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

Abstract

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 MIC of 63.49, 0.22, 15.98 and 0.88 µM, respectively, against the DS strain. For the MDR strain, 2 and 3 exhibited MIC 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.

Biotransformation of Modified Benzylisoquinoline Alkaloids: Boldine and Berberine and In Silico Molecular Docking Studies of Metabolites on Telomerase and Human Protein Tyrosine Phosphatase 1B

“…The total energy of the protein complexes was inspected using Ligand energy inspector of MVD software and the individual energy for different types of binding were analyzed. The parameters used were the same as previously reported in our studies [ 36 , 37 ]. The docking cavities constraints were set to give the best redocking pose.…”

Isoniazid, Mechanism of action, Biological Activity, Resistance and Biotransformation

“…The metabolites were identified as isonicotinic acid, isonicotinic acid Noxide, and isonicotinamide, respectively, as illustrated in Figure 7. 23 Antituberculosis activity of isoniazid and metabolites 1-3 against drug-sensitive, multiple drug resistance (MDR) and extensive drug resistance (XDR) were evaluated using microplate alamar blue assay. Isoniazid was used as a reference.…”

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

“…Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2pyridone class of compounds for the treatment of MDR-TB proteinligand interactions. The in silico pharmacokinetics and hepatotoxicity experiments predicted that the derivatives of isonicotinic acid were with better oral bioavailability and lesser hepatoxicity than isoniazid [27]. A novel ligand screening approach identified 4-aminoquinolines as a potential inhibitor (87 fold) of NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) and an effective growth inhibitor against H37Rv (32 fold inhibition) with no genotoxicity and acute systemic toxicity in a murine model of TB [28].…”