Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until its discontinuation in 2015. History Iproniazid was originally developed for the treatment of tuberculosis, but in 1952, its antidepressant properties were discovered when researchers noted that patients became inappropriately happy when given isoniazid, a structural analog of iproniazid. Subsequently N-isopropyl addition led to development as an antidepressant and was approved for use in 1958. It was withdrawn in most of the world a few years later in 1961 due to a high incidence of hepatitis, and was replaced by less hepatotoxic drugs such as phenelzine and isocarboxazid. Canada surprisingly withdrew iproniazid in July 1964 due to interactions with food products containing tyramine. Nevertheless, iproniazid has historic value as it helped establish the relationship between psychiatric disorders and the metabolism of neurotransmitters. Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications) predates it; and frankincense has been marketed traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of its smoke was found to have antidepressant effects in mice. Structure and reactivity The structure of iproniazid is chemically, in both structure and reactivity, similar to isoniazid. Iproniazid is a substituted hydrazine of which the isopropyl hydrazine moiety is essential for the inhibition of monoamine oxidase activity. Synthesis There are multiple routes to synthesize iproniazid. The most common precursor is methyl isonicotinate which formes isonicotinohydrazide when it reacts with hydrazine. Isonicotinohydrazide can be converted into iproniazid via different pathways. One synthesis pathway involves AcMe which results in the formation of N'-(propan-2-ylidene)isonicotinohydrazide. Subsequently, the C=N linkage is selectively hydrogenated in the presence of a platinum catalyst and with water, alcohol or acetic acid as solvent. In another pathway isonicotinohydrazide reacts with either 2-bromopropane or 2-chloropropane in an N-isopropyl addition reaction to the hydrazine moiety. This directly results in the formation of iproniazid. Reactions and mechanism of action Iproniazid is a known monoamine oxidase inhibitor, it inhibits the