Next Article in Journal
Phosphodiesterase SMPDL3B Gene Expression as Independent Outcome Prediction Marker in Localized Prostate Cancer
Next Article in Special Issue
ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain
Previous Article in Journal
MicroRNA and ROS Crosstalk in Cardiac and Pulmonary Diseases
Previous Article in Special Issue
Looking for a Treatment for the Early Stage of Alzheimer’s Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin
 
 
Article

S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy

1
Jagiellonian University Medical College, Faculty of Pharmacy, Chair of Organic Chemistry, Department of Bioorganic Chemistry, Medyczna 9, 30-688 Kraków, Poland
2
Pedagogical University, Institute of Biology, Podchorążych 2, 30-084 Kraków, Poland
3
Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland
4
Jagiellonian University, Faculty of Chemistry, Gronostajowa 2, 30-387 Kraków, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4372; https://doi.org/10.3390/ijms21124372
Received: 21 May 2020 / Revised: 15 June 2020 / Accepted: 17 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue Amides)
Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world’s human population. Despite availability of multiple treatment options including antiseizure drugs, it is estimated that about 30% of seizures still remain resistant to pharmacotherapy. Searching for new antiseizure and antiepileptic agents constitutes an important issue within modern medicinal chemistry. Cinnamamide derivatives were identified in preclinical as well as clinical studies as important drug candidates for the treatment of epilepsy. The cinnamamide derivative presented here: S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (S(+)-N-(2-hydroxypropyl)cinnamamide, compound KM-568) showed anticonvulsant activity in several models of epilepsy and seizures in mice and rats. It was active in a genetic animal model of epilepsy (Frings audiogenic seizure-susceptible mouse model, ED50 = 13.21 mg/kg, i.p.), acute seizures induced electrically (maximal electroshock test ED50 = 44.46 mg/kg mice i.p., ED50 = 86.6 mg/kg mice p.o., ED50 = 27.58 mg/kg rats i.p., ED50 = 30.81 mg/kg rats p.o., 6-Hz psychomotor seizure model 32 mA ED50 = 71.55 mg/kg mice i.p., 44 mA ED50 = 114.4 mg/kg mice i.p.), chronic seizures induced electrically (corneal kindled mouse model ED50 = 79.17 mg/kg i.p., hippocampal kindled rat model ED50 = 24.21 mg/kg i.p., lamotrigine-resistant amygdala kindled seizure model in rats ED50 = 58.59 mg/kg i.p.), acute seizures induced chemically (subcutaneous metrazol seizure threshold test ED50 = 104.29 mg/kg mice i.p., ED50 = 107.27 mg/kg mice p.o., ED50 = 41.72 mg/kg rats i.p., seizures induced by picrotoxin in mice ED50 = 94.11 mg/kg i.p.) and the pilocarpine-induced status epilepticus model in rats (ED50 = 279.45 mg/kg i.p., ED97 = 498.2 mg/kg i.p.). The chemical structure of the compound including configuration of the chiral center was confirmed by NMR spectroscopy, LC/MS spectroscopy, elemental analysis, and crystallography. Compound KM-568 was identified as a moderately stable derivative in an in vitro mouse liver microsome system. According to the Ames microplate format mutagenicity assay performed, KM-568 was not a base substitution or frameshift mutagen. Cytotoxicity evaluation in two cell lines (HepG2 and H9c2) proved the safety of the compound in concentrations up to 100 µM. Based on the results of anticonvulsant activity and safety profile, S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide could be proposed as a new lead compound for further preclinical studies on novel treatment options for epilepsy. View Full-Text
Keywords: anticonvulsant; antiseizure, cinnamamide derivatives; crystallography; drug development; epilepsy; preclinical safety evaluation anticonvulsant; antiseizure, cinnamamide derivatives; crystallography; drug development; epilepsy; preclinical safety evaluation
Show Figures

Figure 1

MDPI and ACS Style

Gunia-Krzyżak, A.; Żesławska, E.; Słoczyńska, K.; Żelaszczyk, D.; Sowa, A.; Koczurkiewicz-Adamczyk, P.; Popiół, J.; Nitek, W.; Pękala, E.; Marona, H. S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy. Int. J. Mol. Sci. 2020, 21, 4372. https://doi.org/10.3390/ijms21124372

AMA Style

Gunia-Krzyżak A, Żesławska E, Słoczyńska K, Żelaszczyk D, Sowa A, Koczurkiewicz-Adamczyk P, Popiół J, Nitek W, Pękala E, Marona H. S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy. International Journal of Molecular Sciences. 2020; 21(12):4372. https://doi.org/10.3390/ijms21124372

Chicago/Turabian Style

Gunia-Krzyżak, Agnieszka, Ewa Żesławska, Karolina Słoczyńska, Dorota Żelaszczyk, Aleksandra Sowa, Paulina Koczurkiewicz-Adamczyk, Justyna Popiół, Wojciech Nitek, Elżbieta Pękala, and Henryk Marona. 2020. "S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy" International Journal of Molecular Sciences 21, no. 12: 4372. https://doi.org/10.3390/ijms21124372

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop