SYXTHESIS OF TEXCAZOXIC ACIDASD COSGESERS
July 1965
479
TABLE I ACETOACETYLAYINO ACIDS RCHCOOH R'ikCOCH,COCHI
7;-
----Calcd., so.
Amino acid
Isoleuciiie DBEI) salt" N-JIe isoleuciiie N-Benzylvaline 3,3-Diethylalanine Proline Phenylalanine 7 L-Valine 8 DL-Trytophane 9 Methionine 10 L-Aminobut,yric 11 L- Aminop henylacetic 12 L-Aminoisobut yric 13 L-Amino-n-caproic 14 Alanine 15 Glycine 16 a-.4mino-n-heptanoic 17 1-Amino-1-cyclopentylcarboxylic 18 Leucine 19 1-hmino-3-e t hylpentanoic 20 Pseudoleucine 21 0-3lethylthreonine 22 Isoleucine 23 dl-do-Isoleucine 24 n-Isoleucine 2 c5 a-Met hylisoleuciiie 26 5,5,5-Triflnoronorvaliiie 28 a-Amino-n-heptanoic From dibenzylethylenediamine. 1 2 3 4 5 6
It '
hlol. a t .
l I . p . , "C.
C
H CHI Benzyl Benzyl
215.24 698.91 291.36 319.39 199.20 249.19 201.15 288.22 232.28 187. I!) 235.16 187.19 215.24 153.17 159.14 229.27 2 13.23 215.24 229.27 215.24 217.22 305.36 215,24 215,24 229.27 255.19 319,41
120-121
55.80 65.30 65.95 67.68 54.26 62.65 53.73 62.50 46. :X3 51 . 33 61 29 51 . 3 S -. l a . 80 4S.50
H H H H H H H H H H H H H H H H Benzyl H H H H Benzyl
in an accompanying paper. His report s h o w that this activity is quite specific for tenuazonic acid. Gitternian also discovered that tenuazonic acid and other tetrainic acids have a low order of antibacterial activity by the agar plate method and that S-substituted tetraiiiates have a greatly enhanced antibacterial activity in vitro. This enhanced antibiotic activity s e e m to be fairly general for S-substituted tetramates. This work was confirmed by the results tabulated i n Table IT. We wish to thank Dr. E. 0. Stapley and 1Irs. Ann Germain for these assays (Table IV) which were carried out by the general method as published.'' The conipounds were assayed as aqueous solutions by agar plate diffusion eniployirig soaked 6.35-1111~disks or droplets of 0.02 nil. at a concentration of 2 nig./nil. Thin plates using 5 nil. of nutrient agar plus @.a% of yeast extrart /Petri dish were seeded n-it h appropristc niicroorgaiiisiiis and incubated overnight at 25". It will be seen froin Table IV that most of the tetraniic avids utisubstituted on the S have a low order of antibacterial activity (Table 11, 1, 17, 20, 23, arid 26, and Table 111, 1 and 2). Substitutions of the S with a benzyl group generally broadens the antibiotic spectrum and enhances their activities (Table 11, 3, 4, 22, 27, and 28, arid Table 111, 4). Unlike the egg tumor test, the antibiotic artivity is riot restrirted to the 5-sec-butyltetraniates. Dr. Betty 11. Frost and Miss 11. E. Valiant of the LIerck Institute have found that these ?;-substituted rompouiids were toxic t o i n i w at single intrapcritoiicnl (11) E. 0. Stapley, A p p l . -TficrobtoZ. 6, 392 (1958).
129-131 120-123 112-1 14 124-125 163-1 66 .5.5-58
-_ -ia-I I
138-142 145-148 98-101 107-100
4,5.28
157-160 124-126 115- 117 148-1 5(1 107-108
57.69 36. 33 ,5
