Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32
Imidazo[1,2-<i>b</i>]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-<i>b</i>]pyridazine comp...
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MDPI AG
2021-09-01
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| author | Rakesh Kumar Sharma Manisha Singh Khagendra Ghimeray Pinky Juneja Gagan Dev Sridhar Pulavarthi Sabbasani Rajasekhara Reddy Ravi Shankar Akundi |
| author_facet | Rakesh Kumar Sharma Manisha Singh Khagendra Ghimeray Pinky Juneja Gagan Dev Sridhar Pulavarthi Sabbasani Rajasekhara Reddy Ravi Shankar Akundi |
| author_sort | Rakesh Kumar Sharma |
| collection | DOAJ |
| description | Imidazo[1,2-<i>b</i>]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-<i>b</i>]pyridazine compounds (5c and 5h) showed potent acetylcholinesterase (AChE) inhibitory activity (IC<sub>50</sub> 40–50 nM), which we have previously reported. In this study, we wanted to test the biological efficacy of these compounds. Cytotoxicity assays showed that compound 5h mediated greater cell death with over 43% of cells dead at 100 μM and activation of caspase 3-mediated apoptosis. On the other hand, compound 5c mediated a dose-dependent decrease in cell proliferation. Both compounds showed cell cycle arrest in the G<sub>0</sub>/G<sub>1</sub> phase and reduced cellular ATP levels leading to activation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitochondrial oxidative stress. It has to be noted that all these effects were observed at doses beyond 10 μM, 200-fold above the IC<sub>50</sub> for AChE inhibition. Both compounds also inhibited bacterial lipopolysaccharide-mediated cyclooxygenase-2 and nitric oxide release in primary rat microglial cells. These results suggested that the substituted imidazo (1,2-<i>b</i>) pyridazine compounds, which have potent AChE inhibitory activity, were also capable of antiproliferative, anti-migratory, and anti-inflammatory effects at higher doses. |
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| language | English |
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| series | Molecules |
| spelling | doaj.art-b7147101cb5b4cd192dc3036732e5bb92023-11-22T11:02:20ZengMDPI AGMolecules1420-30492021-09-012617531910.3390/molecules26175319Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32Rakesh Kumar Sharma0Manisha Singh1Khagendra Ghimeray2Pinky Juneja3Gagan Dev4Sridhar Pulavarthi5Sabbasani Rajasekhara Reddy6Ravi Shankar Akundi7Neuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaNeuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaNeuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaNeuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaNeuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaDepartment of Chemistry, Vellore Institute of Technology (VIT), School of Advanced Sciences, Vellore 632014, IndiaDepartment of Chemistry, Vellore Institute of Technology (VIT), School of Advanced Sciences, Vellore 632014, IndiaNeuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, IndiaImidazo[1,2-<i>b</i>]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-<i>b</i>]pyridazine compounds (5c and 5h) showed potent acetylcholinesterase (AChE) inhibitory activity (IC<sub>50</sub> 40–50 nM), which we have previously reported. In this study, we wanted to test the biological efficacy of these compounds. Cytotoxicity assays showed that compound 5h mediated greater cell death with over 43% of cells dead at 100 μM and activation of caspase 3-mediated apoptosis. On the other hand, compound 5c mediated a dose-dependent decrease in cell proliferation. Both compounds showed cell cycle arrest in the G<sub>0</sub>/G<sub>1</sub> phase and reduced cellular ATP levels leading to activation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitochondrial oxidative stress. It has to be noted that all these effects were observed at doses beyond 10 μM, 200-fold above the IC<sub>50</sub> for AChE inhibition. Both compounds also inhibited bacterial lipopolysaccharide-mediated cyclooxygenase-2 and nitric oxide release in primary rat microglial cells. These results suggested that the substituted imidazo (1,2-<i>b</i>) pyridazine compounds, which have potent AChE inhibitory activity, were also capable of antiproliferative, anti-migratory, and anti-inflammatory effects at higher doses.https://www.mdpi.com/1420-3049/26/17/5319acetylcholinesteraseanticancer drugscell proliferationcyclooxygenasecytotoxicityimidazopyridazine |
| spellingShingle | Rakesh Kumar Sharma Manisha Singh Khagendra Ghimeray Pinky Juneja Gagan Dev Sridhar Pulavarthi Sabbasani Rajasekhara Reddy Ravi Shankar Akundi Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 Molecules acetylcholinesterase anticancer drugs cell proliferation cyclooxygenase cytotoxicity imidazopyridazine |
| title | Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 |
| title_full | Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 |
| title_fullStr | Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 |
| title_full_unstemmed | Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 |
| title_short | Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32 |
| title_sort | imidazopyridazine acetylcholinesterase inhibitors display potent anti proliferative effects in the human neuroblastoma cell line imr 32 |
| topic | acetylcholinesterase anticancer drugs cell proliferation cyclooxygenase cytotoxicity imidazopyridazine |
| url | https://www.mdpi.com/1420-3049/26/17/5319 |
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