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Novel pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines: design, synthesis, and in vivo TNF-α inhibitory activity

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Abstract

Novel pyrrolo[2,3-d]pyrimidines 5a–j, 6a–j and pyrrolo[2,3-b]pyridines 7a–h; incorporating the common vicinal diaryl motif of tumor necrosis factor-α (TNF-α) inhibitors, were synthesized starting from 2-amino-pyrrole-3-carbonitriles 1a–h. The structures of synthesized compounds were elucidated by spectral data (IR, NMR, and MS) and elemental analyses. Representative compounds were evaluated for their ability to inhibit lipopolysaccharide-induced TNF-α production in vivo in rat at 25 mg/kg p.o. Structure activity relationships are described. The pyrrolo[2,3-d]pyrimidines displayed better inhibitory activity than the pyrrolo[2,3-b]pyridines. The most potent among the biologically tested compounds was the pyrrolopyrimidine 5h (N-(4-ethoxyphenyl)-2-(4-oxo-6-phenyl-7-(pyridine-4-yl)-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)acetamide),showing TNF-α inhibitory activity (96 %) comparable to that of dexamethasone (91 %).

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom, Egypt

    Khaled M. H. Hilmy

  2. Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt

    Hanan G. Abdul-Wahab, Dalia H. Soliman & Maha M. A. Khalifa

  3. Developmental Pharmacology Department, National Organization for Drug Control and Research, Agouza, Egypt

    Amany M. Hegab

  4. P.O. Box 73, Shoubra Misr, Cairo, Egypt

    Khaled M. H. Hilmy

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  1. Khaled M. H. Hilmy
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  2. Hanan G. Abdul-Wahab
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  3. Dalia H. Soliman
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  4. Maha M. A. Khalifa
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  5. Amany M. Hegab
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Correspondence to Khaled M. H. Hilmy.

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Hilmy, K.M.H., Abdul-Wahab, H.G., Soliman, D.H. et al. Novel pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines: design, synthesis, and in vivo TNF-α inhibitory activity. Med Chem Res 24, 2097–2110 (2015). https://doi.org/10.1007/s00044-014-1281-9

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