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
The advantages to be derived from the remarkable in vivo activity and relative atoxicity of the alkylidene, arylalkylidene, and the sugar derivatives of isonicotinylhydrazine (1, 2) are offset to some degree by the lability inherent in the double bond of the -C=Nor Schiff's base linkage. It ivas decided therefore to eliminate this double bond to form more stable alkyl derivatives. That stability could thus be achieved was hardly to be doubted. It was a moot question, however, as to whether the activity would survive the structural change because the possibility existed that the activity of the alkylidenes was due to their scission to the parent isonicotinylhydrazine. If the latter concept were true, it appeared probable that stabilization of the molecules by conversion to the corresponding alkyl derivatives would abolish or, at the very least, markedly reduce the activity. This was not the case. The alkyl, cycloalkyl, and arylalkyl derivatives prepared in this study were actively tuberculostatic in vivo.Most of the compounds were prepared by catalytic reduction, under very mild conditions, of the corresponding alkylidene or arylalkylidene derivatives.
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