860 Journal of Medicinal Chemistry, 1,970, Vol. 13, S o . 6
GILLESPIE, ACHARYA, D.ivis,
~ N R D .u=t~~x
Antimalarials. 11. 8- Quinolinemethanols
Sixteen new oc-(dialkylaminomethyl)-8-quirioliiiemethar~olshave been synthesized for evaluation of their antimalarial activity. Desired substitution on the quinoline nucleus required development of two synthetic pathways to the key intermediates, the 8-quinoliiiecarboxaldehy~es,which were coiiverted through the osirariea into the amino alcohols. 4-Xe substituted compounds required preparation of 4-me thyl-S-quinolinecarboxylic aridi, ejterificatiori, reduction with L.2H, and oxidation to t,he aldehyde. Intermediates without alkyl substitution were prepared by oxidation of S-meth~-lquiriolines. Observations o n reduction of S-quinolinecartmxylatea by LAH are described. Thirteen compounds were tested against Plasmodium berghei in mice. Three of them produced curei at 640 ing,'kg. 6-Chloro-2-(4-chloropher1yI )-oc-(dibutylaminomethyl)-8-quinolinemeth:mol hydrochloride (3b) w m curative arid n o t phototosic.
Interest in yuiiioliriemeth:~nols as potentiwl '1nt inin' larial agents has contiriued because this c1a.s of compounds has denion>trutcd qignificant activity against malarial infections in several \pecies, including man. The potent 2-pheny1-4-c~uinolirieinethariol~ are phototoxic4 and unsuitable for field uw. *\[any molecular modifications5of the basic structure have been prepared in efforts to rnitigate this Y i d t . effect. This paper describes a major modification, that of moving the amino alcohol side chain to t h r S position of the quinoline nucleus. The 8-quinolinemethanols have been studied6 orilj cursorily, and early work uncovered no activity in them. Since nuclear substitution is required for activity in the parallel 4-quinolinemethanols, the unsubstituted compounds tested would not be expected to have antinixlarial activity. The substitutcd 8-yuinolineniethanoli prepared by 11s are illustrated i n Chart I. Conipoundb in series 1, 2, and 3 were prepared from appropriately substituted S-n~ethJ.lyuiIioliriesby SeOL oxidation to the S-yuinolinec:irboxualdeh~d~~~, conversion of the aldehydes into o\ir:LricA> b\ the method ot Corey, e/ al.,' and coiidrns:ttioti of t h(1 ouir:ttic.s with dialkylarniries (Scheme I ) Compounds in series 4, 5 , 6, wid 7 R ere prepared from 4-methyl-8-yuinolinecarbo lic acidh by rzterification, reduction of the esters h IAH, oxidation of thi. alcohols m-ith pyridine-S03 D.\ISO,r conversion of tht. aldehydes to oxiranes, i ~ n dcotideniation of thc ouirnnewith dinlkylamines (Schtmt' TI). Thi. rathrr round(1) (a) For t h e previous paper see J . S. Cillespie, Jr.. I t . .J. R o d e t t , .ir.. a n d R. E . Davis, J . ,\fed. Chem., 11, 425 (1968); lb) the work dehcrilied i n this paper was performed under Contract D.A49-19:3-lf U-2981 witti tlw U. S. Army Medical Reueareli a n d 1)evelopment Command. This ~h Contribution No. 772 from t h e . i r m y Iiesearcli Program on Malaria. This paper was presented a t the 21st Soritlieast~rnKepional lleetiny of rhr .Imerican Chemical Society, Richniond. \.a,, S O Y5-8, 1969: ( r ) T o \ v l i o ~ n inquiries should be addressed. ( 2 ) F. T.Wiselogle, Ed., ".I S u r v e y i,f .\ntimalarial Driigs, 1941-1 94.5," J. IV. E d n - a d s , Ann Arbor. llicli., l ! U f i , (3) G . R . Coatney. "Survey of .intimalarial Agents," Public Healtlr Service Rlonograpli No. 9, Federal Security A g r n r y , 1952; also knun.n a* Public Ilealtli Serl-ice Publication S o . 193. ( 4 ) \V. E. Rotlie and I). P. Jacobus. .J. .bled. Chem.. 11, 366 (1968). ( 5 ) 12. I t . .\tkinson a n d A . .J. Piittick, i h i d . , 11, 1223 (1968). 16) (a) I, . J . . I mrr. f ' h n b . Soc., 87, 1:
