Ilknur Dogan

A new series of chiral hydrazide‐hydrazone derivatives were synthesized and evaluated their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase and urease inhibition and antioxidant activities. The chemical structures of newly synthesized chiral aryl hydrazide‐hydrazone derivatives were clarified using UV–Vis, IR, ¹H and ¹³C NMR, and mass spectroscopies. According to NMR data, due to the partial double bond character of the amide C‐N bond, two conformational isomers (E and Z) exist in solution. Based on this information, the conformational properties of the synthesized compounds were investigated using temperature‐dependent NMR spectroscopy and DFT. The results of DFT studies revealed that E_(C=N)‐E_(C(O)‐N) conformer is the most stable structure for the synthesized hydrazones. In addition, the enzyme inhibition potentials of the synthesized compounds were evaluated. Among all chiral hydrazide‐hydrazones, compound 3b (containing nitro group in the hydrazone part) had the best inhibition profile against AChE, whereas compound 3d was found to be the most active compound against BChE. In addition, compound 3d, which carries a methoxy group in both the benzamide and the hydrazone moiety, attracted attention due to its good activity against all examined enzymes. Furthermore, molecular docking calculations were performed to get insights into the interaction patterns between the synthesized compounds and the selected target protein.

2‐Thiohydantoin derivatives, including different substitutions at N‐1 and C‐5 (5‐methyl‐, 5‐isopropyl‐, 1‐acetyl‐5‐methyl‐, and 1‐acetyl‐5‐isopropyl‐) (1–4, respectively), were synthesized by the known literature methods. In these synthetic pathways, it was reported that enantiomerically pure 2‐thiohydantions were obtained in the absence of any solvent via the reaction of L‐amino acids with thiourea (1&2) and via the reaction of L‐amino acids with NH₄SCN and acetic anhydride (3&4). However, in this study, in contrary to the previous literature studies, racemic mixtures of 2‐thiohydantoins were obtained although the same synthetic methods were used. The racemic nature of 2‐thiohydantoin derivatives (1–4) was proved by using ¹H NMR analysis in the presence of (1R,2S)‐(−)‐ephedrine as a chiral auxiliary. In addition, the enantiomers of 3&4 were also resolved on chiral stationary phases by HPLC analyses. Furthermore, newly synthesized unsymmetrical chiral thioureas (S‐1&S‐2) and previously synthesized symmetrical ones (SS‐3&SS‐4) were used as chiral solvating agent (CSA) for the enantiodiscrimination of the thiohydantoins (5&6), previously reported. Optimal CSA/substrate ratios were determined for the best enantiodiscrimination.

Aldol reactions are one of the most fundamental organic reactions involving the formation of carbon–carbon bonds that are commonly used in the synthesis of complex molecules through the condensation of an enol or enolate with a carbonyl group. The aldol reaction of thiohydantoin derivatives with benzaldehyde starts with hydrogen removal from C5 by lithium diisopropylamide (LDA) to form the enolate. Benzaldehyde adds to the enolate either at the less or more hindered site. The formed products have 3 chiral centers; thus they exist in 8 isomeric forms, RMS*/SPR*, RMR*/SPS*, SMR*/RPS*, and SMS*/RPR*, which are enantiomeric couples. Experimentally the axial chirality of the reactant is protected throughout the reaction; if the starting thiohydantoin is the M isomer, only RMS*, RMR*, SMR*, and SMS* diastereomers can be obtained. In this study, we aim to report a theoretical study of the aldol reactions between benzaldehyde and thiohydantoin derivatives conducted at the M06-2X/6-311+G(d,p) level of theory using the CPCM solvation model for THF as solvent, at 195 K. The investigation of the effect of substituents at C5 (stereocenter) and X positions on selectivity was performed by varying the substituents RCH₃, XCF₃; RCH₃, XCl; RCH₂Ph, XCF₃; RCH(CH₃)₂, and XCF₃. Agreement of calculations (M06-2X/6-311+G(d,p)/CPCM(THF)) with experiment suggests that the enantioselectivity is predominantly governed by thermodynamic control.

As weak acids or bases, in solution, drug molecules are in either their ionized or nonionized states. A high degree of ionization is essential for good water solubility of a drug molecule and is required for drug-receptor interactions, whereas the nonionized form improves a drug's lipophilicity, allowing the ligand to cross the cell membrane. The penetration of a drug ligand through cell membranes is mainly governed by the pK_a of the drug molecule and the membrane environment. In this study, with the aim of predicting the acetonitrile pK_a's (pK_a(MeCN)) of eight drug-like thiazol-2-imine derivatives, we propose a very accurate and computationally affordable protocol by using several quantum mechanical approaches. Benchmark studies were conducted on a set of training molecules, which were selected from the literature with known pK_a(water) and pK_a(MeCN). Highly well-correlated pK_a values were obtained when the calculations were performed with the isodesmic method at the M062X/6-31G** level of theory in conjunction with SMD solvation model for nitrogen-containing heterocycles. Finally, experimentally unknown pK_a(MeCN) values of eight thiazol-2-imine structures, which were previously synthesized by some of us, are proposed.

In this study, we have synthesized a series of 3‐(pyridin‐2‐yl)‐2‐(pyridin‐2‐ylimino)thiazolidin‐4‐ol derivatives regioselectively from 2‐iminothiazolidin‐4‐ones using LiAlH₄ at room temperature. Due to the presence of the restricted rotation around the N3‐C_aryl single bond, the formation of M/P isomers was observed. The OH group of the hemiaminal was found to orient itself on the same side with pyridyl nitrogen during this restricted rotation to form an intramolecular hydrogen bond, which was demonstrated by the computational DFT study. This orientation presumably inhibited the occurrence of dehydration and stabilized the molecule.

5-Benzyl-3-(o-aryl)-2-thiohydantoin and 5-isobutyl-3-(o-aryl)-2-thiohydantoin derivatives (o-aryl = o-tolyl and o-bromophenyl) have been synthesized by reacting o-aryl isothiocyanates with S-phenylalanine methyl ester hydrochloride or with S-leucine methyl ester hydrochloride in the presence of triethylamine (TEA). The synthesized compounds have a chirality center at C5 of the heterocyclic ring and a chirality axis, the N3–C_(aryl) bond. The axially chiral compounds were shown to exist in unequal amounts of SM, SP, RM and RP stereoisomeric forms with a high prevalence of the P isomers over the M isomers. The isomeric assignments were done by comparing the ¹H NMR spectra with the HPLC chromatograms. The stereoisomers were resolved micropreparatively by HPLC on chiral stationary phases and the interconversion of the single isomers has been investigated. The conversion type has been determined as epimerization or rotation by the HPLC analyses. It has been found that although the stereoisomers converted to each other only by rotation in toluene, in ethanol epimerization (racemization at C5 of the heteroring) was accompanied with rotation depending on the duration, temperature of the thermal interconversion experiment and the nature of the ortho substituent. The occurrence of epimerization was also proved through H/D exchange reactions via¹H NMR experiments done in CD₃OD. The rotation and epimerization mechanisms of synthesized compounds were further elucidated by Density Functional Theory (DFT) calculations at M062X/6-311 + G** level of theory and the results were shown to be in harmony with experimental findings.

In this study, we present an accurate protocol for the fast prediction of pKa's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental pKa values. Five charge descriptors, three charge models, three solvent models, gas phase calculations and several DFT methods (combination of eight DFT functionals and fifteen basis sets) were tested. Among those, the best combination to reproduce experimental pKa's is to compute NPA atomic charge using the SMD model at the M06L/6-311G(d,p) level of theory and selecting the maximum atomic charge on carboxylic oxygen atoms (R^2 = 0.955). The applicability of the suggested protocol and its stability along geometrical changes are verified by molecular dynamics simulations performed for a set of aspartate, glutamate and alanine peptides. By reporting the calculated atomic charge of the carboxylate form into the linear relationship derived in this work, it will be possible to estimate accurately the amino acid’s pKa's in protein environment.

Stable, nonracemic axially chiral hemiaminals (O,N‐hemiacetals) have been synthesized stereoselectively from lithium aluminum hydride (LiAlH₄) reductions of nonracemic 5‐methyl‐ and 5‐isopropyl‐3‐(o‐aryl)‐2‐thioydantoins in tetrahydrofuran (THF) at room temperature in 10 min. PredominantlyS‐configured hemiaminals at C‐4 of the heterocyclic ring were produced from the S‐configured thiohydantoins at C‐5 (by 80% when the C5 substituent is methyl and by 97% when it is isopropyl). The configuration at C‐5 was retained during the reduction reaction. The stereochemical outcome of the axially chiral hemiaminals resulted from their conformational preferences.

Chiral hemiaminals (5‐8RR and 5‐8SS) have been synthesized from the corresponding 2‐iminothiazolidine‐4‐ones (1‐4RR and 1‐4SS) by LiAlH₄ reductions stereoselectively and were then converted to single enantiomer thiazol‐2‐imines (9‐12RR and 9‐12SS) by a water elimination reaction. The kinetics of the dehydration reactions which occurred spontaneously both in the solid state and in the solution have been followed by time dependent ¹H nuclear magnetic resonance spectroscopy. The corresponding first order rate constants and free energies of activation values for the conversions have been reported.