These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX.
    Author: Omar YM, Abdu-Allah HHM, Abdel-Moty SG.
    Journal: Bioorg Chem; 2018 Oct; 80():461-471. PubMed ID: 29986191.
    Abstract:
    Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX-2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC50 = 70-100 nM) and selectivity index (SI = 220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC50 = 70 nM, SI = 220) with simultaneous inhibition of 15-LOX (IC50 = 11 µM). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC50 = 49 nM, SI = 308) and zileuton (15-LOX IC50 = 15 µM) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti-inflammatory activity at 3 h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization.
    [Abstract] [Full Text] [Related] [New Search]