Lipase-catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

Edyta Łukowska-Chojnacka , Anna Kowalkowska , Agnieszka Napiórkowska

Abstract

Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug‐resistant Mycobacterium tuberculosis strains (M. tuberculosis H37Rv, 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 tertbutyl 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).
Author Edyta Łukowska-Chojnacka (FC / IBC / DDTB)
Edyta Łukowska-Chojnacka,,
- Department Of Drug Technology And Biotechnology
, Anna Kowalkowska (FC / IBC / DDTB)
Anna Kowalkowska,,
- Department Of Drug Technology And Biotechnology
, Agnieszka Napiórkowska
Agnieszka Napiórkowska,,
-
Journal seriesChirality, ISSN 0899-0042, (A 20 pkt)
Issue year2018
Vol30
No4
Pages457-468
Publication size in sheets0.55
Keywords in Englishantitubercular activity, azole, enzymatic hydrolysis, enzymatic transesterification, lipase
DOIDOI:10.1002/chir.22806
URL https://onlinelibrary.wiley.com/doi/abs/10.1002/chir.22806
Languageen angielski
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wdpb_publikacje_pliki_plik_publikacja_3351_org.pdf 208.94 KB
Score (nominal)25
ScoreMinisterial score = 20.0, 23-07-2018, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, 23-07-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.956 (2) - 2016=1.829 (5)
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