Antimalarial and Antischistosomal Effects of Proximal Hydrazine and Hydroxylamine Analogs of Chloroquine and Quinacrine'
ltepi'esentativr 4-i%,2-dialkylhydrazino)yuiiiiiioli1ies (IV--YII), ti-chloi~o-~-(2,~-tiialkylhydrazi1ioj-2-11iethoxyacridines (VIII, I X ) , 12-C?,2-dialkylhydrazino)benz[b]acridine- (X), 2,2'-(benz[c]acridiii-'i-?-lhydr.axotio)diethanol (XI), 7-chloro-4-{ [2-(dialkylamino)ethoxy]aminof quinolines ( X I ) , and 6-chloro-9-[ [2-(dimethylamiiio)et~hoxy]aminof-L'-methoxyacridiiie ( X I I I ) were synthesized t o enahle an assessment of the antiparasitic effects conferred by sitbstit,iiting a hydrazine or hydrosylarnitie moiety for the proximal a.niiiie function of chloroqriine, quinacrine, aiid i - {~::-(octylamino)pro~~yl]amirlo) benz [clacridine relatives. The compounds were isolat,ed i i i ?-92%, j-ield by t,he condelisation of 4,i-dichloroquinoliiie, 1-chlor0-6-niethos~-qui1ioli1ie, 4-chloro-6-methosywith the appro(liiiiialdine, 6,0-dichloro-2-niet,hos?.acridirie, 12-~hlorobeiiz[b]acridine,Or 7-c~Iiloroberiz[c]~cridiiie priate 1,l-dialkylhydrazine or 2-idialkylaniino)etrhoxyamine in pheuol or EtOI-I. rlniong t,hern, 6-methosy-lirriorpholirioaniino)q~iiiialdine( I V ) exhibited modest activity against Schisfo.sonio w m s o n i in mice and effemti ii 28-51!; reduction of live worms at drug-diet doses of 224-.303 mglkg dailj- for 14 d:iys. Sis compoiinds were :tcqtive again,*t a iiornial strain of Plasmodium berghri in mice at doses ranging from 2.7-219 rng/kg/day for 6 days. ~-Chloro-4-(4-niethyl-l-pipel.azinyla1niiio)q~noline(Vb) arid 4,1'-(1,4-piperazinediyldiimino)bia('ii~i~i~liiie) ( V I I ) were approximat,ely 28 arid 27 times a s potent as quinine, respectively, against P. berghci, but VI1 w:is highly c>ross-resistant,\Ti th chloroqiiine. Stl.iicturc-activit~- relationships are discussed.
To enable an assessment oi tlie c 4 c c t s of :L clistd liydraziiic moiety on the antiprotozoal, :tiithelmintic, : r i d antibacterial properties of q~iiiiacriiie.~ 7- [ [:3~octylarnino)propyl]amino~ benz [~Iacridine.~atid :iz;tcrine5 arialogs, various { [:3-(~,"-dialkylhydraziiio)propyl]amino}acridines (I), beiiz [clncridiries (11),and t)enzo[b] [1,5]naphthyridines (111) ~verc' recently syn-
111 t hesized
for biologicd c>valiiatioii. I on antimalarial substances; for the p r e v i o u s paper, see E. F. Elslager a n d I>. F.T o r t l i , J . N e d . Chern., l a , 955 (1!36ure of 9.9 g (0.05 mole) of 4 , i dichloroqiiinoline, 8.9 g (0.05 inole) of 'L-(di~neth~.laniirio)ethoxyamine dihydrochloride,l2 and 23 g uf phenol wis stirred and heated on a steam bath for 4 hr. The resulting brown soliition was cooled and poured into ?vIe&O. The g m i m y product which formed solidified on standing and was dried i n P U C L ( O . Crystallization from i-PrOH afforded 5.9 g (SS(,:; ) of product, mp 213-216" dec. dnal. (CJ~HI~CIN~O.''HC:I.~.~~FII?O) C, H, N, 1120. 7-Chloro-4-( [2-(diethylamino)ethoxy] amino;quinoline (XIIb).
Lincomycin. IX. 7-Thiol and Thioamido Analogs of Lincomycin'
7-Deoxy-7([2)- and -7(S)-thioliiicolnyci11 (IO arid 15) were prepared frunl nietklyl thioliiicosanliliide, it degradation product of lincomycin. Thioamido analogs (18 and 20) were prepared f r o m lincomycin i l i and clindamycin (16), respectively. The i-thiol analogs possessed slight antibacterial activity, while the thioamido analogs were about one-fourth as active as the antibiotic from which they were derived.
l'oteritintion of antibacterial activit,y of lincomycin a variety of chemical modifications.2 Introduction of halogeri at C-7, prefrixbly ill the 7 ( S ) configurat,ion, enhanced t'h(, i i ~ oitru arid 1'11 vivo :mt,ibact,erialactivity in several series of a~ialogs.~ This subst'it'uent,is also primarily responsible for the aiit'imalnrial activit'y encountered in 1'-demethylclindam y c i ~ i s . ~Introduction ~,~ of ot,her substituents at C-7 was therefore undertaken. The preparation arid antibacterial activity of 7-thiol analogs of lincomycin are now described. In :iddit,ion to the int~roduct~iori of
(1) was achieved by
(1) Presented in part a t the 11th Medicinal Chemistry Sxmyosium, Quebec. Canada, June 1968. ( 2 ) U. J. hlagerlein, R. D. Birkenmeyer. arid F. liagan, Aittimicrobi,il Agents Chemotherapy-1966, 727 (1967). ( 3 ) (a) D. J. Alagerlein, R. D. Birkenmeger. and F. liagan, J . M e d . L ' h p m . . 10, 355 (1967); ih) R. J. hlagerleinand F.Ragan, ibzd., 12, 780 (lV69). 14) C. Lewis, J . I'orasitol., 6 4 , 169 (1968).
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