Synthetic tuberculostats. V. Alkylidene derivatives of isonicotinyhydrazine

Abstract

The search for tuberculoactive pyridine derivatives which led to the discovery of the remarkable in vivo activity of isonicotinyl hydrazine against M. tuberculosis (1-6) had shown that for most of the pyridine tuberculostats the structureactivity relationships were quite specific and that slight structural modifications resulted in marked diminution or total abolition of activit'y. With regard to the hydrazides, it was evident that certain changes, such as the shifting of the hydrazide grouping from the gamma to the beta position, were incompatible with activity (6).To explore this field further, isonicotinyl hydrazine was reacted with acetone to give 1-isonicotinyl-2-isopropylidene hydrazine (I) which proved to be very active. It was decided therefore to syst8ematically investigate alkylidene derivatives of isonicotinyl hydrazine with the two-fold view of discovering superior tuberculostats and determining, if possible, the structural limits of activity. Since the isopropylidene group is a branched chain substituent, the study was extended to the straight chain alkylidenes by preparing 1-isonicotinyl-2-ethylidene hydrazine (11) from isonicotinyl hydrazine and acetaldehyde. Not only did the ethylidene derivative show powerful tuberculostatic activity but, in fact, it was soon discovered that every alkylidene derivative of the l-isonicotinyl-2alkylidene hydrazine type-whether straight or branched chain-was actively tuberculostatic in vivo. Similarly, cycloalkylidene and arylalkylidene derivatives were also notable tuberculostats. CHB / OC--NHN=C I1The effect of introducing heterocyclic nuclei into the hydrazide grouping was determined by condensing isonicotinyl hydrazine with alloxan to give l-iso-983 984 H. H. FOX AND J. T. GIBAS nicotinyl-2-(2,4 , 6-trioxohexahydro-5-pyrimidy1idene)hydrazine (111) and with furfuraldehyde t o give l-isonicotinyl-2-(2-furfurylidene)hydrazine (IV). Both compounds were act,ive.m O=C-NW

Monoamine oxidase inactivation: From pathophysiology to therapeutics

“…The development of MAO inhibitors started with the serendipitous finding of antidepressant effects in patients treated with iproniazid, a hydrazine-based antitubercular agent structurally similar to isoniazid [26]. This discovery, together with the demonstration that iproniazid was a potent MAO inhibitor [27], led to the design and production of other MAO inhibitors, such as phenelzine.…”

Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence

“…The serendipitous discovery of the mood-enhancing effects elicited by MAO pharmacological blockade (Fox and Gibas, 1953) was a historical breakthrough in the pharmacotherapy of mental disorders and gave impetus to the first investigations on the role of MAO in behavioral regulation. It was subsequently discovered that the antidepressant properties of MAO inhibitors were mainly due to the inactivation of MAO-A, which resulted in increased synaptic 5-HT concentrations (Sharp et al , 1997) and modifications of the firing rate of 5-HTergic neurons (Blier and de Montigny, 1985).…”

The biologically active iron chelators 2-pyridylcarboxaldehyde isonicotinoylhydrazone, 2-pyridylcarboxaldehyde benzoylhydrazone monohydrate and 2-furaldehyde isonicotinoylhydrazone

“…Studies assessing the biological activity of compounds (1)- (3) have been completed and will be described elsewhere (Becker & Richardson, 1999). The title compounds have been known for some time [(1), Beyerman et al (1954); (2), Grammaticakis (1956); (3), Fox & Gibas (1953)], but no crystal structures of this series have been published.…”