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<p>This study introduces a novel series of azaheterocyclic compounds (<b>4</b>, <b>7</b>, <b>11</b>, <b>14</b>, <b>16</b>, and <b>20</b>), synthesized through reactions like Guareschi, Knoevenagel condensation, and diazo coupling, resulting in diverse derivatives, including tetrahydropyridines, pyrimidine-2-thiones, pyrazolo[5,1-<i>c</i>][1,2,4]triazines, and thiadiazole hybrids. Computational evaluations using TD-DFT (PBE0) with the 6-311G** (d,p) basis set reveal distinct stability and reactivity profiles, with compounds <b>11</b> and <b>14</b> exhibiting particularly promising stability and electrophilicity that may enhance their antitumor potential compared to doxorubicin <b>DOX</b>. Additionally, thermodynamic analyses indicate a general stability advantage for the <i>E</i> (<i>trans</i>) isomers of selected compounds, providing insight into their structural preferences. This enhanced stability can be attributed to factors such as reduced steric hindrance, stronger intermolecular interactions, and optimized molecular geometry. Cytotoxicity testing across cancer cell lines (MCF-7, HepG2, HCT116) showed that compound <b>4</b> possesses notable anticancer activity, while compound <b>20</b> displayed even greater potency. The suggestion of favorable physicochemical properties, including good oral bioavailability and lower toxicity compared to Doxorubicin, is promising. Molecular docking studies further confirmed effective interactions within the TGFβR1 kinase domain, highlighting these compounds as promising therapeutic agents targeting the TGF-β pathway in cancer treatment.</p>

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Synthesis and Computational Evaluation of Azaheterocyclic Inhibitors Targeting TGFβRI: Integrating TD-DFT, Physicochemical Profiling, Molecular Docking, and Molecular Dynamics

  • 期刊论文

  • 发表日期：

    2025年4月18日

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  • Samir Bondock,
  • Nada Alabbad,
  • Rehab H. Abd El-Aleam,
  • Ahmed A. Elhenawy,
  • Moaz M. Abdou

摘要

This study introduces a novel series of azaheterocyclic compounds (4, 7, 11, 14, 16, and 20), synthesized through reactions like Guareschi, Knoevenagel condensation, and diazo coupling, resulting in diverse derivatives, including tetrahydropyridines, pyrimidine-2-thiones, pyrazolo[5,1-c][1,2,4]triazines, and thiadiazole hybrids. Computational evaluations using TD-DFT (PBE0) with the 6-311G** (d,p) basis set reveal distinct stability and reactivity profiles, with compounds 11 and 14 exhibiting particularly promising stability and electrophilicity that may enhance their antitumor potential compared to doxorubicin DOX. Additionally, thermodynamic analyses indicate a general stability advantage for the E (trans) isomers of selected compounds, providing insight into their structural preferences. This enhanced stability can be attributed to factors such as reduced steric hindrance, stronger intermolecular interactions, and optimized molecular geometry. Cytotoxicity testing across cancer cell lines (MCF-7, HepG2, HCT116) showed that compound 4 possesses notable anticancer activity, while compound 20 displayed even greater potency. The suggestion of favorable physicochemical properties, including good oral bioavailability and lower toxicity compared to Doxorubicin, is promising. Molecular docking studies further confirmed effective interactions within the TGFβR1 kinase domain, highlighting these compounds as promising therapeutic agents targeting the TGF-β pathway in cancer treatment.