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Synthesis, Docking Study, and Pharmacological Evaluation of S-Acetamide Derivatives of 4,6-Dimethyl-2-Thiopyrimidine As Anticonvulsant Agents

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Synthesis, Docking Study, and Pharmacological Evaluation of S-Acetamide Derivatives of 4,6-Dimethyl-2-Thiopyrimidine As Anticonvulsant Agents Journal of Applied Pharmaceutical Science Vol. 10(07), pp 001-008, July, 2020 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2020.10701 ISSN 2231-3354 Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents Hanna Ivanivna Severina1*, Olha Olegivna Skupa2, Natalya Ivanivna Voloshchuk2, Victoriya Akopivna Georgiyants1 1Department of Pharmaceutical Chemistry, National University of Pharmacy, Kharkiv, Ukraine.. 2Department of Pharmaceutical Chemistry, National Pirogov Memorial Medical University, Vinnytsya, Ukraine. ARTICLE INFO ABSTRACT Received on: 05/11/2019 The aim of this study is the direct synthesis of new (4,6-dimethylpyrimidin-2-yl)thio-N-acetamides derivatives as Accepted on: 02/06/2020 possible anticonvulsants. The interaction of thiourea with acetylacetone in sodium ethoxide resulted in the scaffold Available online: 04/07/2020 of 4,6-dimethyl-2-thiopyrimidine. Thioacetamide derivatives were synthesized by alkylation of 4,6-dimethyl-2- thiopyrimidine with comparable α-chloroacetamides in the Dimethylformamide (DMF) environment and in the presence of К СО . The methods of 1H and 13C Nuclear magnetic resonance (NMR) spectroscopy, Liquid chromatography– Key words: 2 3 mass spectrometry (LS/MS), and elemental analysis established the structure of the synthesized compounds. The 2-thiopyrimidine, docking, affinity of the studied compounds with anticonvulsant biotargets— Type-A γ-aminobutyric acid receptor (GABAAR) GABA, anticonvulsant and the gamma-aminobutyric acid-aminotransferase enzyme—was carried out using the molecular-docking method. activity. The highest affinity was predicted for the compound having 4-bromophenyl substituent: −7.0 (GABAA) and −8.0 (GABAАТ) kcal/mol. Nevertheless, all the studied compounds conceded to the reference ligands—phenobarbital (−7.6 kcal/mol) and vigabatrin (−9.0 kcal/mol). The model of pentylenetetrazole-induced seizures in rats has shown that the studied compounds have moderate anticonvulsant activity. 4-Bromophenyl acetamide has also shown the most pronounced activity: the substance statistically significantly extended the latency period and reduced the duration of seizures by 3.4 and 2.2 times, respectively; moreover, it reduced lethality of the laboratory animals by 80% and by 2.5 times severity of seizures. Correspondence between the docking results and in vivo studies, using PTZ-induced seizures, as well as some parameters of “structure-anticonvulsant activity” correlation, was determined. INTRODUCTION and in developing countries to 30 cases (Johnson, 2019; Vogt Epilepsy is one of the most serious brain diseases et al., 2017). Despite the large number of works on epilepsy having uncontrolled seizures and attacks of impaired movement pharmacotherapy, a relatively wide range of antiepileptic drugs and sensory, autonomic, and mental functions, resulting from (AEDs) with different mechanisms of action, including prolonged excessive neuronal discharges (Yuen et al., 2018). According to action, and satisfactory control of seizures is only achieved in the WHO, more than 65 million people suffer from epilepsy in the 65%–70% of patients (Gesche et al., 2019). In some patients, world, and it takes the leading position among psychoneurological AEDs cause an increase in the frequency of attacks and the diseases (Moshé et al., 2015). In developed countries, from 1 to 18 appearance of a large number of side effects, the transformation new cases of the disease per 1,000 people are annually registered, of attacks, and the deterioration of encephalographic indicators (Janmohamed, 2020; Vossler et al., 2018). Therefore, despite the availability of both well-known and successful developments of new AEDs in recent decades, the search for new compounds *Corresponding Author that are promising for the treatment of seizures and epilepsy Hanna Ivanivna Severina, Department of Pharmaceutical Chemistry, in preclinical and clinical studies has improved efficacy and National University of Pharmacy, Kharkiv, Ukraine. tolerability (Bialer and White, 2010). E-mail: severina.ai @ ukr.net © 2020 Hanna Ivanivna Severina et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). 002 Severina et al. / Journal of Applied Pharmaceutical Science 10 (07); 2020: 001-008 A targeted search for new Active pharmaceutical hydrophobic interaction with the active receptor site and create a ingredients (APIs) affecting the central nervous system (CNS), more stable conformation. In addition, modification of the carbonyl particularly pyrimidine derivatives, remains relevant for the group to a methyl usually leads to an increase of the lipophilicity scientists worldwide (Kumar et al., 2015). Phenobarbitale of the molecule, which can improve the permeability through (PHB), having a GABAergic mechanism of pharmacological the blood–brain barrier, which directly affects the expression of activity (Vossler et al., 2018), is the first pyrimidine-structure activity (Lipinski, 2016). anticonvulsant which has been widely used for treatment of The aim of this study is to synthesize 4,6-dimethyl- resistant epilepsy till today (Zhang et al., 2019). An inhibitory 2-thiopyrimidineS-acetamide derivatives, to carry out docking neurotransmitter gamma-aminobutyric acid (GABA) modulates research, and to calculate the Type-A γ-aminobutyric acid the neurological function of the CNS and affects specific processes receptor (GABAAR) and γ-Aminobutyrate aminotransferase such as anxiety, cognition, sedation/sleep, and convulsions. GABA (GABAAT) affinities with the further pharmacological screening of is the most important inhibitory neurotransmitter that regulates the anticonvulsant activity using a pentylenetetrazole model of seizures. central genesis muscle tone due to its ability to activate ionotropic MATERIALS AND METHODS and metabotropic G-protein-coupled receptors: GABAA, Type-C γ-aminobutyric acid receptor (GABAc), and Type-B γ-aminobutyric Chemistry acid receptor (GABA , respectively (Sahu et al., 2018). Scientists B) To carry out research, purified analytical reagents were agree that GABAergic inhibition is the main mechanism affecting used (Sigma-Aldrich, ‎St. Louis, MO‎). The required reagents were neuronal networks and preventing the formation and distribution purified using standard techniques. Thin layer chromatography of paroxysmal brain activities (Trevelyan and Schevon, 2013). (TLC) method on aluminum silica gel plates was used to estimate GABAergic dysfunctions, innate or acquired, can lead to epilepsy the reactions’ progress. The electrothermal digital melting point (Lerche et al., 2013). Normalization or enhancement of GABAergic apparatus IA9100X1 (Bibby Scientific Limited, Staffordshire, inhibition due to allosteric modulation of GABA receptors, GABA UK) was used for the determination of the melting points (°C) in a neuronal reuptake blockade, and GABA degradation inhibition capillary. To record 1H Nuclear magnetic resonance (NMR) spectra remains the main direction for pharmacological correction of in the hexa deutero dimethylsulfoxide-d6 (DMSO-d ) environment, epilepsy and convulsions (Khazipov, 2016). 6 while tetramethylsilane (TMS) was used as an internal standard, Our previous studies identified a number of substances spectrometer Varian Mercury 400 (300 MHz) (Varian Inc., USA) with pronounced anticonvulsant properties and a sufficient was used. Bruker Avance 400 (126 MHz, DMSO-d ) equipment was profile among pyrimidine derivatives Severina( et al., 2019), 6 used to register 13C NMR spectra. Nuclear frequency resonances its annelated (El Kayal et al., 2019) and condensed derivatives (ppm) were described according to internal standards (TMS). Euro (Severina et al., 2017). In each of the study groups, promising Vector EA-3000 microanalyzer (Eurovector SPA, Italy) was used anticonvulsants were found and significant patterns of “structure- for elemental analysis. The deviation of the obtained results did not anticonvulsant activity” were established. However, the search exceed ± 0.4%, relative to the known target values. РЕ SCIEX API for the “ideal” anticonvulsant is ongoing and, in this study, we 150EX chromatograph was used for LC/MS analysis. decided to synthesize the structural analogues of the previously To synthesize 4,6-dimethyl-2-thiopyrimidine, a traditional synthesized thiopyrimidine-4(3H)-one acetamides (Severina et method described as early by Hunt et al. (1959) was used. A al., 2019), by changing the carbonyl group at the fourth position thiourea (100 mmol) was suspended in a solution of acetylacetone of the pyrimidine cycle to the hydrophobic methyl group (Fig. 1). (120 mmol) in 250 ml of ethanol. The obtained mixture was stirred The hydrogen-bonding site, which is a carbonyl group after adding 25 ml of concentrated hydrochloric acid and left for 2 when binding to biotarget, is undoubtedly one of the key factors hours heating under reflux to complete the reaction. As soon as the for the maximal affinity in receptor–ligand interaction. However, solution was cooled down, yellow needle-like crystals of 2-thio- the nature of the bonds is quite diverse, and the introduction of 4,6-dimethyl-pyrimidine hydrochloride were formed. After the a hydrophobic domain, such as a methyl group, can enhance residue was dissolved in hot water (50°C), 1M NaOH was added to the obtained solution for its pH neutralization (optimal
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