A new class of pyrazino[1,2-a]benzimidazole derivatives possessing the SO 2 Me pharmacophore at the para position of the C-3 phenyl ring was designed, synthesized, and tested for their cyclooxygenase-2 (COX-2) inhibitory, anti-cancer and anti-platelet aggregation activities. In vitro COX-1/COX-2 inhibition studies showed that 2-(4methylphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2a]benzimidazole (5g) was the most potent COX-2 inhibitor (IC 50 = 0.08 μM) and 2-(3,4,5-trimethoxyphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2-a]benzimidazole (5m) had the highest selectivity index (SI > 909).Cytotoxicity of the synthesized compounds was also determined against the MCF-7 cell line. Most compounds were cytotoxic against MCF-7 cells and our results showed that compound 5m exhibited the highest anti-proliferative activity compared to the reference compound, cisplatin. Our data also indicated that compound 5k was the most potent platelet aggregation inhibitor according to aggregometry test results. K E Y W O R D S anti-cancer, anti-platelet aggregation, COX-2 inhibitory, docking study, MCF-7, pyrazinobenzimidazole 1 | INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) continue to be one of the most widely used prescription and over-the-counter medications. These drugs interfere with inflammatory mediators (prostaglandins) biosynthesis by inhibiting cyclooxygenase (COX) The pharmacologic effects of NSIADs are attributed to inhibition of COX-1 and COX-2 enzymes. COX-1 produces prostaglandins involved in normal cellular activity such as maintenance of kidney functions and gastric mucosa protection; COX-2 produces prostaglandins at inflammatory sites. [1] Most NSAIDs inhibit both COX-1 and COX-2, but with varying degrees of selectivity. The evidence shows that antiinflammatory activities of NSAIDs are due to the inhibition of COX-2, whereas the ulcerogenic adverse effects are associated with the inhibition of COX-1. The differences in the amino acid sequence of COX-1 and COX-2 binding sites provided valuable strategy for the design of selective COX-2 inhibitors. The main difference involves the presence of a second pocket within COX binding site, which is more available in COX-2, whereas restricted in COX-1 due to the extra steric bulk of Ile 523 in COX-1. The larger volume of COX-2 active site allows larger molecules to enter the active site and inhibit COX-2, selectively. [2] Based upon this, many selective COX-2 inhibitors have been designed and entered the market. These medicines have fewer Arch Pharm Chem Life Sci. 2019;352:e1800265.wileyonlinelibrary.com/journal/ardp
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 IC50 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 Arg513. 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.
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