edited by
JOHN H. WOTlZ Southern Illimis University Carbondale, llllnols 62901
Isoniazid-Destroyer
of the White Plague
George B. Kauffman California State University, Fresno Fresno 93740 Because of its lethality, tuberculosis was called "the white plague" during the Middle Ages, and even as late as 1960 it killed several million persons annually worldwide, causing more deaths than any other infectious disease without intermediate vectors (1). In 1904. the vear that the National Tubrrculuris Association was founded, it was the leading cause of mortalitv in the United States r18R drnthi annuallv. . per 100,000 population). In general. chemotheraov becomes more difficult as the disease hecomes more ch&c ( 11 , and the cauaativ~agent of tuhrrculoris (M~cobocferirrmr u h r ~ r r u l o s ~iss ~particularly resistant tudrug therapy. According to Fox."the numher and variety of subst;mcc.s used in the treatment of ruberculusis is only exceeded by the scientific naivetA which led to their use" (I), but its chemotherapy in the proper sense of the term, dates from 1939, with recent progress being due largely to practicable animal testing methods. Today streptomycin (1944), p-aminosalicylic acid (PAS) (1948), and isoniazid (1952), administered usually in combinations of two, are effective in curing not only the more common pulmonary form hut also all other forms of the disease, including the usually fatal miliarv . ("eallonine . - . consumntion") and menineeal tuherculosis. ~nfortunat&, streptomycin &d PAS have"seriou8 side effects and are toxic in high dosage or in a long course of treatment. Of the literally thousands of compounds screened for antituherculous activity, isoniazid, in particular, has been credited with reducing the death rate for tuberculosis to 4 per 100.000 nonulation in the United States. resultina in the closing o'f sbme larger T B hospitals and many small& sanatoria or their conversion to other uses. Isoniazid (pyridine-4-carhoxylic acid hydrazide or isonicotinic acid hydrazide)
employed Rake-Donovick procedure for in viuo testing of agents in the mouse against the Ravenel strain of Mycobacterium tuberculosis ( 4 ) . By a remarkable coincidence, the drue that became available for the evaluation of this orocedure was p-acetamidubenzaldehyde thiusrmirarbazune t'l'bl ur Tibione), develuped b y Rrhnisch, Durnagk, r t nl. at Rayrr A(; (5,fi). Tibiune was bring tested clinically in Eurol~e,and, althoueh " then the most active of the svntht:tic tulwrculwtats in clinical use, it was ineffective against miliary and meningeal T B and also produced very severe side effects (1, 3). During the summer of 1951, Dr. Harry L. Yale of the Squibb Institute, on the basis of his knowledge of the relationship between chemical structure and toxicity, decided that a compound of structure H=NNHkWH
b
(isonicotinaldehyde thiosemicarbazone)(I) might possess the antituherculous activitv of tihione.. nerhans without unde. sirablesideeffects Fur the preparation uf (11,thc key chwnical intermediate was ovridine-4-mrboxaldehvdeI 111. not available commerciall;at that time. o f severaipossible routes to this compound, Yale chose the following six-step McFadyen-Stevens sequence, starting with commercially available 4-picoline (3, 7)
Isoniazid was found to be far more active against tuberculosis with minimal side reactions than any other known substance, whether synthetic or antibiotic (I,8-10). According to Yale himself (3)
.. .it is of significance that of all thesynthetic procedures considered, only this procedure involved the preparation of isoniazid (SQ 7425) as an intermediate.. . .Thus, had I selected any other of the possible developed by chemists and biologists a t E. R. Squibh & Sons (trademark "Nydrazid") and Hoffmann-La Roche, Inc. (trademark "Rimifon") in the United States and Baever AG in West Germany, was'not originally intended as a drug but was only an intermediate in the synthesis of isonicotinaldehyde tbiosemicarbazone (2). The program a t the Squihb Institute for Medical Research to discover new orally active antituberculous drugs involved 40% of its scientific staff, "the sinele occasion. in the entire historv of The Institute, that so la& a part of i s staff a,as designa;td to whi(.ve a single ohiective" (3).Sauibb invested about Sll., million and more than H million man:hours of work in the discovery of isoniazid, and a team of 24 Sauihh researchers tested more than 8,000 compounds in the process. Indispensable to the screening process was the development a t Squibh of the now widely 448 / Journal of Chemical Education
routes, I would not have prepared isoniazid. Fortunately, too, was the stipulation in theantituberculousdrugprogramat The Institute that all intermediates in any synthesis were also to be evaluated, since it must be recognized that nothing in the structure of isoniazid . . . would suggest activity.. . .To conclude this historical account, compound I, the objective of the entire synthesis, was tested and found to be active against the infection in laboratory studies. It was never considered for clinical trial in humans since isoniazid was so quickly recognized as the drug of choice in the treatment of human tuberculosis. At approximately the same time, the late Dr. Hyman Herbert Fox of Hoffmann-La Roche, Inc. independently discovered isoniazid by a somewhat similar approach. In 1945 Chorine (11) and Huant (12) had discovered that niacinamide, NC5H4CONH2, possesses tuherculostatic activity. In 1948 McKenzie, Kushner, e t al. (13,14) concluded that the tuher-
culostatic effect of niacinamide and its derivatives was a function of their vitamin activity. Intrigued by this conclusion, Fox studied some closely related pyridinecarboxylic acids and found that tuberculostatic activity among pyridine derivatives is not limited to derivatives of niacinamide or to compounds with vitamin B activity (15). In these studies (15, 16), like Yale, he tried to prepare isonicotinaldehyde thiosemicarbazone (I) from methyl isonicotinate (111) by modifying the McFadyen-Stevens reaction (17) isoniazid
111 CsHsS02CI
NazCOs
+ NC5HlCONHNHSOzC~Hs+
[NCsH4CHO]
I1
HzNNHCSNHZ + NCsH4CH=NNHCSNH2
I
Routine testing of the intermediates showed isoniazid to he the most effective tuberculostat known (181, a conclusion confirmed by clinical studies. In 1955 Squibh and Hoffmann-La Roche shared the Albert L. Lasker Clinical Medical Research Award for their contribution to improving public health. the onlv time that ~harmaceuticalfirms had received the award since its inception ( 3 1 . The author acknowledges t h ~ilssistance . of I'rofessor Alfred
Burger, Dr. William R. Sullivan of Hoffmann-La Roche, Inc., and Lora W. Jones, Dr. Harry L. Yale, and Dr. John Vandeputte of E. R. Squihh and Sons, Inc. Literature Cited (1) Fox,H. H.."Chemotherapy of Acid-FastInf~tions."in "Medicinal Chemirtry"(Edi1or Burger, A,), 2nd ed., lntomcienee Publishers, h e . , New York, 1960, pp. 970-996. (2) Burge;.A.,Chrm. Eng. NPWS, 54 (151,149 (ApciIG, 1976). (3) Yale. H. L.,"The Discovery of lsuniazidat U1eSquibbInstituteforM~dicalR~a~arch," pemonal communication to G.B.K.. July 11. 1977. W. ~ . , s n d~ s k eG., , ~ mR .~ U .~ u b a r c .6, 0 . m ~ ~M ~ C , K ~ C.~M., , (4) D O ~ O V a,, (1949). (5) DamagL,C.,Behnisch, R., MieUseh,F.,snd Schmidt, H.,Naturiaso~choftan.33, 315 (1946). (6) Behni~ch,R.,Mietsseh,F.,sndSehmidt.H..Am. Re". Tubrrc., 61.1 (19501. (7) Yaie. H. L . , h e e , K . , Marlins. J., Holsing, M., Peny,F. M.,and Bemsfein,J.,J Amen Chem Soc., 75,1933 (1953). I81 Benson, W.M.,Stefko,P.L.,and Zieper,l.,Am. Rsu. Tuberc.. 65.376(19521. 191 Kelly, J. M.,and Poet, R. B.,Am. Re", Tubeic.. 65,484 (1952). (101 Elmendorf,J~.,D. F., Carthan. W. U., Murchenheim, C., and McDermott. W.. Am. Rau. T u b m . . 65,429 (19621. (11) Chorine.V.. Compt. rend., 229.150(19451. (12) Huanf, E., Gazette des H6pitoux. Aug. 15.1945.
. ~ Kunhner.S..Dddian.H..Carr.ell.R.T..Seniurio.J.L..McKenzie.D..andSubbaHaw. ~ . . . . . . . . ..
1131
J , J . Org Chrm., 13.834 (1948). (14) McKenzie. D. L.,Malone, L.. Kushner, S.,Oleson. J. J., and SubbsRow, Y.. J. Lob., Ciin. M d . 33.1249 (1948). (15) For. H. H . , J Org. Chrm., 17,542,547 (19521. (16) Fox, H. H.. J. Or8 Cham.. 17,555 (1952). (17) McFsdyen, J. $.,and Stouens,T. S., J. Cham. Soc., 581119361. (13) Far, H. H.,snd Gibss, J.T., J. OF& Cham.. 17,1653 11952).
Volume 55. Number 7, July 1978 / 449
