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. 2024 Nov 11;4(11):4507–4517. doi: 10.1021/jacsau.4c00864

CF3-Cyclobutanes: Synthesis, Properties, and Evaluation as a Unique tert-Butyl Group Analogue

Volodymyr Ahunovych †,‡, Anton A Klipkov †,‡, Maksym Bugera †,‡, Karen Tarasenko †,‡, Serhii Trofymchuk †, Bohdan Razhyk †, Andrii Boretskyi †, Oleh Stanko †, Yaroslav Panasiuk †, Oleh Shablykin †,‡, Galeb Al-Maali †,§, Dmytro Lesyk ∥, Oleksii Klymenko-Ulianov ∥, Kateryna Horbatok ∥, Iryna Bodenchuk ∥, Viktoriia Kosach ∥, Petro Borysko ∥, Vladimir Kubyshkin †, Pavel K Mykhailiuk †,⊥,*
PMCID: PMC11600199  PMID: 39610719

Abstract

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Isosteric replacement of functional groups is an emerging strategy for optimizing bioactive molecules in drug discovery. tert-Butyl group is a particularly important moiety, yet its isosteric replacement with 1-trifluoromethyl-cyclobutyl group has been rather neglected. To enable the advance of this molecular fragment in drug discovery programs, we report the synthesis of over 30 small-molecule building blocks featuring the trifluoromethyl-cyclobutyl fragment, achieved by reacting sulfur tetrafluoride with cyclobutylcarboxylic acids on a gram-to-multigram scale. Furthermore, we characterized the structural properties of this group through X-ray analysis, studied its effect on acid–base transitions, and evaluated its Hammett parameters. Finally, we evaluated the replacement of tert-butyl with 1-trifluoromethyl-cyclobutyl in several bioactive compounds that represent commercial drugs and agrochemicals. Our findings indicate that while the trifluoromethyl-cyclobutyl group exhibited slightly larger steric size and moderately increased lipophilicity, it preserved the original mode of bioactivity in the examined cases and, in some cases, enhanced resistance to metabolic clearance.

Keywords: bioisostere, medicinal chemistry, tert-butyl, CF3-cyclopropane, CF3-cyclobutane

Introduction

The trifluoromethyl and difluoromethyl groups are the most popular fluoroalkyl substituents in chemistry.1 Recent achievements in drug discovery, however, also brought the attention of chemists toward other more sophisticated substituents: difluorocyclobutyl, trifluoroethyl, pentafluoroethyl, trifluoro-tert-butyl, and CF3-cyclopropane (Figure 1).2 The latter, in particular, was used as a metabolically improved alternative for the labile tert-butyl group (Figure 1).3 This replacement has eventually become common in chemistry, inspiring academic groups to search for novel synthetic approaches toward CF3-cyclopropanes.4−7 In parallel, various pharmaceutical companies started routinely using CF3-cyclopropane substituents in bioactive compounds, as reflected in at least 600 recent patents (Figure 1).8

Figure 1.

Figure 1

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Unique fluoroalkyl substituents. A tert-butyl group and its analogues: a CF3-cyclopropane substituent (previous study) and a CF3-cyclobutane substituent (this work).

In this work, originally driven by scientific curiosity, we hypothesized that the previously underappreciated chemical substituent—CF3 cyclobutane (Figure 1) that only appeared in a few previous studies9−16—could also be used as a unique tert-butyl group analogue. Here, we have developed a practical modular synthesis of this substituent, comprehensively characterized it, and validated our hypothesis with experimental data.

Results and Discussion

Synthesis

To validate our hypothesis, we first aimed to prepare a library of diverse CF3-cyclobutanes. Poly-substituted CF3-cyclobutanes are typically synthesized using linear approaches: thermal and photochemical [2 + 2]-cycloadditions;17−26 addition of CF3TMS to imines and ketones;27−30 among other methods.31−36 In a search for a modular approach to CF3-cyclobutanes from commercially available starting materials, we focused our attention on a well-known reaction between carboxylic acids and sulfur tetrafluoride.37−39

This transformation has been reported for poly-substituted cyclobutane carboxylic acids.40−46 We envisioned that the same strategy could also be applied to rapidly make a wide variety of appropriate mono-substituted CF3-cyclobutanes, to subsequently mimic tert-butyl groups in drugs.

Pleasingly, a thermal reaction of sulfur tetrafluoride with various (hetero)aromatic cyclobutane carboxylic acids 1–18 efficiently gave trifluoromethyl cyclobutanes 1a–18a in good yields (Scheme 1). The reaction was compatible with nitro groups (4a, 5a), activated chlorine (7a, 13a, and 16a), and bromine (8a) atoms.

Scheme 1. Synthesis of Trifluoromethyl Cyclobutanes.

Scheme 1

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Reaction conditions: (i) carboxylic acid (1.0 equiv), SF4 (3–30 equiv), additives (water or HF), 60–110 °C, 12–144 h; (ii) purification (column chromatography or crystallization or vacuum distillation). Scale of the synthesis: a 100–300 mg; b 500 mg–5 g; c 5–10 g; d >10 g of the isolated product. e The starting carboxylic acids 6–11, and 15 were used in the form of their potassium salts (R-CO2K). f Diisopropyl ester of diacid 24 was directly used in the fluorination reaction. g After the reaction, crude products 22a–26a, 28a–34a were converted into the crystalline pure hydrochloride salts with 1 M HCl in MeOH. X-ray crystal structure of compounds 3a, 14a, 18a, 28a, 29a, and 31a are shown as thermal ellipsoids at a 30% probability level; carbon—white, oxygen—red, nitrogen—blue, bromine—orange, fluorine—green; hydrogen and chlorine (for hydrochloride salts 28a, 29a, 31a) atoms are not shown for clarity.

This transformation also worked well for aliphatic cyclobutane carboxylic acids with diverse substituents (19–34) to produce medicinal chemistry-relevant trifluoromethyl cyclobutanes 19a–34a. Among them were compounds with an ester group (19a, 20a, and 27a), an activated bromine atom (21a), and an unprotected amino group (22a–26a). It is worth noting that the reaction worked for bicyclo[1.1.1]pentanes (26a, 28a), and even for difluoro-substituted bicyclo[1.1.1]pentanes (27a).47−50 The only two products that could not be obtained even when varying conditions were the ortho-substituted bromobenzene and a cubane derivative (Scheme 1). The formation of complex mixtures was observed in both cases.

It is important to note that this method worked equally well on milligram, gram, and even multigram scales (2a, 9a, and 19a). On a milligram scale, products were purified by silica gel column chromatography. On a gram-to-multigram scale, products were isolated by either crystallization or distillation under reduced pressure. The structures of products 3a, 5a, 14a, 18a, 28a, 29a, and 31a were confirmed by X-ray crystallographic analysis.51

Despite the seeming simplicity of the current approach to CF3-cyclobutanes, the preparation of only three products 10a,3322a,52 and 26a(53) from Scheme 1 has been previously reported in the literature by other methods.

Modifications

Representative modifications of the obtained CF3-cyclobutanes were undertaken to obtain functionalized derivatives (Scheme 2).

Scheme 2. Modifications of Trifluoromethyl Cyclobutanes “a”.

Scheme 2

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Treatment of bromide 1a with n-BuLi followed by an addition of sulfur dioxide and subsequent oxidation with sulfuryl chloride gave sulfonyl chloride 1b. Reduction of nitro compounds 4a and 5a with Raney nickel gave anilines 4c and 5c. [Pd]-Catalyzed hydrogenation of the pyridine ring in compounds 6a, 12a, and 15a afforded piperidines 6d, 12d, and 15d respectively. [Pd]-catalyzed carbonylation of the (hetero)aromatic bromides 1a, 2a, 7a, and 9a–11a in methanol followed by saponification of the intermediate esters resulted in the formation of carboxylic acids 1e, 2e, 7e, and 9e–11e, correspondingly. A standard Curtius reaction of pyridine carboxylic acids 7e, 9e–11e followed by acidic N-Boc deprotection gave amino pyridines 7f, 9f–11f. Saponification of the ester group in 27a gave carboxylic acid 27g. The structures of products 1e, 10e, 11e, and 7f were confirmed by X-ray crystallographic analysis.51

Radical modifications of the obtained compounds were unsuccessful at this point (see SI p. S31–S33).

Chemical Stability

We also checked the chemical stability of three representative trifluoromethyl cyclobutanes, 4a, 9a, and 12a (Scheme 1) because we suspected that some of them could eliminate hydrogen fluoride over time. Treatment of them with aqueous 1 M hydrochloric acid or aqueous 1 M sodium hydroxide at room temperature for 1 day did not lead to any decomposition. We stored all products in closed vials at room temperature on the shelf. The 1H- and 19F-NMR, liquid chromatography–mass spectrometry (LC–MS) inspection after three months revealed no decomposition.

Crystallographic Analysis

Small-molecule X-ray structures representing 1-substituted CF3-cyclobutanes have been absent in the literature. Therefore, we studied the conformational preferences of the CF3-cyclobutane ring, based on the X-ray structures solved for eight compounds from this work: 3a, 5a, 14a, 18a, 1e, 10e, 11e, and 7f (Figure 2).51 We examined the axial/equatorial position of the trifluoromethyl substituent and measured the cyclobutane puckering angle γ and dihedral angles φ1 (C(2)–C–C-CF3) and φ2 (C(6)–C–C-CF3) to determine the alignment of the (hetero)aromatic substituent around the cyclobutane ring; and the distance d between two distal carbon atoms in the cyclobutane ring (Figure 2).

Figure 2.

Figure 2

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Definition of angles γ, φ, and distance d (1-Ph trifluoromethyl cyclobutane is shown as an example). φ1 = C(F3)–C-C(Ph)-C2. φ2 = C(F3)–C-C(Ph)-C6. C2 and C6 atoms are chosen so that |φ1|<|φ2|. Geometric parameters γ, |φ1|, |φ2|, and d are for trifluoromethyl cyclobutanes 3a, 5a, 14a, 18a, 1e, 10e, 11e, and 7f. a Two molecules of 7f (A, B) are present in the crystalline lattice.

Interestingly, in seven of eight studied CF3-cyclobutanes, the trifluoromethyl substituent adopted the axial position. Only in compound 18a, the trifluoromethyl substituent adopted the equatorial position (Figure 2).

The cyclobutane puckering angle γ was within the 158–175° range, suggesting an almost flattened cyclobutane ring. The dihedral angles /φ/ were in the range of 83–100°, indicating the “perpendicular” alignment of the (hetero)aromatic and the trifluoromethyl substituents in all compounds. The distance d between the carbon atoms in the cyclobutane ring was 2.1–2.2 Å.

Steric Volume

To estimate the size of the CF3-cyclobutane substituent compared to the tert-butyl group, we calculated54 and compared a steric volume of three molecules: tBu-, CF3-cyclopropane-, and CF3-cyclobutane-benzenes (Figure 3a). The obtained data show that the CF3-cyclobutane substituent is somewhat bigger than the tert-butyl group: 171 Å3 (CF3-cyclobutane) vs 155 Å3 (CF3-cyclopropane) vs 150 Å3 (t-Bu). For a more detailed comparison including other substitutes, see the SI (p. S354).

Figure 3.

Figure 3

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(a) Calculated molecular volume (Å3) of tBu-Ph, CF3-cyclopropane-Ph, and CF3-cyclobutane-Ph. (b) Visual comparison of tBu-Ph (left) and CF3-cyclobutane-Ph (right, the CF3-cyclobutane residue is green). (c) Superposition of tBu-Ph and CF3-cyclobutane-Ph (the CF3-cyclobutane residue is green).

The visual comparison of tBu-Ph and CF3-cyclobutane-Ph (Figure 3b) also shows the bigger steric size of the CF3-cyclobutane substituent compared to the tert-butyl group.

The Acidity of Functional Groups

To better understand the electron-withdrawing effect elicited by the CF3-cyclobutyl substituent, we studied the acid–base transition of pivalic acid and tert-butyl amine as compared to their CF3-cyclopropyl and CF3-cyclobutyl analogues. Toward this goal, we measured experimental pKa values of the corresponding carboxylic acids and amine hydrochlorides (Figure 4).

Figure 4.

Figure 4

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Experimental pKa values of carboxylic acids and amine hydrochlorides that are para-substituted with tert-butyl, CF3-cyclopropane, and CF3-cyclobutane groups.

Replacement of the tert-butyl group in pivalic acid for the fluoroalkyl substituents increased the acidity by ca. 2 pKa units: 4.79 (tBu) vs 2.99 (CF3-cyclopropane) vs 2.92 (CF3-cyclobutane). Analogous replacement in the tert-butyl amine hydrochloride increased the acidity even stronger, pKa: 10.69 (tBu) vs 4.06 (CF3-cyclopropane) vs 5.29 (CF3-cyclobutane). The significant difference of about 1 pKa unit between the cyclopropane and cyclobutane compounds can be explained by a conjugative effect within the aminocyclopropane unit.

These results demonstrate that the CF3-cyclobutane substituent is innately electron-withdrawing, but it is a weaker acceptor than the CF3-cyclopropane (Figure 4).

Hammett Parameters

To further characterize the electronic properties of the CF3-cyclobutane substituent, we also determined its Hammett parameters by adapting the 19F NMR approach developed by Taft.55−57 For comparison, the corresponding parameters for the CF3-cyclopropane substituent were measured, as well.

To this end, we first synthesized the fluorobenzenes substituted with the CF3-cyclobutane at the meta- (35a) and para-positions (36a) (Figure 5) and the corresponding CF3-cyclopropanes (see SI p. S34–S35). By measuring the chemical shift differences between meta- or para-substituted fluorobenzenes and a fluorobenzene internal standard, we determined inductive (σI) and resonance (σR) parameters, and thus meta- and para-σ constants (σm and σp; see SI p. S355–S356). The electron-withdrawing effect of the CF3-cyclobutane group was rather weak, with σm ≈ 0.04 and σp ≈ 0.02 (Figure 5), and can be benchmarked against that of the CH2OH group (σm ≈ 0.00 and σp ≈ 0.00) and that of the CH2F group (σm ≈ 0.12 and σp ≈ 0.11).58 For the CF3-cyclopropane group, we determined similar values of σm ≈ 0.08 and σp ≈ 0.08. In full accordance with the pKa data (Figure 4), the Hammett parameters show that the inductive influence of CF3-cyclobutane is slightly weaker than that of the CF3-cyclopropane substituent.

Figure 5.

Figure 5

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Experimental Hammett parameters of CF3-cyclopropane and CF3-cyclobutane substituents. Negative values of δHp-X and δHm-X denote downfield 19F NMR shifts (deshielding) of para- and meta-substituted fluorobenzene derivatives, respectively, relative to a fluorobenzene standard in <0.02 M solutions in CD3CN. The σI and σR0 parameters were calculated by the method of Taft and used to estimate σm0 and σp0 constants (see SI, p. S355–S356).

Incorporation into Drugs and Agrochemicals

With numerous building blocks in hand (Schemes 1 and 2), we were curious to study the effects of a tert-butyl-to-CF3-cyclobutane replacement on the experimental physicochemical and biological properties of bioactive compounds. Toward this goal, we synthesized CF3-cyclopropane- and CF3-cyclobutane-containing analogues of three drugs and two agrochemicals. CF3-cyclopropanes were included for comparison, representing an already established isosteric substitute. The examined bioactive structures included the antihistamine agent Buclizine, the antifungal agent Butenafine, the antidepressant drug Pyvhydrazine, and the herbicide agrochemicals Pinoxaden and Tebutam. We also synthesized small model amides 37–42 (Figure 2, see SI p. S35–S45).

Physicochemical Properties

Having synthesized the CF3-cyclobutane analogues of model and bioactive compounds (Figure 6), we studied their experimental physicochemical properties, water solubility, lipophilicity (see SI p. S357–S365), and metabolic stability (see SI p. S375–S382), and compared the data with those of the parent models, drugs, and agrochemicals.

Figure 6.

Figure 6

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Physicochemical properties of model compounds 37–42; drugs Buclizine, Butenafine, Pyvhydrazine; agrochemicals Pinoxaden, Tebutatam; and their CF3-cyclopropane/CF3-cyclobutane analogues 43–52. Sol.: the experimental kinetic solubility in phosphate-buffered saline, pH 7.4 (μM). log D (7.0) for compounds 37–42: the experimental distribution coefficient in n-octanol/water. Reliable log D values could be obtained within the range of 1.0–3.0 log D (7.4) for all other compounds: the experimental distribution coefficient in n-octanol/phosphate-buffered saline, pH 7.4. Reliable log D values could be obtained within the range of 1.0–4.5. CLint: experimental metabolic stability in human liver microsomes (μL min–1 mg–1). t1/2 (min): the experimental half-time of a metabolic decomposition in human liver microsomes. *Parameter should be considered as approximate due to the high stability of compounds. ** Parameter should be considered as approximate due to the high instability of compounds.

Water Solubility

Replacement of the tert-butyl group in model compound 40, Butenafine and Pivhydrazine with the CF3-cyclobutane showed a negligible impact on the water solubility: 313 μM (40) vs 338 μM (42); 10 μM (Butenafine) vs 8 μM (46); ≥400 μM (Pivhydrazine) vs 371 μM (52). In Pinoxaden and Tebutam, such replacement led to a notable 20–30% decrease in the solubility: 358 μM (Pinoxaden) vs 282 μM (48); 324 μM (Tebutam) vs 233 μM (50). In model compounds 39 and Buclizine, an effect was not detected due to either too high (39) or too low (Buclizine) solubility outside the sensitivity range of the experimental method.

In three studied compounds—40, Butenafine, and Pivhydrazine—the replacement of the tert-butyl group with the CF3-cyclobutane did not significantly affect the water solubility. In another two compounds studied—Pinoxaden and Tebutam—such replacement led to a notable decrease in solubility.

Lipophilicity

To estimate the influence of a replacement of a tert-butyl group with a CF3-cyclobutane on lipophilicity, we used the experimental index log D.

In model compounds 37 and 40, the replacement of the tert-butyl group with the CF3-cyclobutane led to an increase of the log D index by 0.4–0.5 units: 2.11 (37) vs 2.51 (39); 2.01 (40) vs 2.48 (42).

An analogous impact was observed in four bioactive compounds—Butenafine, Pinoxaden, Tebutam, and Pivhydrazine—the replacement of tert-butyl groups with CF3-cyclobutanes resulted in a notable increase in log D by ca. 0.5 units. In Buclizine, an effect could not be detected due to the high lipophilicity outside the sensitivity range of the experimental method.

Metabolic Stability

The effect of CF3-cyclobutane on the metabolic stability of the bioactive compounds varied among the analogues tested. In model compound 37 and Tebutam, the incorporation of CF3-cyclobutane led to a decrease in the metabolic stability, CLint (mg min–1 μL–1): 11 (37) vs 16 (39); 57 (Tebutam) vs 107 (50).

In model compounds 40 and Butenafine, the analogous replacement led to an increase in the metabolic stability, CLint (mg min–1 μL–1): 12 (40) vs 1 (42); 30 (Butenafine) vs 21 (46).

In Buclizine, Pinoxaden, and Pivhydrazine, effects were not observed because of either too high (Buclizine, Pivhydrazine) or too low (Pinoxaden) stability of bioactive compounds and their analogues outside the sensitivity range of the experimental method.

In summary, the replacement of the tert-butyl group with the CF3-cyclobutane in model/bioactive compounds tended to preserve/slightly decrease the water solubility and increase the lipophilicity. The effect on metabolic stability was inconsistent.

Biological Activity

Finally, we wanted to answer the key question of whether the CF3-cyclobutane motif indeed acts as an analogue of the tert-butyl group in bioactive compounds. To this end, we studied the biological properties of the antifungal agent Butenafine with its CF3-cyclobutane analogue 46; and the antihistamine agent Buclizine with its CF3-cyclobutane analogue 44. For comparison, we also studied the corresponding CF3-cyclopropane analogues 45 and 43.

Testing the antifungal activity Butenafine and its fluoroalkyl-substituted analogues 45, 46 against two fungal strains—Trichophyton mentagrophytes and Trichophyton rubrum—using the disk diffusion method was undertaken (for details, see SI, p. S383–S386).

Although the original drug was slightly more potent against both fungal strains (Figure 7), the patent-free CF3-cyclobutane analogue 46 was found to be reasonably active and showed high growth inhibition of both T. mentagrophytes and T. rubrum (Figure 7).

Figure 7.

Figure 7

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Inhibition of growth of (a) T. mentagrophytes (strain ATCC 18748) and (b) T. rubrum (strain ATCC 28188) (measured as a diameter d of the inhibition zone, in millimeters) by Butenafine and its analogues 45 and 46. (c) Structures of Butenafine and compound 46.

Buclizine is an antihistamine agent used as a drug for the treatment of allergy symptoms and the prevention of nausea and vomiting. Recently, Buclizine was suggested for repurposing for cancer treatment, following an observation that the original target (histamine-releasing factor) and the suggested one (translationally controlled tumor protein) were identical.59 Subsequently, Buclizine was found to exhibit a cytostatic effect in the MCF-7 human cancer cell line. The cell growth arrest was observed in a suppression of cell respiration, followed by the resazurin reduction assay. Buclizine also induced cell differentiation, which was seen in an accumulation of intracellular lipid droplets. In our study, we tested the analogues, 43 and 44, for their ability to arrest cell growth and induce lipid droplets and compared them to the parent Buclizine molecule (for details, see SI, p. S387–S389). By doing so, we expected to characterize indirectly the interaction of the compounds with the tumor protein depending on the nature of the tert-butyl group analogue in the molecule.

In the resazurin reduction assay, the original drug, Buclizine, showed moderate effectiveness (IC50 = 31 μM), while the CF3-cyclopropane analogue 43 was found to be inactive (Figure 8). Conversely, the patent-free CF3-cyclobutane analogue 44 was active and showed a micromolar inhibition (IC50 = 102 μM). Furthermore, in an experiment assisted by fluorescence imaging (Figure 9), the CF3-cyclobutane analogue 44 (EC50 = 15 μM) showed the earliest onset of lipid droplet formation among the tested substances (EC50 = 19 μM for Buclizine; and 21 μM for 43) (Figure 8).

Figure 8.

Figure 8

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Effectiveness of inhibition of (a) the growth of the human cancer cell line MCF-7 (IC50 index) and (b) lipid droplet formation (EC50 index) by Buclizine and its analogues 43 and 44.

Figure 9.

Figure 9

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Confocal images of the lipid droplet formation in MCF-7 cells upon incubation with Buclizine and analogues 43 and 44 for 72 h. Nuclei were stained with Hoechst 33342 (cyan), and lipid droplets were stained with Nile Red (red). Scale bars: 20 μm.

The data presented in this study highlights the CF3-cyclobutane unit as a promising analogue to a tert-butyl group, resulting in a valuable expansion of the structural repertoire available to medicinal chemists.

Conclusions

In this work, we have developed a modular practical approach toward a previously neglected class of compounds containing the CF3-cyclobutane group. We have comprehensively studied the impact of this substituent (pKa, lipophilicity, X-ray, Hammett constants, volume, ADME), and we demonstrated that it can mimic the tert-butyl group in drugs (Buclizine, Butenafine).

It is important to note that while the CF3-cyclopropane analogue 43 of Buclizine was inactive, the CF3-cyclobutane 44 exhibited a reasonable activity, suggesting that the CF3-cyclobutane is a more optimal replacement in this case.

We believe that expanding the repertoire of available analogues of the tert-butyl group will ease the job of medicinal chemists in designing and making new drugs. We anticipate that in the forthcoming decade, CF3-cyclobutyl-containing compounds will become common in chemistry.60

Acknowledgments

P.K.M. is grateful to Dr. S. Shishkina (IOC, Kyiv) for the X-ray studies, Dr. D. Bylina (Enamine) for HRMS measurements, Dr. Y. Holota (Bienta) for the help with ADME measurements, Artem Skreminskyi (Enamine) for logP measurements, Margarita Bolgova (Enamine) for pKa measurements, and Flynn Attard (Australian National University) for proofreading the text and helpful suggestions.

Data Availability Statement

The authors declare that data supporting the findings of this study are available within the paper and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c00864.

  • Details on chemical synthesis procedures including a photo session of the experimental setup with sulfur tetrafluoride; characterization of compounds; copies of the NMR spectra; crystal structures; data on the molecular volume of different substituents; determination of the Hammett parameters; protocols for determination of compound’s solubility, lipophilicity, and acid–base transition constants; and details of the biochemical studies of the metabolic clearance, antifungal activity, and cytostatic effect of the buclizine analogues (PDF)

  • Crystallographic data (ZIP)

Author Contributions

CRediT: Volodymyr Ahunovych data curation, formal analysis; Anton A. Klipkov data curation, formal analysis; Karen Tarasenko data curation, formal analysis; Serhii Trofymchuk data curation, formal analysis; Bohdan Razhyk data curation, formal analysis; Andrii Boretskyi data curation, formal analysis; Oleh Stanko data curation, formal analysis; Yaroslav Panasiuk formal analysis, investigation; Oleh Shablykin data curation, formal analysis; Galeb Al-Maali data curation, formal analysis; Dmytro Lesyk data curation, formal analysis; Oleksii Klymenko-Ulianov data curation, formal analysis; Kateryna Horbatok data curation, formal analysis; Iryna Bodenchuk data curation, formal analysis; Viktoriia Kosach data curation, formal analysis; Petro Borysko data curation, formal analysis, supervision, writing - review & editing; Vladimir Kubyshkin conceptualization, formal analysis, project administration, writing - review & editing; Pavel K. Mykhailiuk conceptualization, supervision, writing - original draft, writing - review & editing.

The authors declare the following competing financial interest(s): Authors of this work are emploees of a chemical supplier Enamine.

Supplementary Material

au4c00864_si_001.pdf (20.7MB, pdf)
au4c00864_si_002.zip (2.1MB, zip)

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