Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives

Abstract

An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well-known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)-induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED 50 : 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models.Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood-brain barrier permeability and high oral absorption, as well as drug-likeness. 5l was found to show affinity to the benzodiazepine binding site of A-type GABA receptor via molecular docking simulations.

Potential of nafimidone derivatives against co‐morbidities of epilepsy: In vitro, in vivo, and in silico investigations

“…Nafimidone and nafimidone alcohol were clinically tested as antiepileptic drug candidates (Figure 1) (Dalkara & Karakurt, 2012). Likewise, some oxime ether derivatives of nafimidone and esters of nafimidone alcohol, including sorbic acid, cyclohexanecarboxylic acid, and 4‐phenylbutanoic acid esters ( 5 g , 5i , and 5 k , respectively) (Figure 1), were found to have potent anticonvulsant effects by the Epilepsy Therapy Screening Program (ETSP) of the National Institute of Neurological Disorders and Stroke (NINDS) (Acar et al, 2019; Ozdemir et al, 2019). 5 g and 5i were reported to show promising anti‐maximal electroshock (MES) activity with ED 50 values of 36.12 and 11.76 mg/kg in rats, respectively, compared to phenytoin (ED 50 = 28.11 mg/kg), while 5 k was reportedly active at 30 mg/kg in mice (Acar et al, 2019).…”

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“…Molecules are required to be between the Solute Dipole Moment of 1.0-12.5 Debye. Many other parameters are indicated as follows - Solute Total SASA: total solvent-accessible surface area; Solute Carbom Pi SASA: Van der Waals surface area of polar nitrogen and oxygen atoms and carbonyl carbon atoms; QPlogPo/w: Predicted octanol/water partition coefficient; QPlogS: Predicted aqueous solubility; log S: S in mol dm-3 is the concentration of the solute in a saturated solution that is in equilibrium with the crystalline solid; QPlogBB: brain/blood partition coefficient; QPlogKhsa: binding to human serum albumin; Apparent Caco-2 Permeability: Predicted apparent Caco-2 cell permeability (nm/s) where Caco-2 cells are a model for the gut–blood barrier; QP log BB for brain/blood: Predicted brain/blood partition coefficient for orally delivered drugs; Apparent MDCK Permeability: Predicted apparent MDCK cell permeability (nm/s) where MDCK cells are considered to be a good mimic for the blood-brain barrier; % Human Oral Absorption in Gl: Human oral absorption on a 0-100% scale (>80% is high, <25% is poor); Solute as Donor-Hydrogen Bonds: Predicted number of donor hydrogen bonds; Solute as Acceptor-Hydrogen: Predicted number of acceptor hydrogen bond; QP log p for X/Y: Predicted X/Y partition coefficient; IC50 value for the blockage of HERG K + channels (acceptable range: above 25.0); Solute CdW Polar SA (PSA): total polar surface area (Acar et al., 2019 ; Bicak et al., 2019; Budama-Kilinc et al., 2018; Ertas et al., 2019 ; Kecel-Gunduz et al., 2020; Menteşe et al., 2019 ; Mermer et al., 2019 ; Sari et al., 2019; Singh & Bast, 2014 ); Lipinski Rule of 5 Violations: Number of violations of Lipinski's rule of five where the rules are: mol_MW (molecular weight of the molecule) < 500; QPlogPo/w (predicted octanol/water partition coefficient) < 5; donorHB (hydrogen-bond donor atoms) ≤ 5; accptHB (hydrogen-bond acceptor atoms) ≤ 10 where compounds that provide these rules are considered as drug-like molecules (Saglık et al., 2019a; Saglık et al., 2019 b; Lipinski et al., 1997 ; Jorgensen & Duffy, 2002); and Jorgensen Rule of 3 Violations: Number of violations of Jorgensen's rule of three where the three rules are: QPlogS (predicted aqueous solubility) > −5.7, QPPCaco (predicted apparent Caco-2 cell permeability in nm/s) > 22 nm/s, # Primary Metabolites < 7 where compounds with fewer (and preferably no) violations of these rules are more likely to be orally available agents. When the numerical values of these parameters are very close to each other, as can be seen from Table 7 , it can be concluded that the results obtained show the potential future use of these three molecules as drugs, and will not cause a problem according to ADME analyses.…”

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“…[42] Another parameter is QPlogHERG, which is the predicted IC 50 value for the blockage of HERG K + channels. [43] Another parameter is QPPCaco, which is the predicted apparent Caco-2 cell permeability in nm/s. QPlogBB, which is the predicted brain/blood partition coefficient.…”