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-
I1
Antiamebic, Antimalarial, and Anthelmintic Effects of Distal Hydrazine Analogs of Azacrine, Quinacrine, and
SH(CH,),NH(CH,)-CH,
I
7 - { [3-(Octylamino)propyl]amino )benz[c]a~ridine'~~ 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 [:?-(octylamii heriz [c]:icridii~edihydromiritic activrio)propyl]:~miiio 3,43
(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 TI aiid 111). Treatment of 7,10-dichloro-2methoxybenzo [ b ][ 1,sjnaphthyridinc" with 2-(3-aniiiiopropyl)-l, 1-diniethj lhydrnzitic~'4 arid 1-[ ( h m i n o p r o ~,y1)amiiio]-4-niethylpiperazine''' in phenol yielded ichloro-10- [3-(2,2--diniethylh) druirio) p r o p y I ]ami n o ?-met hoxybeiizo [b] [ 1,sIiiapht h) ridiiie dihydrochloride (\'ILL) and i-chloro-2-methoxy-10-( {3-[ (4-methyl-l-
SOTES
September 1969 effective in rats at daily doses ranging from 62.5 to 125 mg/kg, and thus showed activity comparable with or huperior to 7- I [3-(octylami1io)propyl]amirio1benz [c]acridine dihydrochloride (111). I 3 Compounds T'a and b and VIa and b killed T . vaginalis in vit1.o at concentrationi of 25 pg/ml, but none was active against L. donova,! z in hamsters. The effects of Va-c, VIb, and VIIn and b against intestinal helminths were assessed in mice infected with S. obvelnta, A . tetrapfern, N . dubius, and H . m n a . 2 Four substances (Va-c and VIb) mere active against the tapeworm H. nana in mice when given at doses of 62.5-125 mg/kg b i d . for 1 day and thus showed taeniacidal activity comparable lyith or superior to quinacrine.6 Three compoundq (Vc, VIb, and VIIb) were also effective against the mouse pinworms S. obuelata and A . tetmptera. S o n e of the compounds te5ted was active agairist S. mansorzi in mice or L . c a ~ i n iin i gerbils. Each of the heterocyclic aminoalkylhydrazirie derivatives caused complete inhibition of S . pyogenes (C203) and S. aui'eus (UC-76) in v i t w a t concentrations of 1.23-20 pg/ml.22 Compounds Va, VIa and b, and TTIa also effected complete inhibition of ill. tuberculosis (HS7Rv)a t concentrations of 0.63-10 pg "1, while YIa killed K . pneumoniae (-ID) a t 20 pg:/ml. Under comparable experimental conditions, quinacrine was active against S. pyogenes ((2203) and Jf. t u b e m d o s i s (HB7Rv)in vitro at 1.23 and 20 pg/ml, respectively. Three iubstances (Va, Vc, and VIa) were tested against btreptococcus, staphylococcus, and tuberculosis infections in mice12*but none was active even at high dose levels. The over-all results of the present study indicate that the substitution of a hydrazide moiety for an amine function at the distal position of quinacrine, azacrine, and the 7- [ (aminoalliyl)amino]benz[clacridines has a deleterious effect on antimalarial activity while potent antiamebic, anthelmintic, and antibacterial properties tire maintained.
957
avoid problems associated with hygroscopic, light-sensitive samples, the yellow solid was allowed to eyiiilibrate with atmospheric HsO in the dark for 24 hr prior to anal) hydrochloride melted a t 213-218". 6-Chloro-2-methoxy-9- { 13-(piperidinoamino)propyl]amino 1 acridine Dihydrochloride (Vb) (Procedure II).--A n~istii1.e of 10.0 g (0.064 mole) of 1-[ (3-arniiiopropyl)ami1i~i]piperidi1ie'~ and 18.0 g (0.064 mole) of 6,!)-dichloro-L'-methosyacridiiiei i i 30 g of phenol was stirred and heated 011 a steam bath for 3 hr. A red-brown solid slowly precipitated f r o m the deep i w l soliitiuii. This hot mixture was then poured into a nell-.tirred .oliition of 27 ml of concentrated €IC1 in 1.3 1. of ;\\Ie&O to give 27.0 g of a yellow solid which was collected by filtration and washed well with Et&. I
