Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies

Jihad Sebhaoui; Sajda Ashraf; Shazia Iqbal; Melek Hajji; Burcu Belmen; Güldeniz Yeşilyurt; Essam Hanashalshahaby; Cheng Zhang; Mathias Uhlen; Jan Boren; Hasan Turkez; Adil Mardinoglu

doi:10.1016/j.molstruc.2024.141110

Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies

Jihad Sebhaoui, Sajda Ashraf, Shazia Iqbal, Melek Hajji^*, Burcu Belmen, Güldeniz Yeşilyurt, Essam Hanashalshahaby, Cheng Zhang, Mathias Uhlen, Jan Boren, Hasan Turkez, Adil Mardinoglu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

This study reports the synthesis and characterization of novel 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives. Compounds 3–12 were synthesized via N-alkylation of compound 2 with various alkyl, benzyl, and heterocyclic halides. Notably, compound 11 was formed through an unexpected intramolecular cyclization mechanism. Furthermore, derivatives 14–24, incorporating a 1,2,3-triazole ring, were prepared using a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between compound 12 and readily synthesized azides. All derivatives were characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Single-crystal X-ray diffraction analysis of derivatives 11 and 25 confirmed their molecular structures and revealed the presence of intramolecular cyclization and tautomerism. The crystal arrangements exhibited a range of noncovalent interactions, including N—H···O, C—H···O, N—H···π, and π-π stacking, which contributed to their stability in the solid state. A computational study using QTAIM and IGM topological analyses was conducted, offering insights into the nature and strength of intermolecular noncovalent interactions. Additionally, conceptual DFT calculations at wB97X-D/cc-pVTZ level provided insights into the global and local reactivity properties of both compounds. Molecular docking studies were conducted to evaluate their binding characteristics as inhibitors of the JNK3 target protein. Finally, in silico ADME (absorption, distribution, metabolism, and excretion) predictions were performed to assess their druglikeness and bioavailability. This work aims to advance our understanding of the chemistry, and potential applications of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives.

Original language	English
Article number	141110
Journal	JOURNAL OF MOLECULAR STRUCTURE
Volume	1326
DOIs	https://doi.org/10.1016/j.molstruc.2024.141110
Publication status	Published - 5 Apr 2025

Keywords

4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carbonitrile derivatives
ADME predictions
DFT calculations
Molecular docking
N-alkylation/CuAAC synthesis
X-ray crystallography

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10.1016/j.molstruc.2024.141110

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Sebhaoui, J., Ashraf, S., Iqbal, S., Hajji, M., Belmen, B., Yeşilyurt, G., Hanashalshahaby, E., Zhang, C., Uhlen, M., Boren, J., Turkez, H., & Mardinoglu, A. (2025). Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies. JOURNAL OF MOLECULAR STRUCTURE, 1326, Article 141110. https://doi.org/10.1016/j.molstruc.2024.141110

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title = "Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies",

abstract = "This study reports the synthesis and characterization of novel 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives. Compounds 3–12 were synthesized via N-alkylation of compound 2 with various alkyl, benzyl, and heterocyclic halides. Notably, compound 11 was formed through an unexpected intramolecular cyclization mechanism. Furthermore, derivatives 14–24, incorporating a 1,2,3-triazole ring, were prepared using a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between compound 12 and readily synthesized azides. All derivatives were characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Single-crystal X-ray diffraction analysis of derivatives 11 and 25 confirmed their molecular structures and revealed the presence of intramolecular cyclization and tautomerism. The crystal arrangements exhibited a range of noncovalent interactions, including N—H···O, C—H···O, N—H···π, and π-π stacking, which contributed to their stability in the solid state. A computational study using QTAIM and IGM topological analyses was conducted, offering insights into the nature and strength of intermolecular noncovalent interactions. Additionally, conceptual DFT calculations at wB97X-D/cc-pVTZ level provided insights into the global and local reactivity properties of both compounds. Molecular docking studies were conducted to evaluate their binding characteristics as inhibitors of the JNK3 target protein. Finally, in silico ADME (absorption, distribution, metabolism, and excretion) predictions were performed to assess their druglikeness and bioavailability. This work aims to advance our understanding of the chemistry, and potential applications of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives.",

keywords = "4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carbonitrile derivatives, ADME predictions, DFT calculations, Molecular docking, N-alkylation/CuAAC synthesis, X-ray crystallography",

author = "Jihad Sebhaoui and Sajda Ashraf and Shazia Iqbal and Melek Hajji and Burcu Belmen and G{\"u}ldeniz Ye{\c s}ilyurt and Essam Hanashalshahaby and Cheng Zhang and Mathias Uhlen and Jan Boren and Hasan Turkez and Adil Mardinoglu",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier B.V.",

year = "2025",

month = apr,

day = "5",

doi = "10.1016/j.molstruc.2024.141110",

language = "English",

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Sebhaoui, J, Ashraf, S, Iqbal, S, Hajji, M, Belmen, B, Yeşilyurt, G, Hanashalshahaby, E, Zhang, C, Uhlen, M, Boren, J, Turkez, H & Mardinoglu, A 2025, 'Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies', JOURNAL OF MOLECULAR STRUCTURE, vol. 1326, 141110. https://doi.org/10.1016/j.molstruc.2024.141110

TY - JOUR

T1 - Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles

T2 - Structural insights, reactivity profiles, and in-silico bioactivity studies

AU - Sebhaoui, Jihad

AU - Ashraf, Sajda

AU - Iqbal, Shazia

AU - Hajji, Melek

AU - Belmen, Burcu

AU - Yeşilyurt, Güldeniz

AU - Hanashalshahaby, Essam

AU - Zhang, Cheng

AU - Uhlen, Mathias

AU - Boren, Jan

AU - Turkez, Hasan

AU - Mardinoglu, Adil

PY - 2025/4/5

Y1 - 2025/4/5

N2 - This study reports the synthesis and characterization of novel 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives. Compounds 3–12 were synthesized via N-alkylation of compound 2 with various alkyl, benzyl, and heterocyclic halides. Notably, compound 11 was formed through an unexpected intramolecular cyclization mechanism. Furthermore, derivatives 14–24, incorporating a 1,2,3-triazole ring, were prepared using a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between compound 12 and readily synthesized azides. All derivatives were characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Single-crystal X-ray diffraction analysis of derivatives 11 and 25 confirmed their molecular structures and revealed the presence of intramolecular cyclization and tautomerism. The crystal arrangements exhibited a range of noncovalent interactions, including N—H···O, C—H···O, N—H···π, and π-π stacking, which contributed to their stability in the solid state. A computational study using QTAIM and IGM topological analyses was conducted, offering insights into the nature and strength of intermolecular noncovalent interactions. Additionally, conceptual DFT calculations at wB97X-D/cc-pVTZ level provided insights into the global and local reactivity properties of both compounds. Molecular docking studies were conducted to evaluate their binding characteristics as inhibitors of the JNK3 target protein. Finally, in silico ADME (absorption, distribution, metabolism, and excretion) predictions were performed to assess their druglikeness and bioavailability. This work aims to advance our understanding of the chemistry, and potential applications of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives.

AB - This study reports the synthesis and characterization of novel 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives. Compounds 3–12 were synthesized via N-alkylation of compound 2 with various alkyl, benzyl, and heterocyclic halides. Notably, compound 11 was formed through an unexpected intramolecular cyclization mechanism. Furthermore, derivatives 14–24, incorporating a 1,2,3-triazole ring, were prepared using a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between compound 12 and readily synthesized azides. All derivatives were characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Single-crystal X-ray diffraction analysis of derivatives 11 and 25 confirmed their molecular structures and revealed the presence of intramolecular cyclization and tautomerism. The crystal arrangements exhibited a range of noncovalent interactions, including N—H···O, C—H···O, N—H···π, and π-π stacking, which contributed to their stability in the solid state. A computational study using QTAIM and IGM topological analyses was conducted, offering insights into the nature and strength of intermolecular noncovalent interactions. Additionally, conceptual DFT calculations at wB97X-D/cc-pVTZ level provided insights into the global and local reactivity properties of both compounds. Molecular docking studies were conducted to evaluate their binding characteristics as inhibitors of the JNK3 target protein. Finally, in silico ADME (absorption, distribution, metabolism, and excretion) predictions were performed to assess their druglikeness and bioavailability. This work aims to advance our understanding of the chemistry, and potential applications of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC) derivatives.

KW - 4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carbonitrile derivatives

KW - ADME predictions

KW - DFT calculations

KW - Molecular docking

KW - N-alkylation/CuAAC synthesis

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85212573920&partnerID=8YFLogxK

U2 - 10.1016/j.molstruc.2024.141110

DO - 10.1016/j.molstruc.2024.141110

M3 - Article

AN - SCOPUS:85212573920

SN - 0022-2860

VL - 1326

JO - JOURNAL OF MOLECULAR STRUCTURE

JF - JOURNAL OF MOLECULAR STRUCTURE

M1 - 141110

ER -

Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies

Abstract

Keywords

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