Article 2025 · 1 atıf

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

Sebhaoui, Jihad, Ashraf, Sajda, Iqbal, Shazia, Hajji, Melek, Belmen, Burcu, Yesilyurt, Guldeniz, Hanashalshahaby, Essam, Zhang, Cheng, Uhlen, Mathias, Boren, Jan, Turkez, Hasan, Mardinoglu, Adil

Özet

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 1 H NMR, 13 C 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 & sdot;& sdot;& sdot;O, C-H & sdot;& sdot;& sdot;O, N-H & sdot;& sdot;& sdot;it, and it-it 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.

Anahtar Kelimeler

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

WoS Kategorileri

Chemistry, Physical

Sürdürülebilir Kalkınma Amaçları

Sağlık ve Kaliteli Yaşam

Künye

Dergi: JOURNAL OF MOLECULAR STRUCTURE
Yıl: 2025
Cilt: 1326
ISSN: 0022-2860
eISSN: 1872-8014
DOI: 10.1016/j.molstruc.2024.141110
WoS UID: WOS:001381318800001

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