Design, synthesis, and biological evaluation of new pyrazino[1,2‐a]benzimidazole derivatives as selective cyclooxygenase (COX‐2) inhibitors

Abstract

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

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

“…The compounds displayed a commendable selectivity index of 909 for COX‐2 over COX‐1 isoenzyme. The compounds demonstrated marked anti‐proliferative properties against the MCF‐7 breast cancer cell‐line, comparable to the commercial anticancer drug cisplatin and inhibited the aggregation of platelets in human platelet rich plasma with arachidonic acid in the aggregometry test (Movahed, Daraei, Shahosseini, Esfahanizadeh, & Zarghi, 2019). Since the over‐expression of COX‐2 manifests cancer condition, therefore the antiproliferative activity of the test compounds suggested their high efficacy toward the attenuation of the complications instigated by the COX‐2 isoenzyme (Bakhle, 2001).…”

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…The benzimidazole-imidazo[1,2-a]pyrazines 53a,b (GI 50 : 0.8-7.0 µM and 1.9-3.0 µM, respectively, MTT assay) possessed potent broadspectrum activity against a panel of 60 cancer cell lines derived from NSCLC, leukemia, colon cancer, ovarian cancer, CNS cancer, melanoma, renal cancer, breast cancer, and prostate cancer. [113][114][115] Hence, both compounds were worthy of further investigation. ASP4132 (54, IC 50 : 30.0 nM, CellTiter-Glo ® luminescent cell viability assay), a benzimidazole-pyridine hybrid, was highly active against MDA-MB-453 breast cancer cells and was stable in human liver microsomes (HLM CL int : 61.0 ml/min/kg).…”

Antiproliferative activity of new derivatives of pyrazino[1,2‐a]benzimidazole: Integrated cell‐based assay and computational studies with divalent magnesium, iron, and copper ions

“…According to the previous study, the general synthetic route of the target compounds is described in Figure 1. [14] The reaction of 2-acetylbenzimidazole [1] and α-bromo-4-(methylsulfonyl)acetophenone [2] in the presence of K 2 CO 3 , afford 1-(2-4-(methylsulfonyl)phenyl-2oxoethyl)−2-acetylbenzimidazole [3] as the intermediate. The final compounds,…”