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<p>A series of thiadiazole-pyrrole and -thiophene hybrid compounds were synthesized, and their structures were elucidated using IR, NMR, and MS techniques. The hybrids DFT/B3LYP modeling revealed planar structures for the phenyl pyrroles 3a-e, but the phenylamino thiophenes 6 and 7a-c were non-planar. The FMOs plots of phenyl pyrroles 3a-e presented matching HOMO and LUMO, however the phenylamino thiophenes 6 and 7a-c displayed alternative configurations. Moreover, the in vitro cytotoxic efficacy of the produced hybrids was evaluated against three distinct human cancer cells using the MTT assay. Compounds 3c, 3e, and 7b established the highest activity against HT-29 and MCF-7 cell lines, while exhibiting lower toxicity to normal cells, emphasizing their potentiality as candidates for development of innovative anticancer drugs. In addition, a molecular docking study of the manufactured derivatives performed against essential amino acid residues in the target PDB:3NU0 protein, and the results were compared to doxorubicin. Hybrids 6, 7a, and 7c disclosed strong and diverse binding interactions, comprising H-bonding, π–π, and π–H stacking. Meanwhile, in silico pharmacokinetic analysis revealed the roles of molecular weight, polarity, and hydrogen bonding in oral bioavailability of the thiadiazole hybrids. The analogues 2, 3a, 3b, and 3e demonstrated the optimum pharmacokinetic properties.</p>

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Synthesis of Thiadiazole-Pyrrole and Thiadiazole-Thiophene Hybrid Compounds: Molecular Modeling as Anticancer Agents

  • 期刊论文

  • 发表日期：

    2025年12月8日

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  • Samar J. Almehmadi,
  • Hadeer Mattar,
  • Nuha M. Halawani,
  • Nadiyah M. Alshammari,
  • Saeed Samman,
  • Hossa F. Alshareef,
  • Hanadi A. Katouah,
  • Fathy Shaaban

摘要

A series of thiadiazole-pyrrole and -thiophene hybrid compounds were synthesized, and their structures were elucidated using IR, NMR, and MS techniques. The hybrids DFT/B3LYP modeling revealed planar structures for the phenyl pyrroles 3a-e, but the phenylamino thiophenes 6 and 7a-c were non-planar. The FMOs plots of phenyl pyrroles 3a-e presented matching HOMO and LUMO, however the phenylamino thiophenes 6 and 7a-c displayed alternative configurations. Moreover, the in vitro cytotoxic efficacy of the produced hybrids was evaluated against three distinct human cancer cells using the MTT assay. Compounds 3c, 3e, and 7b established the highest activity against HT-29 and MCF-7 cell lines, while exhibiting lower toxicity to normal cells, emphasizing their potentiality as candidates for development of innovative anticancer drugs. In addition, a molecular docking study of the manufactured derivatives performed against essential amino acid residues in the target PDB:3NU0 protein, and the results were compared to doxorubicin. Hybrids 6, 7a, and 7c disclosed strong and diverse binding interactions, comprising H-bonding, π–π, and π–H stacking. Meanwhile, in silico pharmacokinetic analysis revealed the roles of molecular weight, polarity, and hydrogen bonding in oral bioavailability of the thiadiazole hybrids. The analogues 2, 3a, 3b, and 3e demonstrated the optimum pharmacokinetic properties.