Isonicotinic acid N -oxide, from isoniazid biotransformation by Aspergillus niger , as an InhA inhibitor antituberculous agent against multiple and extensively resistant strains supported by in silico docking and ADME prediction.
Amany Elsayed RagabEbtisam T BadawyShaimaa M AboukhatwaMarwa M Abdel-AzizAmal KabbashKamilia A Abo ElseoudPublished in: Natural product research (2022)
Biotransformation of isoniazid produced isonicotinic acid ( 1), isonicotinic acid N -oxide ( 2 ), and isonicotinamide (3) which were isolated by column chromatography using silica gel and Sephadex LH 20 and elucidated using various spectroscopies. This is the first report for isolation of 2 . Antituberculosis activity was evaluated against Mycobacterium tuberculosis strains: drug sensitive (DS), multiple drug resistant (MDR) and extensively drug resistant (XDR). 1-3 and isoniazid showed MICs of 63.49, 0.22, 15.98 and 0.88 µM, respectively, against the DS strain. For the MDR strain, 2 and 3 exhibited MICs of 28.06 and > 1000 µM, respectively, while 1 was inactive. Moreover, 2 had an MIC of 56.19 µM against XDR strain, while 1 and 3 were inactive. Docking simulation using enoyl ACP reductase (InhA) revealed favorable protein-ligand interactions. In silico study of pharmacokinetics and hepatotoxicity predicted 1-3 to have good oral bioavailability and 2 to have a lower hepatoxicity probability than isoniazid.
Keyphrases
- drug resistant
- multidrug resistant
- mycobacterium tuberculosis
- acinetobacter baumannii
- molecular docking
- protein protein
- pulmonary tuberculosis
- molecular dynamics simulations
- escherichia coli
- molecular dynamics
- mass spectrometry
- liquid chromatography
- emergency department
- small molecule
- tandem mass spectrometry
- high speed
- high performance liquid chromatography
- cystic fibrosis
- amino acid
- solid phase extraction