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

Abstract

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.

Cinnamamide pharmacophore for anticonvulsant activity: evidence from crystallographic studies

“…The reported compounds were synthesized as described previously by the N-acylation of an appropriate aminoalkanol using (E)-cinnamoyl chloride. The reactions were carried out in a two-phase system (toluene/water/K 2 CO 3 ) (Gunia-Krzyżak et al, 2016a). Crystals suitable for X-ray diffraction measurements were obtained by slow evaporation of the solvent at room temperature.…”

“…Our previous studies have also focused upon cinnamamide derivatives, as evaluated in rodent models of seizures. Some of the reported compounds showed promising anticonvulsant activity in models of generalized and partial seizures, as well as in some models of resistant seizures (Gunia et al, 2012;Gunia-Krzyżak et al, 2016a,b, 2017a. The crystal structures have been determined for selected cinnamamide derivatives showing anticonvulsant activity (Gunia-Krzyżak et al, 2016a,b, 2017aŻ esławska et al, 2017).…”

“…Some of the reported compounds showed promising anticonvulsant activity in models of generalized and partial seizures, as well as in some models of resistant seizures (Gunia et al, 2012;Gunia-Krzyżak et al, 2016a,b, 2017a. The crystal structures have been determined for selected cinnamamide derivatives showing anticonvulsant activity (Gunia-Krzyżak et al, 2016a,b, 2017aŻ esławska et al, 2017). Crystallographic studies enable an in-depth structural analysis of active derivatives, and result in the identification of a pharmacophore for anticonvulsant activity within this group of compounds.…”

Crystallographic studies of cinnamamide derivatives as a means of searching for anticonvulsant activity

“…(Gunia-Krzyżak et al, 2016a). Table 5 presents selected results of anticonvulsant activity for these compounds and other cinnamamide derivatives for which crystal structures have been reported (Gunia-Krzyżak et al, 2016b, 2017b. All of the structures contain moieties suggested by Khan et al (2012) as being necessary for anticonvulsant activity, viz.…”

“…We analyzed the molecular geometries, intermolecular interactions and crystal packings and compared them to the published crystal structures of cinnamamide derivatives (Scheme 2), viz. (S)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (Gunia-Krzyżak et al, 2016b), (5), (R)-N-(1-hydroxypropan-2-yl)-3phenylprop-2-enamide (Gunia-Krzyżak et al, 2016b), (6), (R,S)-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (Gunia-Krzyżak et al, 2017b), 7, and (2E)-1-(2-oxopropyl)-3-phenylprop-2-en-1-one (Gunia-Krzyżak et al, 2016a), (8). We also compared the investigated structures to similar structures containing the cinnamamide fragment deposited in the Cambridge Structural Database (CSD, Version 5.37; Groom et al, 2016).…”