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COMMUNICATIONS TO THE EDITOR
Vol. 76
present experiments the 6-carbon dicarboxylic acids and P-hydroxyisovalerate were poorly utilized, their participation in cholesterol synthesis and their metabolic relation to DMA remain unsettled.
three hundred and fifty samples examined to date, over fifty have shown effectiveness a t or below 0,276 in diet. During the course of our studies with CzHS-S-R DEPARTMENT O F BIOCHEMISTRY KONRAD BLOCH compounds we encountered the report by Del OF CHICAGO UNIVERSITY L. C. CLARKE Pianto* on the antituberculosis effect noted after CHICAGO 37, ILLINOIS ISAACH A R A R Y ' ~injecting a combination of sodium ethyl thiosulfate RECEIVED APRIL29, 1954 and mercaptobenzothiazole derivatives in guinea (11) This work was supported by a grant from the Life Insurance pigs. In our hands s3dium ethyl thiosulfate alone Medical Research Fund. was more active orally than by subcutaneous (12) Postdoctoral Fellow, American Cancer Society. injection in mice. Table I is intended to show the relative activities of representative members of some of the classes of THE ANTITUBERCULOSIS ACTIVITY OF SOME compounds covered in this investigation. On the ETHYLMERCAPTO COMPOUNDS basis of data obtained by direct comparisoiis in Sir: it may be said that S-ethylcysteine (I. and In the course of studies dealing with the phenom- mice, DL) is a t least twice as active as pyrazinamide and enon of nitrification in soil' i t was noted that proliferation of nitrifying organisms was inhibited several times more effective than p-aminosalicylic acid.3 Compound I1 was equally effective against by several alkyl mercapto acids. This led to the isonicotinic acid hydrazide resistant and sensitive testing of (3-ethylmercaptopropionic acid (I) for antibacterial activity. Only slight activity was strains of Mycobacteria. found in witro against several gram-positive and TABLE I gram-negative bacteria. Definite protection was, ANTITUBERC~LOSIS ACTIVITY OF SOME CzH&-R COMhowever, afforded to mice infected with the H37Rv POUNDS strain of Mycobacterium tuberculosis (human type) Antituberculosis activity when fed 0-ethylmercaptopropionic acid a t a level of 0.2% in diet ad libitum. Further tests with other I CzH6-S-CHzCH2COOH t compounds of this type indicated that the ability I1 CzHb-S-CH&H(NH2)COOH (I, of a given compound to inhibit proliferation of and DL) 111 C~I-Is-S-CH~CI-T(~H~)CO~T~nitrifying bacteria is not a sufficient qualification for in vitro activity in experimental tuberculosis. .1 0 A systematic investigation of the relationship of I \' structure to in vivo antituberculosis activity in V derivatives of I was next undertaken. Substitution VI of various terminal alkyl groups (methyl through VI1 octadecyl) on the sulfur atom gave activity only VI11 with the CzH6-homolog. Aryl and heterocyclic IX moieties were equally disappointing. Variation of x the distance between sulfur and carboxyl to give XI mercaptoacetic through merwptovaleric acids indicated that the P-relationship between sulfur and carboxyl was essential. Replacement of carboxyl (2) Enrico Del Pianto, Riccra sci., a0, 83 (1950). by -CHtOH, -CHO, -COOR was achieved with (3) M. Solotorovsky, e1 ol., to be published. retention of activity. Elevating the oxidation LABORATORIES OF THE H . D . BROWN state of sulfur to sulfoxide or sulfone destroyed the RESEARCH DIVISION OF MERCK & Co., INC., A . R . MATZVK capacity to inhibit the experimental tuberculosis. CHEMICAL H J . BECKER Replacement of the sulfur atom in I by oxygen or RAHWAY,N. J. J . P. COXBERE nitrogen was also deleterious. I n an effort to J . M. CONSTANTIN find compounds with more acceptable properties, MERCKINSTITUTEFOR M. SOLOTOROVSKY S-ethyl-L-cysteine (11) was early tested and shown THERAPEUTIC RESEARCH, RAHWAY, N. J . S. WINSTEN E. IRONSON to be worthy of practical consideration on the basis RESEARCH INSTITUTE, MONTREAL GENERALJ . H . QUASTEL of efficacy and acute and chronic toxicity studies. MONTREAL, CANADA Concurrently with the study of the structure HOSPITAL, RECEIVED JUNE 14, 1954 requirements for efficacy in I, attention was given to the possible metabolic fate of P-ethylmercaptopropionic*acid in the animal body. This seemed especially pertinent in view of the lack of in vitro OXIDATIVE PHOSPHORYLATION IN THE CYTOCHROME SYSTEM OF MITOCHONDRIA' activity. With the testing of ethyl disulfide a significant increase in efficacy over I was noted. Sir: Results of the above tests opened a broad horizon 'It least two and probably three phosphorylations for the study of CzH6-S-R compounds. In general, are coupled to the passage of a pair of electrons structural modifications which decreased the tend- from reduced diphosphopyridine nucleotide to ency for cleavage of the C2H6S-linkage decreased oxygen via the respiratory chain in isolated liver the antituberculosis activity. Of the more than [ I I Supported by grants from the Nutrition Foundation, Inc., and
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(1) W. T.Brown, J . H. Quastel, P. G. Scholefield, J. Appl Microbial.. in press.
Ndtiondl Institutes of Health. S.O.N.is fellow of E H. Petersen I'ounddion and recipient of Fulbright travel grant.
