KOTES
September 1969
053
TABLE I1 OF 1~1:uucriolr C O M P W I F OOF N THF. RATI.;A N D EYTLNI. O F ~ I S C O S I T YO F ?\IUCOPROILIS sOLUTION"
7'
decrease in viscosity 3 min 30 min 60 min
Compd
20 27 30 L-N-Salfanilylcybteine ( 5 ) ~-3-RIercapto-2-11reidopropiorlamide (6) 22 26 27 L-3-Mercapto-2-methaiiesulfonamido21 30 30 propionamide (7) 2-rlcetamido-?J-(~-I-carboxy-2-mercapto18 28 30 ethyl)-3-mercapto-~~-propionamide (8) 2-Acetamido-X-(~-l-carbamoyl-2-mercapto- 23 29 30 ethylj-3-mercapto-DL-propionamide(9)* N-Acetyl-L-cybteinec 11 20 2.5 a See ref 3b, Table 11. * Saturated soliltion of 0.036 M, i l l stead of the usual 0.05 JI, was uied. e Included as reference material.
L. ~-3-(Diphenylmethylthio)-2-(methanesulfonamido)propionic Acid (17).--A mixture of 6 g (0.0073 mole) of 16 was 4iiiiwd with 150 ml of 33v0 aqiieous IlIeOH while acidifying with 1 .V HCI. The compound was Isolated by extracting v, ith EtOAc, concentrating, and recrystallizing from EtOAc-Skellysolve B; yield 3.7 g (69%).
M. Compoiiid 17 may be isolated directly from the EtOAc extract of procedure K in an over-all improved yield of 6 8 5 by adding Skellysolve B and seeding. N. ~-3-(Diphenylmethylthio)-2-(methanesulfonamido)propionamide (IS).-A solution of 15 2 g (0.01 mole) of 15 aiid 175 nil of MeOH caturated a t 15' n i t h S H , was allowed to ctaiid for 2 days. The solid waj collected; yield 9.3 g (617c) in three crops.
Acknowledgment.-The author is grateful to Dr. A. L. Sheffner and A h . L. W.Jacobs for the mucolytic data, to 11r. J. P. Catlett and Mr. W. F. Kavanaugh for technical assistance, to Dr. J. R. Corrigan and Dr. W. T. Comer for their interest arid advice in this work, and to I I r . C. 11. Combs, A h . C. I. Kennedy, and A h . J. G. Schmidt for analytical and spectral data.
Aniides of 5-Acylcysteines as Potential Amino Acid Antagonists in Bacteria ~ ' A L T c I tA. ZYGMUST A I D h
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TELLIS 9.?\I.IR'l'Ih'
Jlead Johnson Reseaych Center, Eaanscille, Indiana 47721
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Received May 9,1969
Recently, we reported' on the activity of 21 cysteine or cyst'ine analogs as potential amino acid ant'agonists in bacteria. Of these, N-acetyl-L-cysteine, K-propionylL-cysteine, L-cysteine hydantoin, arid L-cystine hydantoin were the most effective inhibitors of L-cysteine utilization. As an extension of these studies, 38 additional analogs were tested as inhibitors of cysteine or cystine utilization by Leuconostoc mesenteroicles, a cysteine-cystinedependent bacterium, and by Escheiichia coli, an organism able to synt,hesize all its amino acid requirements. Nost of these analogs2were amides of cysteines or cystines. IT. .-%.Zygniunt and T. 4. AIartin, J . .Veil. Chem.. 11, 623 (19681. (2) (a) T. A. Martin. D. H. Causey, A . L. Sheffner, A. G. Wheeler, a n d J. R. Corrigan, i b i d . , 10, 1172 (1967); (11) T. h. Martin and .i. L. Plieffner, U. S. P a t e n t 3.340,14T(1967). (1)
\'oi.
I:!
September 1969 pg,/ml. Of the remaining compounds tested in E . coli moderate growth inhibition (80-9070) was found with L-:3,3'-dithiobis(?-amiriopropionamide)dihydrochloride (800 pg/ml) and L-?-amirio-:%(diphenylmethylthio)propionnmide (600 pg/ml). Sone of the 38 compounds tested showed any significant cysteine-cystine replacement activity for growth of 1,. nzesentei,oirles. I n summary, none of the 38 compounds tested showed significant growth inhibition of 1,. meseirte/,oirles and I?. coli. In most instances, this inhibition was readily reversed by the addition of cysteine. The microbiological ;i were similar to those pre
chloride (111), I d and azacrine (IV) have beeri demonstrated to have appreciable antiprotozoal arid anthel-
*2HCI
c1
0-
Antiamebic, Antimalarial, and Anthelmintic Effects of Distal Hydrazine Analogs of Azacrine, Quinacrine, and 7 - { [3-(Octylamino)propyl]amino )benz[c]a~ridine'~~
I1 SH(CH,),NH(CH,)-CH,
I
I11
& h i array of basically substituted 9-aminoacridines,3-11 i-aminoheriz [c ]acridines, 9 , 1 n ~ 1 2 - 1 4 and amiiiobeiizoiiaphth;\-ridiiie~~~~~'"-'~ exhibit, noteworthy antiprotozo:il, anthelmintic, :intibacterial, and antitumor properties. Amoiig them, quiriacriiie (I) 33--6 3chloro-9- [~-(diet.hylanii~io)1-methylhutyl ]amino/ acridine 10-oxide dihydrochloride (11),' i-1 [:?-(octylamirio)propyl]:~miiioi heriz [c]:icridii~edihydromiritic activ3,43
(11 This is p a p e r S of a series on synthetic arnehicides a n d paper S V I I of a series relating to antimalarial whstances. F o r t h e previous paper, see I.. >I. \\-erbel, E. F. Elslager. -4. .I. Pliillips, D. F. \Vortli, P. .J. Islip, and 11,C. Xeville, .I. M e d Chem., 12, ,521 (1969). ( 2 ) Tliis is communication I l l of a series on anthelmintic drugs. For paper 11. see I). 1%. Capps. 0. 11. 13ird. E. F. Elslager, Z . n. Gavrilis. J . I. Roiisli. 1'. E . Tliompson. and .I. \ \ , Vaitkus, .I. Heteroiyrlic Cliem., 6, 35.5 (1968). (3) .\. .\ll>ert, "Tlie .\cridines." 2nd eii, Edward .\mold, London, 1966. ( 4 ) F o r a review. see E. F. Elslager in "Lledicinal Chemistry." .i. U u r g e r , E d . , 3 r d ed, Interscience Division of .Jolin \Vile? a n d Sons. Inc.. N e w I-ork. X. I-.. 1969. 1.5) For a r e v i e w see P.11. R i i s s e l l in "1Iedicinal Chemistry," .i, Ilurger, Ed.. 2nd e d , Interscience I'iil~lisliers, I n c . , S e w l - o r k , X. Y.,1Y60, pp 814-
IV
ity in man. It was therefore of iriterest t o synthesize representative { [3-(2,2-dialkylhydrazino)alkyl]amino) acridines, benz [c]acridines, and benzo [b] [l,5]naphthyridiries to enable a determination of the effects of a distal hydrazine moiety on antiprotozoal and anthelmintic activity. The coriderisation of 6,9-dichloro-2-methoxyacridine with 2-(3-aminopropyl)-l, 1-dimethylhydrazine, l9 1-[ (3aminopropyl) amino I~iperidine,'~ arid 1-[ (3-aminopropyl)amino]-4-methy1piperazinel9 in phenol afforded 6chloro-9- { [3-(2,2-dimethylhydrazino)propyl]ami1io) -2methoxyacridine dihydrochloride (Va) (Xiyo), 6-chloro2-methoxy-9- { [3-(piperidinoamino)-propyl]amino) acridine dihydrochloride (Vb) (:Byc), and B-chloro-
850. 16) For a revieiv, see 0. I). Standen in "Experimental Chemotherapy," Yol. I , R . .J. Sclinitxer a n d 1.; H a x k i n r , Ed.. .\cailemic Press, Yen. Tork. K . Y..196:i. pp T01-8Y2. F. Elslager. R . E. llowman, F. H . Tendick, D. .J. Tivey, a n d r t h . J . .Meit. l'ttttrm. Chem., 6, 1159 (1962). 18) l-:. F. Elslager and F.€1. Tendick. iM., 6 , 1153 (1962). (9) N . 13. . \ e k e m a n , I). I
