical Preparations
3-(5-nitrofuryl)-7-(5-nitrofurfurylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole
1,2,4-triazine

Cite this

Kim, Taehun ; Son, Woo Seung ; Morshed, Mohammad Neaz ; Londhe, Ashwini M. ; Jung, Seo Yun ; Park, Jong Hyun ; Park, Woo Kyu ; Lim, Sang Min ; Park, Ki Duk ; Cho, Sung Jin ; Jeong, Kyu-Sung ; Lee, Jiyoun ; Pae, Ae Nim. / Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 141. pp. 240-256.
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title = "Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity",
abstract = "Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.",
author = "Taehun Kim and Son, {Woo Seung} and Morshed, {Mohammad Neaz} and Londhe, {Ashwini M.} and Jung, {Seo Yun} and Park, {Jong Hyun} and Park, {Woo Kyu} and Lim, {Sang Min} and Park, {Ki Duk} and Cho, {Sung Jin} and Kyu-Sung Jeong and Jiyoun Lee and Pae, {Ae Nim}",
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Kim, T, Son, WS, Morshed, MN, Londhe, AM, Jung, SY, Park, JH, Park, WK, Lim, SM, Park, KD, Cho, SJ, Jeong, K-S, Lee, J & Pae, AN 2017, 'Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity', European Journal of Medicinal Chemistry, vol. 141, pp. 240-256. https://doi.org/10.1016/j.ejmech.2017.09.033

Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity. / Kim, Taehun; Son, Woo Seung; Morshed, Mohammad Neaz; Londhe, Ashwini M.; Jung, Seo Yun; Park, Jong Hyun; Park, Woo Kyu; Lim, Sang Min; Park, Ki Duk; Cho, Sung Jin; Jeong, Kyu-Sung; Lee, Jiyoun; Pae, Ae Nim.

In: European Journal of Medicinal Chemistry, Vol. 141, 21.09.2017, p. 240-256.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity

AU - Kim, Taehun

AU - Son, Woo Seung

AU - Morshed, Mohammad Neaz

AU - Londhe, Ashwini M.

AU - Jung, Seo Yun

AU - Park, Jong Hyun

AU - Park, Woo Kyu

AU - Lim, Sang Min

AU - Park, Ki Duk

AU - Cho, Sung Jin

AU - Jeong, Kyu-Sung

AU - Lee, Jiyoun

AU - Pae, Ae Nim

PY - 2017/9/21

Y1 - 2017/9/21

N2 - Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.

AB - Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.

U2 - 10.1016/j.ejmech.2017.09.033

DO - 10.1016/j.ejmech.2017.09.033

M3 - Article

C2 - 29031071

VL - 141

SP - 240

EP - 256

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -