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Virtual Screening of Putative Anticonvulsant Hydantoin Derived Drugs and Biological Evaluation

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Virtual Screening of Putative Anticonvulsant Hydantoin Derived Drugs and Biological Evaluation Central Annals of Medicinal Chemistry and Research Bringing Excellence in Open Access Research Article *Corresponding author Ignacio A. Rivero, Centro de Graduados e Investigación, Instituto Tecnológico de Tijuana, P.O. Box Virtual Screening of Putative 1166, 22000, Tijuana, B.C. México, Tel: 52-664-6233772; Anticonvulsant Hydantoin Submitted: 16 August 2016 Accepted: 05 October 2016 Published: 07 October 2016 Derived Drugs and Biological ISSN: 2378-9336 Copyright Evaluation © 2016 Rivero et al. Sandy Santiago-Ruiz1, Eugenia Polverini2, Joaquin Manjarrez3, OPEN ACCESS 1 1 1 Karla A. Espinoza , Edgar Reynoso , and Ignacio A. Rivero * Keywords 1Centro de Graduados e Investigación, Instituto Tecnológico de Tijuana, México • Anticonvulsant 2Department of Physics and Earth Sciences, University of Parma, Italy • Hydantoin 3Departmento de Formación Reticular del Instituto de Neurología y Neurocirugía, • Piperidineshydantoins Nacional de Neurología y Neurocirugía, México • Epilepsy Abstract It has been found that derivatives of benzyl N-piperidin-4-one have similar effect than phenytoin drug as an anticonvulsant for the treatment of epilepsy according to docking simulation studies. This is due to the similar binding mode in these chemicals. In this study, a series of six N-piperidinespirohydantoins derivatives were prepared by Bucherer-Bergs reaction, from corresponding N-piperidin-4-ones derivatives benzyl and phenethyl groups, substituted in the aromatic ring with metoxy and nitro groups. The hydantoins were evaluated for anticonvulsant activity with maximal electroshock (MES) induced method in vivo in male Wistar rats in the treatment of epilepsy. ABBREVIATIONS epileptic seizures, muscle spasms, physical injury, damage to the brain, and unconsciousness, to name a few symptoms that MES: Maximal Electro Shock; AEDs: Anti Epileptic Drugs; manifest within this disease. As thus, there exists a need for the CASH: Cycloalkanespirohydantoins; ADT: Autodock Tools; PSH: development of new anti seizure medication with improved Piperidinespirohydantoins; TLC: Thin-Layer Chromatography; IR: Infrared Spectra; TMS: Tetramethylene Silane; MS: Mass antiepileptic drugs (AEDs) have been associated with undesirable Spectra; ESI-MS: Electrospray Ionization Mass Spectra; LC/MSD: sideefficacy effects and [2-4]. tolerability, as several of the currently available Liquid Chromatography/ Mass Spectra Detector There are several drugs that are able to control this disease; INTRODUCTION one of the most used is the phenytoin, which contains a hydantoin The search for new chemical compounds that have biological ring. Hydantoin (imidazolidine-2,4-dione) moiety constitutes an attractive and multifaceted pharmacological scaffold present in security, has become paramount to the constant improvements several drugs [7]. This small and rigid heterocyclic backbone, has onactivity, current efficiency, medication. effectiveness, This is important reproducibility, because stability,of a trend and in potential to act on various pharmacological targets. patients of developing resistance to outdated and sometimes Hydantoin-1,3-imidazolidinedione derivatives [5,6] Figure even current medication creating a constant need for more (1) exhibit diverse and interesting pharmacological properties innovative pharmaceutical products. [7,8]. Several such derivatives (phenytoin, mephenythoin, Neurodegenerative diseases have been a huge challenge norantoin, methetoin, ethotoin, osphenytoin) are renowned for the development of new drugs, since many of them are not anticonvulsive drugs [9,10] (Table 1). attractive from a commercial point of view. This is the case with The anticonvulsant activity of hydantoins has been epilepsy, which is one of many diseases that require lifelong known since 1938 when Merrit and Putman discovered that treatment for the patient to remain in a controlled manner and 5,5-diphenylhydantoin (phenytoin) Figure (2) showed anti- to be allowed to do all their independent normal activities [1]. epileptic acivity [11]. Phenytoin acts on brain by reducing Epilepsy is the most common neurological disorder electrical conductance among neurons by stabilizing the inactive throughout the world. It is characterized by current unpredictable state of voltage gated sodium channel [12-14] (Table 2). Cite this article: Santiago-Ruiz S, Polverini E, Manjarrez J, Espinoza KA, Reynoso E, et al. (2016) Virtual Screening of Putative Anticonvulsant Hydantoin Derived Drugs and Biological Evaluation. Ann Med Chem Res 2(1): 1016. Rivero et al. (2016) Email: Central Bringing Excellence in Open Access Table 1: Yield of the alkylated piperidin-4-ones 6a-f. These P loops fold back into the membrane to make a shallow funnel, with the innermost four residues (the DEKA motif) forming N-Piperidinespirohydantoins Entry n R (yield %)a the inner mouth of the pore, and it includes hydrophobic residues 6a 1 2-NO 96 2 fromthe selectivity the four S6 filter. segments The channel’s (Figure activation1). gate is located near 6b 1 3-NO2 98 Anticonvulsant drugs typically have a tricyclic structure, with 6c 1 4-NO 98 2 a hydantoin ring in the middle, like 2. Cycloalkanespirohydantoins 6d 1 3-OCH 83 3 (CASH, Figure 2,3 a-f) and piperidinespirohydantoins (PSH, 6e 1 4-OCH3 86 Figure 2,4 a-c) are two new classes of molecules that are designed to be potential anticonvulsant drugs candidates; they 6f 2 4-OCH3 70 n: number of methylene also contain a hydantoin ring and were recently synthesized R: type and position of the groups in the aromatic system from cycloalkanones and N-piperidin-4-ones under microwave- assisted conditions [22] (Figure 2). Table 2: Yield of the Bucherer-Bergs reaction to produce the substituted The interaction of this set of new molecules with the open piperidinspirohydantoins 7a-f. state of the neuronal Na+ channel was explored by means of N-Piperidinspirohydantoins docking simulations to the aim of investigating their putative Entry n R a (yield %) action as anticonvulsant drugs on the basis of their binding 7a 1 2-NO2 73 7b 1 3-NO2 72 structural basis of their block of neuronal Na+ channels may help mode and their binding affinity for the channel. Insight into the 7c 1 4-NO2 71 for new anticonvulsants. On these bases, some derivatives of a 7d 1 3-OCH 76 3 veryto explain favored their compound, target specificity were then and synthesized assist in anda rational tested searchin vivo 1 4-OCH 73 7e 3 for their anticonvulsant activity. 7f 2 4-OCH 70 3 The benzene dimer was the prototypical system to study the n: number of methylene R: type and position of the groups in the aromatic system is favored by the stacking of aromatic systems, it is weak, but π stacking, stabilization energy is 2-3 kcal. This interaction π-π Other 5-substituted hydantoins such as 5,5-dithienylhydantoin, 5,5-dipyridylhydantoin, spirothio-hydantoin, thiohydantoin O and dithiohydantoins also possess anticonvulsive activity [13]. HN Hydantoin derivatives can also be found in antiarrhythmic O NH (azimilide), antimicrobial agents (nitrofurantoin), skeletal R1 R2 muscle relaxants (dantrolene) and nonsteroidal antiandrogens (nilutamide), while allantoin is used as a keratolytic, astringent, 1 antiacid and antipsoriatic drug [15]. Hydantoins also display O NH antidepressant, antiviral and antithrombotic activities, as well N O as inhibitory activity against some enzymes (human aldose H reductase and human leucocyte elastase) [16]. Finally, some herbicides (spirohydantoin, thioxohydantocidin), fungicides 2 O (clodantoin) and insecticides also have the hydantoin skeleton in O their structure [17,18]. N N Voltage-gated sodium channels are the molecular targets for several important commonly used classes of drugs including anticonvulsant drugs (antiepileptic), local anesthetic and 8 antiarrhythmic drugs, and antidepressants, which bind in the gating states. In fact, all of these types of drugs block sodium currentsinner pore with of the noticeable channel withvoltage affinities dependence, related toshowing the channel low affinityThe atNa+ resting channel states is a and multimolecular strong block complex for open (Figure states [19,20]. 1) [21]. composedA large α-subunit of four forms highly the homologous channel’s poredomains and gating(I–IV), machinery each with and contains the principal drug binding sites. This α-subunit is Figure 1 Na+ open channel model (Lipkind and Fozzard, 2005) used clockwise pattern around the central pore. The pore itself has for the docking simulations, coloured by chain. The S6 helix of each asix fairly trans-membrane large outer vestibule, α-helical formedsegments by (S1–S6)the four assembledextracellular in Pa domain is labeled. In ball and stick are the four DEKA residue of the loop segments between each S5 and S6. selectivity filter [21]. Ann Med Chem Res 2(1): 1016 (2016) 2/7 Rivero et al. (2016) Email: Central Bringing Excellence in Open Access gel F plates (Merck). Melting points were obtained on an H 254 O H H O N N O N Electrothermal 88629 apparatus and are uncorrected. Infrared NH NH NH spectra (IR) were recorded on a Perkin Elmer FT-IR 1600 1 13 O O O spectrophotometer. H and C nuclear magnetic resonance spectra at 200 Hz and 50.289 Hz, respectively, were recorded on (3a) (3b) (3c) a Varian Mercury 200 MHz Spectrometer in CDCl3 and DMSO-d6 O H H O HN with TMS as internal standard. Gas Chromatography 793 A N O N NH Automatic Liquid Sampler (EM) was obtained and the intensities NH NH O are reported as a percentage relative to the base peak after the O O corresponding m/z value.
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