An Old Story in the Parallel Synthesis World: An Approach to

Research Article Cite This: ACS Comb. Sci. 2018, 20, 35−43

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An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries Andrey V. Bogolubsky,†,§ Yurii S. Moroz,†,‡,§ Olena Savych,†,‡,⊥,§ Sergey Pipko,†,‡ Angelika Konovets,†,‡ Maxim O. Platonov,† Oleksandr V. Vasylchenko,† Vasyl V. Hurmach,†,‡ and Oleksandr O. Grygorenko*,†,‡ †

Enamine Ltd., 78 Chervonotkatska Street, Kyiv 02094, Ukraine National Taras Shevchenko University of Kyiv, 60 Volodymyrska Street, Kyiv 01601, Ukraine

‡

S Supporting Information *

ABSTRACT: An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200−350, cLogP 1−3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings. KEYWORDS: condensation, nitrogen heterocycles, 2,2,2-trifluoroethylcarbamates, amino esters, kinase inhibitors

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INTRODUCTION Development of synthetic methods which are compatible with the requirements of combinatorial chemistry has always been a tremendous task, and with more and more increased pressure on the library quality, synthesis of even well-known compound types becomes a problem to solve.1−6 For example, hydantoins (1) have been known for more than 150 years,7−9 and even a (good) beginning organic chemist can name at least one or two methods for their preparation. These methods include the classical Bucherer−Bergs reaction (i.e., reaction of carbonyl compounds with cyanide and ammonia carbonate) and a number of its variations (Figure 1, pathway A)10 and (in situ) cyclization of hydantoic acids or their esters (2). In turn, the latter are prepared by the reaction between α-amino esters 3 and isocyanates,11,12 carbamoyl chlorides,13 or silylated Ncarboxyanhydrides of α-amino acids (Figure 1, pathway B).14 Alternatively, α-amino esters 3 react with phosgene, triphosgene, or CDI and, then, primary amine (pathway C).15,16 In some cases, formation of 2 is followed by hydrolysis prior the cyclization.17−22 Other methods include the Ugi reaction (Figure 1, pathway D),23,24 cyclization of activated carbamates 4 (pathway E),25,26 reaction between amides of amino acids and triphosgene (pathway F),27 condensation of 1,2-dicarbonyl compounds with ureas (pathway G),28 or domino condensation of α,β-unsaturated acid esters with carbodiimides (pathway H).29 Since the hydantoin moiety is present is several marketed and investigational drugs, that is, an anticonvulsant medications phenytoin (5) and etotoin (6), a nonsteroidal antiandrogen © 2017 American Chemical Society

Figure 1. Synthetic routes to form a hydantoin core.

nilutamide (7), a postsynaptic muscle relaxant dantrolene (8), or an aldose reductase inhibitor sorbinil 9) (Figure 2),30 an efficient and robust approach to the hydantoin libraries would be of high interest to early medicinal chemistry programs. Most of the approaches shown in Figure 1, however, are inconvenient for the parallel synthesis conditions due to the use of toxic, gaseous, or scarcely available reagents; some of these methods also do not allow for variation at all the possible substitution Received: November 2, 2017 Revised: December 8, 2017 Published: December 11, 2017 35

DOI: 10.1021/acscombsci.7b00163 ACS Comb. Sci. 2018, 20, 35−43

ACS Combinatorial Science

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RESULTS AND DISCUSSION

Method Development. Depending on the substrate, one of the following synthetic procedures was used (Scheme 3):

Scheme 3. Synthesis of the Hydantoin Library 1 and Selected Examples of the Products

Figure 2. Hydantoins: Marketed and investigational drugs.

points of the hydantoin core. Nevertheless, examples of hydantoin libraries synthesis were described in the literature previously. Many of them relied on the use of isocyanates (Figure 1, pathway B and other transformations);31−39 some allowed for the preparation of the libraries with specific substitution patterns36−46 or were multistep.32,47−50 But isocyanates are toxic, have limited shelf stability and commercial availability (as compared to other common building blocks), which hampers wide application of the synthetic procedures cited above in the parallel conditions. A few years ago, we had introduced parallel methods of assembling two different amino components to obtain unsymmetrical ureas51,52 with 2,2,2-trifluoroethylchlorocarbonate (10a) or bis(2,2,2-trifluoroethyl)carbonate (10b) (Scheme 1). The intermediate 2,2,2-trifluoroethylurethane 11

• Method AIn situ generation of carbamate 11 from the aromatic or heteroaromatic amine 12 and reagent 10a, followed by reaction with amino acid ester 3. • Method BIn situ generation of carbamate 11 from the aliphatic amine 12 and reagent 10b, followed by reaction with 3. The choice of the procedure was restricted by reactivity of the nucleophile at the first step (formation of 11). For the aromatic and heteroaromatic substrates, the choice of the method was defined by their lowered reactivity, so that more reactive 10a should be applied. With reactive aliphatic amines 12, symmetric 10b could be used. Whereas the method B followed the reaction conditions published by us previously for the urea synthesis,52 in the method A, we had slightly modified the synthetic procedure51 for our purposes, as, for example, replacing DBU with DIPEA and using dioxane as a solvent. To validate the process, we have randomly selected 20 amino esters 3(1−20) and 20 primary amines 12(1−20) with varied chemical reactivity and hydrophilicity as the starting compounds (Figures S1 and S2). Both methods A and B gave satisfactory results in these preliminary experiments: the 20 corresponding hydantoins were obtained with moderate to good yields (25−84%), which are acceptable for parallel synthesis. Moderate yields observed in some cases could be explained as a result of parallel workup procedures, in which compounds were not fully extracted from the aqueous solution. Indeed, LC-MS and/or 1H NMR analysis of the crude reaction mixtures of the validation set showed that hydantoin formation had proceeded with high yields (>80% of the desired product). To demonstrate utility of the method for the lead-oriented synthesis, we have designed a library of 1461 lead-like hydantoins 1 starting from 185 amino esters 3(1−185) and 629 primary amines 12(1−629) (Figures S1 and S2 in the Supporting Information). The physicochemical parameters of the library were adjusted according to the definition of leadlikeness by Churcher and co-workers (MW 200−350, cLogP 1−3, except 11 compounds prepared in the validation step).4,53 Further prioritization of the compounds for including into the final library was performed using REAL methodology,54

Scheme 1

can be presynthesized, or generated in situ from amines and reagents 10. By replacing one of the amino components with the α-amino acid ester 3, this method could be extrapolated to the hydantoin synthesis since hydantoinic acid ester 2 is formed, which would undergo cyclization under basic conditions (Scheme 2). This strategy follows pathway C of Scheme 2

Figure 1; however, since less toxic and easily handled reagents 10a or 10b are used instead of phosgene, triphosgene or CDI, and the only byproduct formed in the cyclization step is volatile 2,2,2-trifluoroethanol, this procedure should be amendable for parallel synthesis conditions. In this work, utility of the approach depicted in the Scheme 2 to the preparation of hydantoin libraries has been shown. In addition, the developed method has been applied in discovery of Aurora kinase A inhibitors with a combination of rational design, parallel synthesis, in silico and in vitro screenings, which resulted in submicromolar primary hits. 36


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ACS Combinatorial Science Tanimoto index-based diversity selection using ECFP4 fingerprints,55 and visual inspection. Parallel synthesis of the library 1 resulted in successful isolation of 1158 library members (79% success rate), with 42% average yield (Figure 3).

might be again related to the isolation issues since formation of the corresponding hydantoins with moderate to good yields was observed in the crude reaction mixtures by LCMS. Design and Synthesis of the Potential Aurora Kinase A Inhibitor Library. To demonstrate utility of the hydantoin libraries for medicinal chemistry projects, we have applied them to discovery of Aurora kinase A inhibitors. Kinases of Aurora family play crucial role in cell proliferation.56 Aurora kinase A, particularly, takes part in the mitotic spindle formation and therefore segregation of chromosomes. Overexpression of this kinase is tightly connected with tumor formation,57−59 and its inhibition is an important issue in cancer therapy. Various Aurora inhibitors have been reported60 and are now at clinical trials stage,61 but still a lot of relevant chemical space remains unexplored. Our choice of this target relied on our preliminary results which included in silico search within our medicinal chemistry data set of already synthesized compounds and analysis of the reported ligands. This allowed us to suggest main pharmacophore features for the ligand (Figure 6). It consisted of a hingebinding group with H-bond acceptor and a steric group attached to it, an anchor−aromatic fragment with H-bond acceptor, and a linker−flexible chain between hinge-binding group and anchor. Among the set, several fragments represented hinge-binding motif repeatedly, and a hydantoin core was found quite often. Preliminary in vitro screening at 10 μM revealed over 50% inhibition of the target for some of these virtual hits. Encouraged by these positive results, we decided to create a library of hydantoins 13 that met the presented pharmacophore scheme. To simplify enumeration and further synthesis of the library 13, we have not separated the steric fragment from the hingebinding motif and considered this fragment as a hydantoin with (di)alkyl or spiro substitution at C-5 position; also, we circumscribed set of hydantoins steric fragment to those containing 2−9 carbon atoms. As the linkers, we have selected nonbranched ω-chlorocarboxylic acids of 2−4 carbon atoms due to simplicity of attachment to the hinge-binding group and further modification of the carboxylic group with an anchorintroducing reagent. As the latter, we have chosen aromatic frameworks of 1−3 rings, with a heteroaromatic moiety (for biand tricyclic systems) or an amide bond for the monocyclic system. The linker attachment functionality was either aliphatic amino group (to form an amide bond) or aliphatic halogen (to form an ester bond with carboxylic part of the linker). Enumeration of the library 13 involved 24 α-amino esters 3 with only saturated and mostly conformationally restricted moieties to form the hydantoin core, three linkers introduced by ω-chloro esters 14(1−3), and two groups of the anchorintroducing building blocks, that is, ester (alkylation agents 16(1−1500)) and amide (amines 17(1−1000)) bond-forming. These building blocks were selected to be capable of introducing an aromatic fragment and H-bond acceptor into the anchor. The resulting database of 108 000 compounds was subjected to in silico screening against Aurora A kinase. The binding site model was created on the basis of entry 2C6E in Protein Data Bank.62 Filtering was based on such criteria as the built-in QXP scoring function,63 the number of hydrogen bonds, the protein−ligand contact surface area and the distance from ligand to key points of the corresponding pharmacophore model. The main interactions for a selected series of compounds were the formation of two hydrogen bonds with

Figure 3. Yields of the hydantoin library members 1{3(1−185),12(1− 629)}.

Figure 4 shows that calculated physicochemical parameters of the library 1{3(1−185),12(1−629)} comply well with the leadlikeness criteria. The average values are molecular weight (MW), 309; calculated logarithm of the partitioning coefficient (cLogP), 1.23; H-bond acceptor and donor counts (HAcc and HDon), 3.5 and 0.3, respectively; rotatable bond count (RotB), 3.2; Fsp3, 0.52. It was found that the yield weight of the product was not affected strongly by the above-mentioned parameters (except HDon, which led to significant drop in average method efficiency upon its increasing). In particular, no “LogP drift” effect4 was observed. It is also interesting to note that the highest average yields were observed for the compounds with Fsp3 = 0.4−0.8. These facts demonstrate suitability of the methods developed for lead-oriented synthesis. In general, reactivity of the substrates 12(1−629) followed trends described in our previous works on urea synthesis,51,52 and it correlated positively with nucleophilicity of these primary amines. Nevertheless, the products could be obtained even in the case of low-nucleophilic amines (e.g., 12(39), 12(57), 12(60), 12(72), 12(83), or 12(409), Figure 5), although these substrates showed low success rate. It should be noted that steric factors affecting nucleophilicity of 12 appeared to be of lesser importance for the reaction outcome as compared to the electronic ones. The presence of additional basic centers in the molecules of 12 also diminished both yields of the products 1 and the success rate, which might be related to the isolation issues. Similar tendencies were observed for the reactivity of the amino esters 3(1−185). In particular, steric hindrance seem not to be very important factor since α-substituted and α,αdisubstituted amino esters gave comparable average yields of the products. Primary amino esters were less effective substrates for the hydantoin synthesis than secondary ones; the presence of additional basic centers also diminished average yields of the products. Both these facts can be addressed to more problematic isolation of the target compounds. Interestingly, primary amino esters with a single (het)aryl or COOEt substituent at the α position showed low success rate (28%), hence the method showed poor effectiveness for the preparation of hydantoins with the (het)aryl substituent at the C-5 position. The reason behind this fact is not clear but it 37


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Figure 4. Calculated physicochemical parameters of the library members 1{3(1−185),12(1−629)} and their correlation with yields of the products.

The selection procedure, followed by visual inspection gave 367 compounds with high predicted binding affinity. Synthesis of these library members was performed according to the Scheme 4. To allow for the linker variation, the synthesis commenced from 1,3-unsubstituted hydantoins 1{3(10− 191),12(630)} modifiable at the N-1 position, which were in turn prepared from ammonium chloride (12(630)), bis(2,2,2-

Ala 212, the hydrogen bond with Lys 161, and placing the hydrophobic heterocycle in a subpocket remote from the kinase binding site (Figure 7). The substituents R1 and R2 additionally stabilized the position of hydantoin in the binding site model. According to the proposed interaction model, the optimal length of the linker between the two parts of the molecule was optimal at 4−5 atoms. 38


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Scheme 4. Synthesis of the Hydantoin Library 13a

Figure 5. Examples of low-nucleophilic amines 12: substrates for the hydantoin synthesis.

a

CMPI = 2-chloro-1-methylpyridinium iodide.

Table 1. Results of in Vitro Testing of the Hydantoins 13 against Aurora Kinase A

Figure 6. General features of the potential Aurora kinase A ligands proposed.

trifluoroethyl)carbonate (10b), and amino esters 3. To introduce the linkers, alkylation of these hydantoins with ωchloro esters 14(1−3) were used. After deprotection, carboxylic acids 15{3(10−191),14(1−3)} were obtained. It should be noted that these three steps were performed as a single parallel reaction sequence, so that carboxylic acids 15{3(10− 191),14(1−3)} were obtained directly from the amino esters 3. The crude products 15 were used in the ester/amide formation step, which gave 302 of 367 compounds 13{3(10− 191),14(1−3),16(1−174)} or 13{3(10−191),14(1−3),17(1− 63)} in 9−34% overall yield (82% success rate) (Figure S3). In Vitro Evaluation of the Library. In vitro testing of the 302 hydantoins 13 was performed at 10 μM concentration of the ligand (Figure S3). For the compounds which showed at least 50% inhibition at this concentration, IC50 was determined. Five compounds inhibited Aurora kinase A in a (sub)micromolar range, with IC 50 of the most active one (13{3(189),14(1),16(5)}) being equal to 0.97 μM (Table 1).

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CONCLUSIONS Synthesis of hydantoins by reaction of in situ generated 2,2,2trifluoroethylcarbamates and α-amino esters is an efficient method for the preparation of combinatorial libraries. The procedures developed are amenable for wide range of substrates including aliphatic, aromatic and heteroaromatic amines, as well as compounds with additional functional groups (e.g., hydroxyl, amide, or additional basic center). A library of 1158 hydantoins which fully comply with lead-likeness criteria was prepared with 79% success rate and 42% average yield. It was shown that the average yield of the products only slightly increased upon increase of the product molecular weight (MW), and no “LogP drift” was observed; thus the method is compatible with criteria

Figure 7. Schematic interaction between Aurora kinase A and ligand 13{3(189),14(1),16(5)} (left), and 3D structure with a pharmacophore model (right). The constraints are shown in red−hydrogen bond acceptor, blue−hydrogen bond donor, orange−aromatic part of the molecule. 39


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vial for 2 h. After the mixture was cooled, xylene (0.3 mL) was added, and the volatile liquids were removed in vacuo. Then MeCN (2 mL), amino ester 3 (1 mmol), and DBU (1.5 mmol; 2.6 mmol for the hydrochloride) were added to the residue, and the resulting mixture was heated at 100 °C for 4 h. After the mixture was cooled, 10% aq AcOH (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL). Extract was washed twice with H2O (6 mL), and CHCl3 was evaporated in vacuo to give the target product 1. One-Pot Parallel Synthesis of Carboxylic Acids 15. Hydantoin 1{3(10−191),12(630)} was prepared by method A starting from amino ester 3 (1 mmol) and NH4Cl (1.2 mmol). The crude product was dissolved in DMF (2 mL), i-Pr2NEt (1.2 mmol) was added, and the mixture was stirred at rt for 0.5 h. Then tert-butyl ester 14 (1 mmol) was added, and the mixture was stirred at rt for 1 h and at 100 °C for 6 (14(1)), 9 (14(2)), or 12 h (14(3)) and then cooled to rt. H2O (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL). The organic phase was evaporated in vacuo; CH2Cl2 (1 mL) and CF3COOH (1 mL) were added, and the mixture was stirred at rt for 12 h. The volatiles were removed in vacuo to give the crude product 15 which was used in the next step without characterization. Parallel Synthesis of Esters 13{3(10−191),14(1− 3),16(1−174)}. Carboxylic acid 15 (0.1 mmol) was dissolved in DMF (0.5 mL); i-Pr2NEt (0.12 mmol) was added, and the mixture was stirred at rt for 0.5 h. Then alkyl halide 16 (0.1 mmol) was added, the mixture was stirred at rt for 1 h and at 100 °C for 6 h, and then cooled to rt. H2O (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL). The organic phase was evaporated in vacuo to give the target product 13. Parallel Synthesis of Amides 13{3(10−191),14(1− 3),17(1−63)}. Carboxylic acid 15 (0.1 mmol) was dissolved in MeCN, and DIPEA (0.12 mmol) was added. The mixture was stirred at rt for 0.5 h, 2-chloro-1-methylpyridinium iodide (CMPI) (0.1 mmol) was added, and the mixture was stirred at rt for additional 0.5 h and then at 100 °C for 6 h. H2O (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL). The organic phase was evaporated in vacuo to give the target product 13. Virtual Screening. Molecular docking was performed using a flexible ligand and a fixed receptor model. We used an algorithm of systematic docking (SDOCK+) implemented in QXP docking software, which had shown high reproducing ability of ligand conformation with minimum RMSD as compared to the crystallographic data.64 The maximum number of SDOCK+ routine steps was set to 100, and the 10 best structures (based on built-in QXP scoring function63) were retained for each compound. In accordance with the defined pharmacophore models, the resulting protein−ligand complex structures had been filtered by intrinsic Flo+ filters and multiRMSD software package.65 Prior to the docking routine, water molecules were removed from the PDB structures. All Arg and Lys residues were protonated in order to be capable of forming a large number of hydrogen bonds. A set of 108 000 small molecule structures was docked into the model binding sites. All possible stereoisomers were generated (maximum 8) resulting in about 486 000 three-dimensional structures, subsequently docked into the binding sites using QXP/Flo software with 100 steps of SDOCK+ routine. The 10 lowest energy complex structures were selected for each small molecule, resulting in a total of about 4 860 000 of protein−ligand complexes, which

of lead-oriented synthesis. Analysis of other factors showed that while H-bond acceptor count (H-Acc) did not influence the yield of the products significantly, increasing the number of Hdonors (H-Don) resulted in significant drop in average method efficiency. The method was more effective for the products with higher rotatable bond count (RotB), and the highest average yields were observed for the compounds with Fsp3 = 0.4−0.8. Finally, the utility of the approach was demonstrated by discovery of submicromolar Aurora kinase A inhibitor bearing the hydantoin moiety.

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EXPERIMENTAL PROCEDURES General. All chemicals and solvents were obtained from Enamine Ltd. and used without further purification. 1H and 13C NMR spectra were acquired on Bruker Advance DRX 400 and Bruker Avance DRX 500 spectrometers using DMSO-d6 as a solvent and tetramethylsilane as internal standard. Melting points were determined on a Buchi melting point apparatus. LCMS data were recorded on Agilent 1100 HPLC equipped with diode-matrix and mass-selective detector Agilent LC/MSD SL, column: Zorbax SB-C18, 4.6 mm × 15 mm; eluent, A, acetonitrile−water with 0.1% of TFA (95:5), B, water with 0.1% of TFA; flow rate: 1.8 mL/min. Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Kyiv National Taras Shevchenko University. Syntheses of the libraries 3 and 13 were performed in 8 mL vials (Figure S1); loading of the reagents, as well as workup of the reaction mixtures was performed manually in a parallel fashion. Reactions were performed in ultrasonic baths or laboratory ovens with a shaker (Figure S2); up to 1000 vials could be used simultaneously (the whole library 3 was synthesized in three runs). The shaking of the reaction vials and extraction were done in an ultrasonic bath; the phases were separated manually with Pasteur pipettes. Centrifugal evaporators were used to remove the solvents from the vials in a parallel fashion. The target library members were typically obtained with >90% purity. If necessary, they were purified by the following method: the crude product (obtained from 1 mmol of the starting compound) was dissolved in MeOH (1 mL), and C18modified silica gel (100 mg) was added. The suspension was stirred for 2 h, filtered, and the filtrate was evaporated in vacuo. If the product still was not pure enough, it was subjected to preparative flash chromatography (Combiflash Companion chromarograph, 12 g RediSep columns, gradient hexanes−iPrOH as eluent). Parallel Synthesis of Hydantoins 1 from Amino Esters 3 and (Hetero)Aromatic Amines 12 (Method A). To a solution of amine 12 (1 mmol) in dioxane (1 mL), i-Pr2NEt (2.5 mmol; additional 1 mmol for the amine/amino ester hydrochlorides) and 2,2,2-trifluoroethyl chloroformate (10a) (1 mmol) were added successively. This mixture was shaken at rt for 1.5 h and then amino ester 3 (1 mmol) was added, and the mixture was heated at 100 °C for 12 h. After the mixture was cooled, 10% aq AcOH (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL). The extract was washed twice with H2O (6 mL), and the organic phase was evaporated in vacuo to give the target product 1. Parallel Synthesis of Hydantoins 1 from Amino Esters 3 and Aliphatic Amines 12 (Method B). A mixture of amine 12 (1.2 mmol; for the hydrochloride, i-Pr2NEt (1.3 mmol) was also added) and bis-2,2,2-trifluoroethylcarbonate (10b) (1.5 mmol) in acetonitrile (2 mL) was heated at 75 °C in a sealed 40


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ACS Combinatorial Science were then filtered by the internal Flo+ filters and the geometrybased filters. Filtering criteria for the internal scoring functions were as following: pI > 3, Cntc < −59, Pslv >8. These criteria eliminated frankly unsuccessful protein−ligand complexes. At the next step of filtering, conditions that we deemed necessary for the binding of the substance in the active site model were given. For the filtering, the following modules were used: Nearest atom filter, Hydrogen bonds filter. The created model of interaction included five parameters: minimum three hydrogen bonds, Ala 212.A O − 2.25 Å − H, Ala 212.A NH − 2.25 Å − O, Lys 161.A NZH 2.65 Å, any acceptor and Gln 184.A CG − 5.5 Å − any atom. All complexes retained after filtering were the subject for visual inspections.

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(6) Garcia-Castro, M.; Zimmermann, S.; Sankar, M. G.; Kumar, K. Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery. Angew. Chem., Int. Ed. 2016, 55 (27), 7586−7605. (7) Ware, E. The Chemistry of the Hydantoins. Chem. Rev. 1950, 46, 403−470. (8) Meusel, M.; Gütschow, M. Recent Developments in Hydantoin Chemistry. A Review. Org. Prep. Proced. Int. 2004, 36, 391−443. (9) Avendaño, C.; Menendez, J. C. Hydantoin and Its Derivatives. In Kirk-Othmer Encyclopedia of Chemical Technology; John Wiley & Sons, Inc., 2000. (10) Li, J. J. Bucherer-Bergs Reaction. In Name Reactions: A Collection of Detailed Reaction Mechanisms; Springer: Berlin, 2006; pp 92−93. (11) Scozzafava, A.; Supuran, C. T. Protease Inhibitors: Synthesis of Potent Bacterial Collagenase and Matrix Metalloproteinase Inhibitors Incorporating N-4-Nitrobenzylsulfonylglycine Hydroxamate Moieties. J. Med. Chem. 2000, 43, 1858−1865. (12) Von Geldern, T. W.; Kester, J. A.; Bal, R.; Wu-Wong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J. Azole Endothelin Antagonists. 2. Structure-Activity Studies. J. Med. Chem. 1996, 39, 968−981. (13) Plechanovová, A.; Byun, Y.; Alquicer, G.; Škultétyová, L.; Mlčochová, P.; Němcová, A.; Kim, H. J.; Navrátil, M.; Mease, R.; Lubkowski, J.; Pomper, M.; Konvalinka, J.; Rulíšek, L.; Bařinka, C. Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity. J. Med. Chem. 2011, 54, 7535− 7546. (14) Mateos-Caro, J.; Robin, Y.; Levacher, V.; Marsais, F. Controlled Ring Opening of N-Sulfinyl- and N-Silyl-N-Carboxyanhydrides (NCA): One-Pot Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas from Unprotected NCA. Synlett 2009, 2009, 279−283. (15) Nique, F.; Peixoto, C.; Lefranc, J.; Alvey, L.; Manioc, M.; Housseman, C.; Klaassen, H.; Van Beeck, K.; Namour, F.; Minet, D.; Van der Aar, E.; Feyen, J.; Fletcher, S.; Blanque, R.; RobinJagerschmidt, C.; Deprez, P. Identification of a 4- (Hydroxymethyl)diarylhydantoin as a Selective Androgen Receptor Modulator. J. Med. Chem. 2012, 55, 8236−8247. (16) Schulze, W. Zur Synthese von N-Chlorcarbonyl-N-ArylAlaninmethylestern Und Deren Reaktion Rnit Aminen. Z. Chem. 1989, 29, 285−286. (17) Nakane, M.; Reid, J. A.; Han, W.-C.; Das, J.; Truc, V. C.; Haslanger, M. F.; Garber, D.; Harris, D. N.; Hedberg, A.; Ogletree, M. L.; Hall, S. E. 7-Oxabicyclo[2.2.1]heptyl Carboxylic Acids as Thromboxane A2 Antagonists: Aza O-Chain Analogues. J. Med. Chem. 1990, 33, 2465−2476. (18) Hartwig, S.; Schwarz, J.; Hecht, S. From Peptides to Their Alternating Ester-Urea Analogues: Synthesis and Influence of Hydrogen Bonding Motif and Stereochemistry on Aggregation. J. Org. Chem. 2010, 75, 772−782. (19) Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; Fouquet, A.; Maillet, M.; Nicolai, E.; Dorgeret, L.; Chevallier, F.; Besse, D.; Dufort, M.; Caussade, F.; Ahmad, S. Z.; Stetsko, D. K.; Skala, S.; Davis, P. M.; Balimane, P.; Patel, K.; Yang, Z.; Marathe, P.; Postelneck, J.; Townsend, R. M.; Dhar, T. G. M.; et al. Discovery and Development of 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-Dichlorophenyl)-1-Methyl-2,4-Dioxo-1,3,7-triazaspiro[4.4]non-7-Yl-Methyl]-3-Thiophenecarboxylic Acid (BMS-587101). A Small Molecule Antagonist of Leukocyte Function Associated Antigen-1. J. Med. Chem. 2006, 49, 6946−6949. (20) Turner, E. M.; Blazer, L. L.; Neubig, R. R.; Husbands, S. M. Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med. Chem. Lett. 2012, 3, 146−150. (21) Xie, Z.; Chai, K.; Piao, H.; Kwak, K.; Quan, Z. Synthesis and Anticonvulsant Activity of of 7-Alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3a]quinolines. Bioorg. Med. Chem. Lett. 2005, 15, 4803−4805. (22) Park, K. H.; Kurth, M. J. Diastereoselective Synthesis of Hydantoin- and Isoxazoline-Substituted Dispirocyclobutanoids. J. Org. Chem. 2000, 65, 3520−3524.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscombsci.7b00163. Parallel reactions set up, laboratory oven with a shaker, structures of amino esters 3(1−185), structures of amines 12(1−629), parallel synthesis of hydantoins 1{3(1−185),12(1−629)}, structures of the hydantoins 13{3(10−191),14(1−3),16(1−174)}, 13{3(10− 191),14(1−3),17(1−63)} and their inhibition of Aurora kinase A, compound characterization data, 1H NMR and 13 C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Oleksandr O. Grygorenko: 0000-0002-6036-5859 Present Address ⊥

(O.S.): Department of Chemistry of Bioactive NitrogenContaining Heterocyclic Bases, Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv, 02094, Ukraine. Author Contributions §

A.V.B., Y.S.M., and O.S. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Mr. Vitaliy V. Polovinko for NMR measurements. REFERENCES

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