Lipase‐catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

Abstract

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).

Novozym 435: the “perfect” lipase immobilized biocatalyst?

“…Benzoxazole derivatives were synthesized using chiral alcohols and esters which were previously resolved by N435 catalyzed transesterification or hydrolysis. 315 N435 was used in the resolution of trans-2-phenylcyclopropyl azolides via hydrolysis or alcoholysis in methyl, giving trans-2-phenylcyclopropyl 1,2,4-azolide (trans-2-PCPT) of high optical purity. 316 N435 sequential acetylation/hydrolysis has permitted the production of (S)-C5-lipidic dialkynylcarbinols in 97% ee and (R)-C5-lipidic dialkynylcarbinols in 99% ee from racemic mixtures.…”

In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives

“…The synthesis of benzoxazole derivatives 5 – 8 is outlined in Scheme 1 and Scheme 2 , as well as benzoxazoles summarized in Table 1 . At first, 5-bromo-2-mercaptobenzoxazole 2 and 5,7-dibromo-2-mercaptobenzoxazole 3 were obtained according to procedures reported earlier [ 21 ] with the modification of one step. Instead of using a mixture of stannous chloride dihydrate and concentrated hydrochloric acid in a methanol reduction in the respective nitrophenols [ 21 ], it was carried out by NaBH 4 in the presence of activated carbon in the THF-H 2 O mixture [ 22 ].…”

“…At first, 5-bromo-2-mercaptobenzoxazole 2 and 5,7-dibromo-2-mercaptobenzoxazole 3 were obtained according to procedures reported earlier [ 21 ] with the modification of one step. Instead of using a mixture of stannous chloride dihydrate and concentrated hydrochloric acid in a methanol reduction in the respective nitrophenols [ 21 ], it was carried out by NaBH 4 in the presence of activated carbon in the THF-H 2 O mixture [ 22 ]. Ketones 5 – 7 were synthesized from 2-mercaptobenzoxazoles 1 – 3 and phenacyl bromides or chlorides 4 by S -alkylation carried out in the K 2 CO 2 /MeCN system ( Scheme 1 ).…”

“…The most intensive signals were reported. Ketones 5–7 were synthesized according to procedures reported previously [ 21 , 22 ].…”

Advances in the synthetic strategies of benzoxazoles using 2-aminophenol as a precursor: an up-to-date review

“…For over a century, heterocyclic compounds have been a privileged area of research in organic chemistry as they have high signicance in industrial and medicinal elds to help human society to thrive. 1,2 Heterocyclic scaffolds are momentous for drug discovery and evolution. [3][4][5] Among all U.S. FDA (United States Food and Drug Administration) approved small-molecule drugs, 75% of the drugs contain nitrogen heteroatoms.…”