Design, Synthesis and Antiviral Activity of 2-(3-Amino-4-piperazinylphenyl)chromone Derivatives

Abstract

Previously, we have confirmed that the antiviral activities of the chromone derivatives were controlled by the type as well as the position of the substituents attached to the chromone core structure. In the course of our ongoing efforts to optimize the antiviral activity of the chromone derivatives, we have been attempting to derivatize the chromone scaffold via introduction of various substituents. In this proof-of-concept study, we introduced a 3-amino-4-piperazinylphenyl functionality to the chromone scaffold and evaluated the antiviral activities of the resulting chromone derivatives. The synthesized 2-(3-amino-4-piperazinylphenyl)-chromones showed severe acute respiratory syndrome-corona virus (SARS-CoV)-specific antiviral activity. In particular, the 2-pyridinylpiperazinylphenyl substituents provided the resulting chromone derivatives with selective antiviral activity. Taken together, this result indicates the possible pharmacophoric role of the 2-pyridinylpiperazine functionality attached to the chromone scaffold, which warrants further in-depth structure-activity relationship study.

Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds

“…Benzopyrone-based compounds, such as chromone, coumarin, and flavonoids have come to the attention of many investigators in recent years, due to their distinctive chemical and biological properties (1234). In this context, benzopyran and its derivatives constitute an important class of natural compounds representing a broad range of biological activities such as antibacterial and antiviral (56), anticancer (78), antioxidant (59), anti-inflammatory (10), monoamine oxidase B inhibition (111213), interaction with A3 adenosine receptor (1415), and anticoagulant effects (16). Moreover, they are important intermediates in the synthesis of several natural products and medicinal agents (1317).…”

Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands

“…As stated, 5-HPEC (5) showed neuroprotective activity against glutamate excitotoxicity; however, the potential mechanisms of action leading to the protective activity of 5-HPEC are not fully known. Through a series of biological screening experiments, it was possible to show that 5-HPEC (5) can act as a selective serotonin receptor 2B (5-HT 2B ) antagonist with reasonable affinity (pK i = 5.6).…”

“…As stated, 5-HPEC (5) showed neuroprotective activity against glutamate excitotoxicity; however, the potential mechanisms of action leading to the protective activity of 5-HPEC are not fully known. Through a series of biological screening experiments, it was possible to show that 5-HPEC (5) can act as a selective serotonin receptor 2B (5-HT 2B ) antagonist with reasonable affinity (pK i = 5.6). 13 The biological activity of chromones has largely been attributed to their antioxidative properties, and only recently have they been considered as potential ligands for G-protein coupled receptors like 5-HT 2B .…”

“…1 Flavones and isoflavones have been of interest for many years, as they have shown a broad range of biological activities, which include but are not limited to antioxidant, 3 anti-inflammatory, 4 and antiviral effects. 5 Recently, a relatively new class of naturally occurring chromones, the 2-(2-phenylethyl)chromones (4), have begun to receive growing attention. 2-(2-Phenylethyl)chromones were first described in 1978 and have a rare phenylethyl substituent at the C-2 position.…”

“…7−11 Of interest is 5-hydroxy-2-(2phenylethyl)chromone (5-HPEC, 5), which was isolated from Imperata cylindrica P. Beauv. (Poaceae) by Yoon et al 9 The impetus for isolating and characterizing 5-HPEC (5) was its neuroprotective activity against glutamate excitotoxicity in primary cultures of rat cortical cells. Glutamate excitotoxicity describes the process of neuronal cell death that occurs when ionotropic glutamate receptors (iGluR) are overstimulated due to disruptions in glutamate homeostasis that increase extracellular glutamate concentrations.…”