Heteroaromatic Diazirines in Material and Medicinal Chemistry: Comparison
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n materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as ligand–receptor, nucleic acid–protein, lipid–protein, and protein–protein interactions. In particular, use of TPD has increased in materials science to create novel electric and polymer devices with comparative ease and reduced costs. Therefore, a combination of heteroaromatics and (3-trifluoromethyl)diazirine is a promising option for creating better materials and elucidating the unknown mechanisms of action of bioactive heteroaromatic compounds.

  • diazirine
  • heteroaromatics
  • medicinal chemistry

1. Diazirinyl-Substituted Pyridines and Pyrimidines

Recently, use of (3-trifluoromethyl)phenyldiazirine (TPD) has been widely increasing in materials science for creation of crosslinking of component parts of organic light-emitting diodes [1][2], for primers for fiber-reinforced polymer composites [3], and for patterning of wearable elastic circuits [4]. Despite the success of TPD as a photocross-coupling agent, in order to establish functional materials more efficiently and easily with versatile photocrosslinking, there is a need to improve the photolabeling performance of TPD. This includes factors such as stability against ambient light and water solubility to enable reactions in aqueous solutions. Kumar et al. designed and synthesized novel 3-pyridyl and 3-pyrimidyl-substituted 3-trifluoromethyl-diazirines 11 and 12, which possess stability under ambient light and have aqueous solubility [5]. As shown in Scheme 1, 5-bromo pyridyl compound 1 and pyrimidyl compound 2 were subjected to the protection of primary alcohol with silyl groups (tert-butyldimethylsilyl, TBS; tert-butyldiphenylsilyl, TBDPS); subsequently, trifluoroacetylation of compounds 3 and 4 was conducted with n-BuLi and methyl trifluoroacetate to obtain 5 and 6 with a moderate yield. Next, the trifluoroacetyl groups were converted to oximes, followed by tosylation in an appropriate manner for each compound. Tosyl oximes 7 and 8 underwent the addition of ammonia (liquid) to give diaziridines 9 and 10 with a good yield. Finally, the desired products, diazirines 11 and 12, were obtained through oxidation of the diaziridinyl moiety with silver oxide and deprotection of the silyl group with tetrabutylammonium fluoride (TBAF).
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Scheme 1. The synthesis of 3-trifluoromethyl-diazirinyl pyridine 11 and pyrimidine 12.
The photoactivation and the ambient light stability of synthesized diazirinyl compounds 11 and 12 were tested and compared to those of (4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol 13. The photoreactive kinetics of these three compounds were calculated through photoactivation of a solution of the photolabel in methanol-d4 with UV light and measurement of the compound change using 19F NMR over time. Neither electron-withdrawing pyridine nor pyrimidine rings affected the ratio of generation of carbene from a diazirine, and they indicated the same photoreactive efficiency as in compound 13. Moreover, the ambient light stability of 11 and 12 was investigated. Compound 13 had already demonstrated significant photodecomposition after seven days with ambient light exposure. In contrast, compounds 11 and 12 were negligibly photodecomposed. After exposure of the probes to ambient light for a period of one month, only 27% of compound 13 remained, whereas 79% of compound 11 and 90% of compound 12 remained.
Green chemistry in materials science is one of the most vital challenges: for example, replacement of organic solvents, success of organic reactions in aqueous solutions, etc. The aqueous-solubility enhancements of compounds 11 and 12 were demonstrated, and it was confirmed, using a HPLC-based assay, that the 11 and 12 derivatives were 100–7500 times more soluble than the 13 derivatives at pH = 7.4 and 5.0 [6].
Therefore, 3-pyridyl and 3-pyrimidyl-substituted 3-trifluoromethyl-diazirines 11 and 12 demonstrated significant ambient-light-stability and aqueous-solubility improvements over the conventional 3-trifluoromethyl-3-aryldiazirines. These physicochemical properties could contribute huge advantages, and not only for photolabeling experiments in materials science.

2. Diazirinyl-Substituted Benzimidazoles

Benzimidazole and imidazole derivatives are medicinally used as anticancer [7][8][9][10][11], antioxidant [12][13], anti-inflammatory [14][15], anticoagulant [16][17], anthelmintic, or opioid products, and for analgesic activity [18]. Therefore, in order to discover better medicinal reagents or drugs, it is important to identify the target biomolecules of benzimidazole and imidazole derivatives and understand the mechanism of action of their pharmacological effects. Diazirinyl-substituted benzimidazole was reported by Raimer et al., and its chemical properties, thermal stability, and photoreactivity have been demonstrated [19]. The starting material, 14, was prepared following a previous report [20], then converted to oxime, tosyloxime, diaziridine 15, and diazirine 16 in four steps according to standard protocol (Scheme 2). Moreover, the synthesis of diazirinyl-substituted imidazoles was also attempted, but only diaziridines were able to be reached due to the violent decomposition of the diazirinyl imidazoles with self-ignition.
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Scheme 2. The synthesis of diazirinyl benzimidazole 16.
Next, the physical properties of diazirinyl-substituted benzimidazole 16 were investigated. The photoreaction of 16 in EtOH was slow, and ethoxy adduct 17 was formed, with a moderate yield (46%). Interestingly, in the case of decreasing the ethanol ratio to one equivalent of 16 in the presence of CH2Cl2, the reaction proceeded more quickly and gave a higher yield (60%; Scheme 3). This observation was already reported, identifying which solvent effect on the carbene reaction explained its different reactivity [21][22][23][24]. Furthermore, compound 16 was proved to have thermal stability at up to 88 °C in differential-scanning calorimetry measurement. Therefore, diazirinyl-substituted benzimidazole 16 could be the backbone of a reliable photoaffinity labeling (PAL) probe and contribute to new drug discovery through identification of target molecules of benzimidazole-containing bioactive substances.
Molecules 28 01408 sch003 550
Scheme 3. Photoreaction of diazirinyl-substituted benzimidazole 16 (10 mM) in the presence of EtOH and EtOH/CH2Cl2.

3. Diazirinyl-Substituted Pyrazoles

Pyrazoles, five-membered heterocyclic compounds including two nitrogen atoms, are an important class of compounds for drug development, with a wide application in medicinal chemistry [25][26][27]. Pyrazole derivatives exhibit diverse targets and resistance: for example, to cancer [28][29], acquired immunodeficiency syndrome [30][31], tubercular [32], insects [33], etc. Furthermore, 5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-cyano-4-(trifluoromethyl)sulfinylpyrazole (fipronil, Scheme 4), a chemical pesticide, is a widely used broad-spectrum insecticide. Fipronil, as a noncompetitive blocker, inhibits the γ-aminobutyric acid (GABA)-gated chloride-ion channel receptor. Furthermore, within the GABA receptor family, dysfunction of the Type A GABA receptor leads to neurological disorders and mental illnesses in humans; therefore, the GABA receptor is a drug-discovery target for these disorders [34][35][36]. Moreover, understanding fipronil’s noncompetitive binding site in the GABA-gated chloride channel might be a fascinating matter for medicinal chemistry.
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Scheme 4. The synthesis of diazirinyl fipronil based on benzimidazole skeleton 18.
For this purpose, fipronil-based photoaffinity probe 18 (Scheme 4) was prepared by the Casida J.E. group [37][38]. Its synthesis was started from commercially available pyrazole 19, reacted with iodine and ceric ammonium nitrate to produce 4-iodopyrazole 20. Compound 21 was obtained via the nucleophilic aromatic substitution of 20 with potassium carbonate in DMF at 100 °C with a quantitative yield. Subsequently, an iodine–magnesium exchange of 21 was performed with i-propylmagnesium chloride, followed by nucleophilic substitution with N-(trifluoroacetyl)piperidine to obtain 4-trifluoroacetylpyrazole 22. Finally, compound 18 was prepared according to a previous synthetic method [39][40][41] (Scheme 4).
The use of radioisotopes incorporated in a PAL probe is an efficient method for detection of labeled molecules because of the radioisotopes high sensitivity. Thus, the incorporation of tritium into fipronil-based photoaffinity probe 18 was also attempted. Initially, iodine incorporation into compound 18 or 22 was attempted several times via ortho lithiation; however, the desired products could not be obtained. Conversely, compound 25, which was prepared through the reduction of 22 with NaBH4, was smoothly subjected to iodination under standard lithiation conditions [42]. Compound 24 was reoxidized back to trifluoroacetyl 25, with the Dess–Martin reagent [43][44], which was followed by conversion to diazirine 26. Next, reduction of diiodoarene 26 with tritium gas, 10% Pd/C, and triethylamine in ethyl acetate was conducted to obtain tritium-labeled, fipronil-based photoaffinity probe 27 (Scheme 5). The binding potency of 18 for the GABA receptor was also evaluated through competitive inhibition with 4′-ethynyl-4-[2,3-3H2]propylbicycloorthobenzoate, and the molar concentrations for 50% inhibition via 18 indicated approximately 2 nM. Therefore, compounds 18 and 27 could be suitable mimics of fipronil for use in photoaffinity labeling.
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Scheme 5. The synthesis of tritium-labeled, fipronil-based photoaffinity probe 27.

4. Diazirinyl-Substituted Benzoxazolinone

Benzoxazolinones 28, 29, and 30 (Table 3), isolated from light-grown maize (Zea mays L.) shoots, have the potential to interfere with auxin behavior or inhibit the auxin receptor [45]. Kosemura, S. et al. reported that the structure–activity relationships of benzoxazolinones 31 and 32 were related to auxin-induced growth and auxin-binding protein [46]. The precise mechanism through which this bioactivity is triggered via benzoxazolinones has remained unknown. To address this subject, Kosemura, S. et al. tried synthesizing two photolabile benzoxazolinone analogues, 33 and 34, and evaluated their photoreactivities [47].
Photoreactive compound 42 was prepared from starting material 3-bromoanisole 35 according to a previous method [48][49]. Briefly, compound 35 was converted to the Grignard reagent treated with magnesium, followed by nucleophilic substitution with N-(trifluoroacetyl)piperidine to obtain 3-trifluoroacetylanisole 36. Compound 40 was prepared from 36, following the general diazirine synthetic method. Subsequently, nitration of 40 with fuming nitric acid and demethylation of 41 with BBr3 were conducted to obtain compound 42 with a moderate yield, 42%, in two steps. The reduction of the nitro group in 42 was carried out with Na2S2O4 while diazirine reduction was avoided as much as possible. Finally, Compound 43 was subjected to phenyl carbamation 44, followed by intramolecular cyclization to obtain the desired product, 33, with 14% in three steps (Scheme 6).
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Scheme 6. The synthesis of diazirinyl benzoxazolinone analogue 33.
Moreover, photoreactive compound 34 was synthesized with the following procedure: Phenolic alcohol 45 was protected with chloromethyl methyl ether (MOMCl), followed by bromination with N-bromosuccinimide (NBS), to obtain compound 46. Trifluoroacetylation of 46 was carried out through a bromine–lithium exchange with n-BuLi, followed by nucleophilic substitution with ethyl trifluoroacetate, to obtain compound 47. Diazirine 48 was prepared according to the same procedure to construct 40 from 36. Nitration of 48 with fuming nitric acid was conducted at −72 °C to avoid the decomposition of the diazirine moiety. Compound 49 was deprotected with acidic hydrolysis 50 and then protected again with acetic anhydride to obtain compound 51. The nitro group of 51 was subjected to reduction with Na2S2O4 within 5 min, followed by carbamation with phenyl chloroformate, then treated with sodium hydroxide to obtain the desired diazirine, 34 (32% in three steps) (Scheme 7).
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Scheme 7. The synthesis of diazirinyl-substituted benzoxazolinone analogue 34.
Next, diazirinyl benzoxazolinones 33 and 34 were evaluated as to whether they had suitable characteristics for photoaffinity-labeling reagents. The photoirradiation of compound 33 (1 mM in methanol) was smoothly carried out with a black light (12 W) to produce methanol adduct 53 with a moderate yield. The half-life (t1/2) of 33 was calculated to be approximately 16 min, whereas the photoreactive kinetics of 34 with the black light (12 W) were much slower than those of 33. Using a 500 W high-pressure mercury lamp for photolysis of 34, compound 54 was produced, and the half-life (t1/2) of 34 was 6 min (Scheme 8). Therefore, both of the compounds have suitable characteristics for photoaffinity-labeling reagents.
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Scheme 8. Photoreaction of diazirinyl-substituted benzoxazolinones 33 and 34 (1 mM) in the presence of MeOH.

5. Diazirinyl-Substituted Benzoxazole

Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, leads to progressive muscle degeneration and results in heart and respiratory failure [50][51]. Although quality of life and longevity have been improved with developments in the clinical standard of care [52][53][54], there is no complete treatment available for DMD. Recently, ezutromid (55) has been developed as a utrophin modulator and demonstrated reduced muscle-fiber damage and increased levels of utrophin after 24 trial weeks [55]. However, due to an administration effect, ezutromid could not retain this effect for a long period, and the mechanism of action of ezutromid is unknown. The development of ezutromid was discontinued. Therefore, to elucidate the mechanism of action of ezutromid for these effects and discover new drugs for DMD, Wilkinson, I.V.L. et al. synthesized photoreactive ezutromid derivatives 56 and 57 [56] for use in affinity-based protein profiling (ABPP) [57][58][59]. As a photophore of 56 and 57, 3-trifluoromethyldiazirine was chosen to replace the ethylsulfonyl group of ezutromid because of the similarity in the electronics of the diazirine and sulfonyl groups. The naphthyl moiety was replaced with alkynyl-phenyl substituents for installation of detection tags with click chemistry. The synthetic scheme of photoreactive compounds 56 and 57 is shown in Scheme 9, beginning with microwave-assisted benzoxazole cyclization 60 from 3-amino-4-hydroxybenzoic acid 58, and the corresponding acid chloride, 59, without purification [60]. The carboxylic acid was subjected to conversion of Weinreb amides 61 and 62, followed by trifluoroacetylation with the Ruppert–Prakash reagent to obtain 63 [61]. Diazirine derivatives 64 and 65 were introduced according to the general method [62]. Finally, Sonogashira couplings with TMS-acetylene were followed by TMS deprotection to obtain the desired products, 56 and 57, with a moderate yield (50–70%).
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Scheme 9. The synthesis of diazirinyl-substituted benzoxazole analogues 56 and 57.
Furthermore, compounds 56 and 57 were applied to ABPP and found to bind the aryl hydrocarbon receptor (AhR). As a result, ezutromid was revealed as a novel AhR antagonist, inhibiting nuclear translocation and downregulating AhR-responsive genes such as AhRR and Cyp1b1.

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