Lipase‐Catalyzed Kinetic Resolution of Novel Antifungal <i>N</i>‐Substituted Benzimidazole Derivatives

Łukowska-Chojnacka, Edyta; Staniszewska, Monika; Bondaryk, Małgorzata; Maurin, Jan K.; Bretner, Maria

doi:10.1002/chir.22591

Cited by 10 publications

(5 citation statements)

References 34 publications

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“…This phenomenon mainly stems from their high catalytic activity and thermal stability in organic solvents as well as wide substrates specificity toward xenobiotic substances. It is worth mentioning that in our previous synthetic campaigns the enzymatic method based on lipase catalysis was utilized to obtain optically pure CK2 inhibitors possessing both 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) [59,60] and TBBi [61] scaffolds. In this study, the biocatalytic approach allowed us to obtain final compounds with higher yields (58 to 88%) than when using convenient esterification conditions, while vinyl esters were used as acyl donors, instead of toxic and highly corrosive acyl chlorides.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Chojnacki

Wińska

Karatsai

et al. 2021

IJMS

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Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC50 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC50 values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.

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Section: Chemistrymentioning

confidence: 99%

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Chojnacki

Wińska

Karatsai

et al. 2021

IJMS

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“…To date, a plethora of synthetically useful hydroxylated/acylated derivatives have been investigated as the racemic substrates for the lipase-catalyzed kinetic resolution (KR) and/or dynamic kinetic resolution (DKR). Among the most important are the secondary alcohols and the corresponding esters possessing (hetero)aromatic substituents, such as imidazole [31], 1,2,4-triazole [32][33][34], pyrazole [35], isoxazole [36], thiazole [37,38], tetrazole [39,40], thiophene [41,42], tetrahydrothiophene [43], furan [44][45][46][47], benzimidazole [48], benzotriazole [49,50], benzothiazole [51], benzothiophene [52,53], benzofuran [54][55][56], tetrahydrofuran [57], pyridine [58,59], piperidine [44,60], piperazine [61], pyrrolidine [62,63], pyran [64], quinoline [65], phenothiazine [66][67][68][69][70], 1,10-phenanthroline [71], 1,3-dimethylxanthine [72,73], azetidine…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Synthesis of Optically Active Alcohols Possessing 1,2,3,4-Tetrahydroquinoline Moiety Employing Lipases or Variants of the Acyltransferase from Mycobacterium smegmatis

Zdun

Kopińska²,

Dranka³

et al. 2022

Catalysts

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The enzymatic kinetic resolution (EKR) of racemic alcohols or esters is a broadly recognized methodology for the preparation of these compounds in optically active form. Although EKR approaches have been developed for the enantioselective transesterification of a vast number of secondary alcohols or hydrolysis of their respective esters, to date, there is no report of bio- or chemo-catalytic asymmetric synthesis of non-racemic alcohols possessing 1,2,3,4-tetrahydroquinoline moiety, which are valuable building blocks for the pharmaceutical industry. In this work, the kinetic resolution of a set of racemic 1,2,3,4-tetrahydroquinoline-propan-2-ols was successfully carried out in neat organic solvents (in the case of CAL-B and BCL) or in water (in the case of MsAcT single variants) using immobilized lipases from Candida antarctica type B (CAL-B) and Burkholderia cepacia (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT) as the biocatalysts and vinyl acetate as irreversible acyl donor, yielding enantiomerically enriched (S)-alcohols and the corresponding (R)-acetates with E-values up to 328 and excellent optical purities (>99% ee). In general, higher ee-values were observed in the reactions catalyzed by lipases; however, the rates of the reactions were significantly better in the case of MsAcT-catalyzed enantioselective transesterifications. Interestingly, we have experimentally proved that enantiomerically enriched 1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-2-ol undergoes spontaneous amplification of optical purity under achiral chromatographic conditions.

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“…14 The number of synthetic benzoxazole derivatives is enormous, and they exhibit various types of activity eg, antibacterial, antifungal, antiinflammatory, antiviral, anticancer, analgesic, anticonvulsant, antioxidant, antidepressant, anthelmintic, and herbicidal. [49][50][51] Taking into consideration a wide pharmacological potential of compounds containing benzoxazole moiety and our interest in the enzyme-catalyzed kinetic resolution (KR) of azole derivatives, [52][53][54] we present studies on the chemoenzymatic synthesis of new benzoxazole derivatives. 40 There are also benzoxazole derivatives, which are potent 5-HT 3 receptor antagonists.…”

Section: Introductionmentioning

confidence: 99%

“…[46][47][48] Other benzoxazole derivatives exhibiting a promising tuberculostatic activity are also described. [49][50][51] Taking into consideration a wide pharmacological potential of compounds containing benzoxazole moiety and our interest in the enzyme-catalyzed kinetic resolution (KR) of azole derivatives, [52][53][54] we present studies on the chemoenzymatic synthesis of new benzoxazole derivatives. Two enzymatic approaches were applied to obtain the optically active molecules with benzoxazole nucleus: a lipase-catalyzed transesterification of appropriate alcohols and a lipase-catalyzed hydrolysis of corresponding esters.…”

Section: Introductionmentioning

confidence: 99%

Lipase‐catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

2017

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Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug-resistant Mycobacterium tuberculosis strains (M. tuberculosis H Rv, M. tuberculosis sp. 210, M. tuberculosis sp. 192, Mycobacterium scrofulaceum, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium avium, and Mycobacterium kansasii) was evaluated. The chemical step included preparation of ketones, alcohols, and esters bearing benzoxazole moiety. All racemic mixtures of alcohols and esters were separated in Novozyme SP 435-catalyzed transesterification and hydrolysis, respectively. The transesterification reactions were carried out in various organic solvents (tert-butyl methyl ether, toluene, diethyl ether, and diisopropyl ether), and depending on the solvent, the enantioselectivity of the reactions ranged from 4 to >100. The enzymatic hydrolysis of esters was performed in 2 phase tert-butyl methyl ether/phosphate buffer (pH = 7.2) system and provided also enantiomerically enriched products (ee 88-99%). The antitubercular activity assay has shown that synthesized compounds exhibit an interesting antitubercular activity. Racemic mixtures of alcohols, (±)-4-(1,3-benzoxazol-2-ylsulfanyl)butan-2-ol ((±)-3a), (±)-4-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3b), and (±)-4-[(5,7-dibromo-1,3-benzoxazol-2-yl)sulfanyl]butan-2-ol ((±)-3c), displayed as high activity against M. scrofulaceum, M. intracellulare, M. fortuitum, and M. kansasii as commercially available antituberculosis drug-Isoniazid. Moreover, these compounds exhibited twice higher activity toward M. avium (MIC 12.5) compared with Isoniazid (MIC 50).

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Lipase‐Catalyzed Kinetic Resolution of Novel Antifungal N‐Substituted Benzimidazole Derivatives

Cited by 10 publications

References 34 publications

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Chemoenzymatic Synthesis of Optically Active Alcohols Possessing 1,2,3,4-Tetrahydroquinoline Moiety Employing Lipases or Variants of the Acyltransferase from Mycobacterium smegmatis

Lipase‐catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

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