Dataset Information

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives via an Au-?-allene intermediate.

ABSTRACT: Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives with a structural rearrangement. The mechanism of these new annulations does not involve ?-imino gold carbenes generated from gold ?-alkyne intermediates. We postulate alkyne attack on gold ?-allenes, yielding vinyl gold carbenes. These newly generated carbenes react with isoxazole derivatives to yield Z-3-imino-2-en-1-als, further enabling sequential cyclizations to deliver indolizine derivatives in two distinct classes.

SUBMITTER: Kulandai Raj AS

PROVIDER: S-EPMC6610539 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives <i>via</i> an Au-π-allene intermediate.

Kulandai Raj Antony Sekar AS Tan Kuo-Chen KC Chen Liang-Yu LY Cheng Mu-Jeng MJ Liu Rai-Shung RS

Chemical science 20190522 26

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives with a structural rearrangement. The mechanism of these new annulations does not involve α-imino gold carbenes generated from gold π-alkyne intermediates. We postulate alkyne attack on gold π-allenes, yielding vinyl gold carbenes. These newly generated carbenes react with isoxazole derivatives to yield Z-3-imino-2-en-1-als, further enabling sequential cyclizations to deliver indolizin ...[more]

PMID: 31341595

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Project description:Indolizines are heteroaromatic compounds, and their synthetic analogues have reportedly showed promising pharmacological properties. In this study, a series of synthetic 7-methoxy-indolizine derivatives were synthesised, characterised and evaluated for in vitro whole-cell anti-tuberculosis (TB) screening against susceptible (H37Rv) and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) using the resazurin microplate assay method. The cytotoxicity was evaluated using the MTT assay. In silico molecular-docking study was conducted for compounds 5a-j against enoyl-[acyl-carrier] protein reductase, a key enzyme of the type II fatty acid synthesis that has attracted much interest for the development of novel anti-TB compounds. Thereafter, molecular dynamic (MD) simulation was undertaken for the most active inhibitors. Compounds 5i and 5j with the methoxy functional group at the meta position of the benzoyl group, which was at the third position of the indolizine nucleus, demonstrated encouraging anti-TB activity against MDR strains of MTB at 16 μg/mL. In silico studies showed binding affinity within the range of 7.07-8.57 kcal/mol, with 5i showing the highest binding affinity. Hydrogen bonding, π-π- interactions, and electrostatic interactions were common with the active site. Most of these interactions occurred with the catalytic amino acids (Pro193, Tyr158, Phe149, and Lys165). MD simulation showed that 5j possessed the highest binding affinity toward the enzyme, according to the two calculation methods (MM/PBSA and MM/GBSA). The single-crystal X-ray studies of compounds 5c and 5d revealed that the molecular arrangements in these two structures were mostly guided by C-H···O hydrogen-bonded dimeric motifs and C-H···N hydrogen bonds, while various secondary interactions (such as π···π and C-H···F) also contributed to crystal formation. Compounds 5a, 5c, 5i, and 5j exhibited no toxicity up to 500 μg/mL. In conclusion, 5i and 5j are promising anti-TB compounds that have shown high affinity based on docking and MD simulation results.

Dataset Information

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives via an Au-?-allene intermediate.

Publications

Gold-catalyzed bicyclic annulations of 4-methoxy-1,2-dienyl-5-ynes with isoxazoles to form indolizine derivatives <i>via</i> an Au-π-allene intermediate.

Similar Datasets

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