Arcadius V. Krivoshein

Permanent URI for this collectionhttps://hdl.handle.net/10657.1/2342

Dr. Arcadius V. Krivoshein is an Assistant Professor of Chemistry, at University of Houston-Clear Lake. Dr. Krivoshein's research interests are in the areas of Analytical chemistry, (U)HPLC and mass spectrometry method development;Biochemistry and biophysics of proteins and peptides;Solid-state chemistry and molecular pharmaceutics of antiepileptic drugs; Medicinal chemistry and molecular pharmacology, especially as applied to receptors and ion channels.

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Absolute Configuration and Polymorphism of 2-phenylbutyramide and a-methyl -a-phenylsuccinimide
(Crystal Growth & Designs, 2014) Krivoshein, Arcadius
Crystal structures of racemic and homochiral forms of 2-phenylbutyramide (1) and 3-methyl-3-phenylpyrrolidine-2,5-dione (2) were investigated in detail by a single crystal X-ray diffraction study. Absolute configurations of the homochiral forms of 1 and 2, obtained by chromatographic separation of racemates, were determined. It was revealed that racemate and homochiral forms of 1 are very similar in terms of supramolecular organization (H-bonded ribbons) in crystal, infrared (IR) spectral characteristics, and melting points. The presence of two different molecular conformations in homochiral forms of 1 allowed mimicking of crystal packing of the H-bonded ribbons in racemate 1. Two polymorph modifications (monoclinic and orthorhombic) comprising very similar H-bonded zigzag-like chains were found for the homochiral forms of compound 2 that were significantly different in terms of crystal structure, IR spectra, and melting points from the racemic form of 2. Unlike compound 1, homochiral forms of compound 2 have a higher density than the corresponding racemate which contradicts the Wallach rule and indicates that, in this case, homochiral forms are more stable than racemate forms.
Anticonvulsants Based on the a-substituted Amide Group Pharmacophore Bind to and Inhibit Functions of Neuronal Nicotinic Acetylcholine Receptors
(ACS Chemical Neuroscience, 2016) Krivoshein, Arcadius
Although the antiepileptic properties of α-substituted lactams, acetamides, and cyclic imides have been known for over 60 years, the mechanism by which they act remains unclear. I report here that these compounds bind to the nicotinic acetylcholine receptor (nAChR) and inhibit its function. Using transient kinetic measurements with functionally active, nondesensitized receptors, I have discovered that (i) α-substituted lactams and cyclic imides are noncompetitive inhibitors of heteromeric subtypes (such as α4β2 and α3β4) of neuronal nAChRs and (ii) the binding affinity of these compounds toward the nAChR correlates with their potency in preventing maximal electroshock (MES)-induced convulsions in mice. Based on the hypothesis that α-substituted amide group is the essential pharmacophore of these drugs, I found and tested a simple compound, 2-phenylbutyramide. This compound indeed inhibits nAChR and shows good anticonvulsant activity in mice. Molecular docking simulations suggest that α-substituted lactams, acetamides, and cyclic imides bind to the same sites on the extracellular domain of the receptor. These new findings indicate that inhibition of brain nAChRs may play an important role in the action of these antiepileptic drugs, a role that has not been previously recognized.
Distinct Molecular Structures and Hydrogen Bond Patterns of a, a-diethyl-substituted Cyclic Imide, Lactam, and Acetamide-derivatives in the Crystalline Phase
(Journal of Molecular Structure, 2016) Krivoshein, Arcadius
α,α-Dialkyl- and α-alkyl-α-aryl-substituted cyclic imides, lactams, and acetamides show promising anticonvulsant, anxiolytic, and anesthetic activities. While a number of crystal structures of various α-substituted cyclic imides, lactams, and acetamides were reported, no in-depth comparison of crystal structures and solid-state properties of structurally matched compounds have been carried out so far. In this paper, we report molecular structure and intermolecular interactions of three α,α-diethyl-substituted compounds – 3,3-diethylpyrrolidine-2,5-dione, 3,3-diethylpyrrolidin-2-one, and 2,2-diethylacetamide – in the crystalline phase, as studied using single-crystal X-ray diffraction and IR spectroscopy. We found considerable differences in the patterns of H-bonding and packing of the molecules in crystals. These differences correlate with the compounds’ melting points and are of significance to physical pharmacy and formulation development of neuroactive drugs.
Anticonvulsant Lactams, Cyclic Imides and Acetamides: From Chemical Crystallograpy to Molecular Pharmaceutics
(Current Pharmaceutical Designs, 2016) Krivoshein, Arcadius
The antiepileptic activity of α-substituted acetamides, lactams, and cyclic imides has been known for over six decades. We recently proposed an α-substituted amide group as the minimum pharmacophore responsible for inhibition of neuronal nicotinic acetylcholine receptors by these compounds, with the implication that inhibition of these receptors in the brain might be the unifying mechanism of action for these classes of antiepileptic drugs. In order to realize the pharmacological potential of these orally administered drugs, the relevant aspects of solid-state chemistry and pharmaceutics (including solubility and stability) need to be addressed. A better - more cohesive and generalized - understanding of the solid-state properties of these drugs would pave the road for a rational approach to their development, formulation, and manufacturing. In this paper, Pharmaceutically relevant aspects of the crystal structure and solid-state chemistry of antiepileptic drugs containing the α-substituted amide bond pharmacophore - α-substituted acetamides, lactams, and cyclic imides and the structurally related barbiturates, hydantoins, and acetylureas are reviewed. The applicable experimental and computational approaches are also briefly mentioned.
Molecular Pharmaceutics and Solid-state Chemistry of Drugs
(Current Pharmaceutical Design, 2016) Krivoshein, Arcadius
Racemic and Enantiopure forms of 3-ethyl-3-phenylpyrrolidin-2-one Adopt Very Different Crystal Structures
(Chirality, 2017) Krivoshein, Arcadius
3-Ethyl-3-phenylpyrrolidin-2-one (EPP) is an experimental anticonvulsant based on the newly proposed α-substituted amide group pharmacophore. These compounds show robust activity in animal models of drug-resistant epilepsy and are thus promising for clinical development. In order to understand pharmaceutically relevant properties of such compounds, we are conducting an extensive investigation of their structures in the solid state. In this article, we report chiral high-performance liquid chromatography (HPLC) separation, determination of absolute configuration of enantiomers, and crystal structures of EPP. Preparative resolution of EPP enantiomers by chiral HPLC was accomplished on the Chiralcel OJ stationary phase in the polar-organic mode. Using a combination of electronic CD spectroscopy and anomalous dispersion of X-rays we established that the first-eluted enantiomer corresponds to (+)-(R)-EPP, while the second-eluted enantiomer corresponds to (-)-(S)-EPP. We also demonstrated that, in the crystalline state, enantiopure and racemic forms of this anticonvulsant have considerable differences in their supramolecular organization and patterns of hydrogen bonding. These stereospecific structural differences can be related to the differences in melting points and, correspondingly, solubility and bioavailability.

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