Synthesis of novel tetrahydrobenzo[b]thiophene-3-carbonitrile (THBTC)-based heterocycles: Structural insights, reactivity profiles, and in-silico bioactivity studies
A B S T R A C T
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 variousalkyl, benzyl, and heterocyclic halides. Notably, compound 11 was formed through an unexpected intramolecularcyclization mechanism. Furthermore, derivatives 14–24, incorporating a 1,2,3-triazole ring, wereprepared using a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between compound 12 andreadily 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 andrevealed the presence of intramolecular cyclization and tautomerism. The crystal arrangements exhibited a rangeof noncovalent interactions, including N—H⋅⋅⋅O, C—H⋅⋅⋅O, N—H⋅⋅⋅π, and π-π stacking, which contributed to theirstability 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, conceptualDFT calculations at wB97X-D/cc-pVTZ level provided insights into the global and local reactivityproperties of both compounds. Molecular docking studies were conducted to evaluate their binding characteristicsas inhibitors of the JNK3 target protein. Finally, in silico ADME (absorption, distribution, metabolism, andexcretion) predictions were performed to assess their druglikeness and bioavailability. This work aims to advanceour understanding of the chemistry, and potential applications of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile(THBTC) derivatives.
