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Design, synthesis, and biological evaluation of new 1,4‐diarylazetidin‐2‐one derivatives (β‐lactams) as selective cyclooxygenase‐2 inhibitors
Author(s) -
Arefi Hadi,
Naderi Nima,
Shemirani Amir B. Irani,
Kiani Falavarjani Mina,
Azami Movahed Mahsa,
Zarghi Afshin
Publication year - 2020
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900293
Subject(s) - pharmacophore , chemistry , moiety , stereochemistry , cyclooxygenase , selectivity , biological activity , structure–activity relationship , chemical synthesis , potency , lactam , molecular model , celecoxib , enzyme , in vitro , biochemistry , catalysis
A new series of 1,4‐diarylazetidin‐2‐one derivatives (β‐lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase‐2 (COX‐2) inhibitors. In vitro COX‐1 and COX‐2 inhibition studies showed that all compounds were selective inhibitors of the COX‐2 isozyme with IC 50 values in the 0.05–0.11 µM range, and COX‐2 selectivity indexes in the range of 170–703.7. Among the synthesized β‐lactams, 3‐methoxy‐4‐(4‐(methylsulfonyl)phenyl)‐1‐(3,4,5‐trimethoxyphenyl)azetidin‐2‐one ( 4j ) possessing trimethoxy groups at the N‐1 phenyl ring exhibited the highest COX‐2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX‐2 active site for interactions with Arg 513 . The structure–activity data acquired indicate that the β‐lactam ring moiety constitutes a suitable scaffold to design new 1,4‐diarylazetidin‐2‐ones with selective COX‐2 inhibitory activity.