Synthesis and Biological Evaluation of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H)‐ones as Potent and Safer Anti‐inflammatory and Analgesic Agents

Abstract

A series of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H)‐ones was synthesized and the structures were established using various spectroscopic techniques. The target compounds were screened for anti‐inflammatory and analgesic activities at 20 and 40 mg/kg. The safety of the synthesized derivatives was evaluated by assessing anti‐platelet activity and ulcer index. The obtained pharmacological data revealed that 6‐morpholinyl derivatives 4a–12a were found to be somewhat more potent than 6‐piperidinyl derivatives 4b–6b. The 6‐morpholinyl substituted pyridazinone 12a exhibited maximum anti‐inflammatory and analgesic activities. Homoveratrylamine substituted compounds 6a and 6b emerged as promising leads in both the series with good anti‐inflammatory and analgesic activities without any ulcerogenicity. Anti‐platelet activity results of the compounds of both the series showed significantly low bleeding time in comparison with standard drug aspirin indicating the cardiovascular safety of new pyridazinones.

Anti‐inflammatory activity of pyridazinones: A review

“…The pyridazinone 25 showed the highest anti-inflammatory activity (70.96% inhibition after 4 h) at a dose of 40 mg/kg, while compounds 21). These compounds displayed superior gastrointestinal safety at both tested doses in comparison with standard drug indomethacin [59] (Figure 21).…”

“…The pyridazinone 25 showed the highest anti‐inflammatory activity (70.96% inhibition after 4 h) at a dose of 40 mg/kg, while compounds 26 and 27 exerted good anti‐inflammatory activity (61.29% and 52.17% edema inhibition, respectively, after 4 h at a dose of 40 mg/kg) compared to indomethacin (80.8% edema inhibition after 4 h at a dose of 20 mg/kg) and celecoxib (82.61% edema inhibition after 4 h at a dose of 20 mg/kg) (Figure 21). These compounds displayed superior gastrointestinal safety at both tested doses in comparison with standard drug indomethacin [ 59 ] (Figure 21).…”

Polymorphism of 2-(5-benzyl-6-oxo-3-phenyl-1,6-dihydropyridazin-1-yl)acetic acid with two monoclinic modifications: crystal structures and Hirshfeld surface analyses

“…Pyridazin-3(2H)-ones are an important family of heterocycles because of their great chemical reactivity (Chelfi et al, 2015;Zarrouk et al, 2010), with new products reported recently (Chakraborty et al, 2018;El Kalai et al, 2019a). In addition, the importance of pyridazinones in medicinal chemistry has increased in recent years thanks to their pharmacological properties, including anticancer (Yarden & Caldes, 2013), antihypertensive (Siddiqui et al, 2011), antibacterial (Akhtar et al, 2016), anti-HIV (Livermore et al, 1993), anti-inflammatory (Singh et al, 2017), antidepressant (Boukharsa et al, 2016), anti-convulsant (Partap et al, 2018) and cardiotonic (Costas et al, 2015) activities. Several pyridazinone-based products are already present in the pharmaceutical market such as Minaprine (Sotelo et al, 2003), Azanrinone (Mahmoodi et al, 2014), Indolidan (Abouzid et al, 2008) and Levosimendan (Archan & Toller, 2008).…”