Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives.
Bioorg Chem, 2020/09;102:104091.
Heiran R[1], Sepehri S[2], Jarrahpour A[3], Digiorgio C[4], Douafer H[5], Brunel JM[5], Gholami A[6], Riazimontazer E[6], Turos E[7]
Affiliations
PMID: 32717692DOI: 10.1016/j.bioorg.2020.104091
Impact factor: 5.307
Abstract
This study reports the synthesis and biological investigation of three series of novel monocyclic β-lactam derivatives bearing a morpholine ring substituent on the nitrogen. The resulting β-lactam adducts were synthesized via Staudinger's [2 + 2]-ketene-imine cycloaddition reaction. New synthesized products were fully characterized by spectral data and elemental analyses, and then evaluated for anti-inflammatory activity toward human inducible nitric oxide synthase (iNOS) and cytotoxicity toward HepG2 cell line. The compounds 3e, 3h, 3k, 5c, 5f, 6c, 6d and 6f showed higher activity with anti-inflammatory ratio values of 38, 62, 51, 72, 51, 35, 55 and 99, respectively, in comparison to the reference compound dexamethasone having an anti-inflammatory ratio value of 32. Hence, these compounds can be considered as potent iNOS inhibitors. They also exhibited IC50 values of 0.48 ± 0.04 mM, 0.51 ± 0.01 mM, 0.22 ± 0.02 mM, 0.12 ± 0.00 mM, 0.25 ± 0.05 mM, 0.82 ± 0.07 mM, 0.44 ± 0.04 mM and 0.60 ± 0.04 mM, respectively, in comparison with doxorubicin (IC50 < 0.01 mM) against HepG2 cells, biocompatibility and nontoxic behavior. In silico prediction of drug-likeness characteristic indicated that the compounds are compliant with the Lipinski and Veber rules. Molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response.
Keywords: 2-Azetidinone; Anti-inflammatory; In silico; Morpholine; NOS; Staudinger reactions
MeSH terms
Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Lipopolysaccharides; Mice; Molecular Docking Simulation; Molecular Structure; Morpholines; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Structure-Activity Relationship; beta-Lactams
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