Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols

Gunia‐Krzyżak, Agnieszka; Żesławska, Ewa; Słoczyńska, Karolina; Koczurkiewicz, Paulina; Nitek, Wojciech; Żelaszczyk, Dorota; Szkaradek, Natalia; Waszkielewicz, Anna M.; Pękala, Elżbieta; Marona, Henryk

doi:10.1016/j.ejmech.2015.10.051

Cited by 17 publications

(27 citation statements)

References 29 publications

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“…The 3‐phenylprop‐2‐enamide moiety is almost planar, with the interplanar bond angles between the planes of aromatic ring and amide group 5.7(3)° and 6.9(2)° for 1 and 2 , respectively. These values are close to that observed in the crystal structure of racemic form 5.3(1)° …”

Section: Resultssupporting

confidence: 89%

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Anticonvulsant Activity of Enantiomeric N‐trans‐Cinnamoyl Derivatives of 2‐Aminopropan‐1‐ols and 2‐Aminobutan‐1‐ols

et al. 2016

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Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N-trans-cinnamoyl derivatives of R and S-2-aminopropan-1-ol, as well as R and S-2-aminobutan-1-ol. The structures were confirmed by spectroscopy and for derivatives of 2-aminopropan-1-ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine-induced status prevention. Additionally, derivatives of 2-aminopropan-1-ols were tested in benzodiazepine-resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(-)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide pharmacological parameters were found as follows: ED50 = 76.7 (68.2-81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED50 = 127.2 (102.1-157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD50 = 208.3 (151.4-230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2-aminopropan-1-ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482-488, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 89%

“…), N‐trans ‐cinnamoyl derivative of R , S ‐2‐aminopropan‐1‐ol, showed ED 50 s of 86.6 and 60.9 mg/kg when tested in mice after intraperitoneal (i.p.) administration in maximal electroshock and 6‐Hz test, respectively …”

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confidence: 99%

Anticonvulsant Activity of Enantiomeric N‐trans‐Cinnamoyl Derivatives of 2‐Aminopropan‐1‐ols and 2‐Aminobutan‐1‐ols

et al. 2016

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“…Potential AEDs must require favorable physicochemical parameters and pharmaceutically relevant properties . Lipophilicity has been characterized as vital physicochemical parameter affecting CNS activity because only appropriate partition coefficient of a molecule enables sufficient penetration of the blood‐brain barrier . Hence, optimal lipophilic and hydrophilic balance (log P ) is a very important issue in designing of novel antiepileptic drugs.…”

Section: Resultsmentioning

confidence: 99%

“…Epilepsy is a complex disorder of brain function which results in enduring predisposition to engender seizures . It is the second most common chronic neurological condition seen by neurologists .…”

Section: Introductionmentioning

confidence: 99%

Structural Exploration of Quinazolin‐4(3H)‐ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies

Ugale

Bari

2016

Archiv der Pharmazie

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Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED = 23.5 mg/kg, MES, mice, i.p.; ED = 32.6 mg/kg, scPTZ, mice, i.p.; ED = 45.2 mg/kg, 6-Hz, mice, i.p.; TD = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED = 26.1 mg/kg, MES, mice, i.p.; ED = 79.4 mg/kg, scPTZ, mice, i.p.; TD = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.

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“…Antiepileptic drugs (AEDs) therapy is mainstay of treatment for many patients with epilepsy. Development of new AEDs resulted into increased treatment options for patients with epilepsy but making drug selection a more complex task . Despite decades of research, it is still not clearly understood how AEDs act to control seizures.…”

Section: Introductionmentioning

confidence: 99%

Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies

et al. 2020

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In recent years, design and synthesis of anticonvulsants effective against multiple seizures has attracted much attention of medicinal chemists. In an attempt to find novel anticonvulsants, herein we have reported structurally optimized sixteen different substituted quinazolinones explored through molecular fragmentation approach. The anticonvulsant activity of synthesized compounds was assessed by using predictable seizure models in mice. Two most promising analogues 8 d (ED50 = 35.1 mg/kg, MES, mice, i. p.; ED50 = 41.5 mg/kg, scPTZ test, mice, i. p.) and 8 l (ED50 = 21.2 mg/kg, MES, mice, i. p.; ED50 = 32.4 mg/kg, scPTZ test, mice, i. p.) exhibited broad spectrum anticonvulsant action in preclinical models of seizures. Compound 8 l was also shown profound activity against pharmaco‐resistant limbic seizures produced in 6 Hz test. Most of the synthesized molecules exhibited moderate to high anticonvulsant activity in all seizure models with no symptoms of neurotoxicity and hepatotoxicity. We have also used in‐silico protocol for prediction of physiochemical and pharmacokinetic properties of synthesized quinazolinones. The promising anticonvulsant activity of synthesized analogues, ex‐vivo toxicity, in‐silico molecular docking, physiochemical and pharmacokinetic predictions make us to anticipate emergence of synthesized quinazolinones as valid leads for the treatment of convulsive disorder.

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Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols

Cited by 17 publications

References 29 publications

Anticonvulsant Activity of Enantiomeric N‐trans‐Cinnamoyl Derivatives of 2‐Aminopropan‐1‐ols and 2‐Aminobutan‐1‐ols

Anticonvulsant Activity of Enantiomeric N‐trans‐Cinnamoyl Derivatives of 2‐Aminopropan‐1‐ols and 2‐Aminobutan‐1‐ols

Structural Exploration of Quinazolin‐4(3H)‐ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies

Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies

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