Formation of N-Oxide metabolites from isoniazid hydrazones of substituted benzaldehydes by hepatic washed pig microsomal preparations

Year 2023, Volume: 27 Issue: 1, 241 - 250, 28.06.2025

Göknil Coşkun , Elif Göksu Algın , Jülide Cansu Karakoç , Başak Türk Erbul , Mert Ülgen

Abstract

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. It is highly transmissible through air droplets suspended in the air. Isoniazid has long been the first-choice drug for pulmonary and extra-pulmonary tuberculosis treatment and prophylaxis. It was first synthesized by Malley and Meyer in 1912. It is known that isoniazid is metabolized through hydrolysis, but there are less information on its metabolism into N-oxide metabolites in the presence of hydrazone structure. In this study, three different hydrazone structures ie 2-hydroxyphenyl, 4-methylphenyl and 4-bromophenyl derivatives were synthesized from the isoniazid with substituted aldehydes. Their purity were proven by chromatographic analysis. The potential N-oxide metabolites and the corresponding aldehyde hydrazones were synthesized and their structures were elucidated by spectroscopic methods. All the hydrazone derivatives were incubated with pig liver microsomal preparations fortified with NADPH. The formation of the metabolites were observed using LC-MS. The results indicated that 2-hydroxyphenyl and 4-methylphenyl derivatives produced N-oxide metabolite in the presence of enzyme and co-factors (NADPH) and 4-bromophenyl derivative produced N-oxide metabolite in the presence of enzyme but in the absence of co-factors. Hydrolysis was detected for only 4-methylphenyl and 4-bromophenyl derivatives (independently with enzyme and co-factor) but not with 2-hydroxyphenyl derivatives. These results indicated that the hydrazone derivatives might undergo metabolic oxidation reaction rather than hydrolytic reaction. The present study is the first example of N-oxide formation from hydrazide hydrazones bearing a pyridine ring.

Keywords

Isoniazid , tuberculosis , N-oxide , hydrazine , metabolism

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