Journal of Medicinal Chemistry, 1970, Vol. 1 3 , S o . 3 535
NOTES
Notes Potential Naphthoquinone Antimalarials. 2-Acylhydrazino-1,4-naphthoquinones] KENNTH
H.
D U D L E Y 2 ASD
H.W.1Yh.E
?rhLLCR
Chemistry and Life Sciences Laboratory, Research Triangle Instzticte, Research Triangle Park, Sorth Carolina 27707 Received October 2, 1969
The 2-hydroxy-3-alkyl-1,4-naphthoquinones[I, R = alkyl or (CH2),-cycloalkyl] have received considerable attention during the malaria chemotherapy programs since 1940, a remarkable feat being the synthesis and successful clinical trial of lapinone [I, R = (CH2)sC(OH) (n-CbHg)2].3 Success of lapinone stemmed largely from knowledge of metabolic disposition (fate of the side chains) and of the correlation of in vitro antirespiratory activity with the cyitical extraction value, P E , which ~ reflects the drug’s “hydrophilic-lipophilic balance.” The most active member in any active series of I generally possessed a p E value near or within the range 10-12.3,4
were synthesized by a general reactiori involving condensation of a carboxylic acid hydrazide with 2hydroxy-1,4-naphthoquinone in 80% Ac0H.j Compounds IIg and I I h were obtained in adequate yield and purity when 80% trifluoroacetic acid was employed as solvent. iidaptation of 2-~z-hexa1ioylhydrasi1io-l,4-naphthoquinone (IId) to p E theory4 MW checked by calculatiori of pE from determinations conducted at several H + and quinone concentrations. The data here (Table 11) supported the theory4 with an accuracy of h 0.05 p E unit. Critical extraction values, pE, for each series of 2acylhydrazino-l,4-naphthoquinones(11) increased 1i:iearly with molecular weight. Interestingly, a close similarity in p E values was observed for specific analogs of related series of I4and 11; for example, I I m had p E 8.53 and the corresponding analog of I (R = CH2c y ~ l o h e x y lhad ) ~ p E 8.43. -4sharp distinction in the physicochemical properties of specific analogs of I and I1 mas apparent through comparison of the log K term in eq 2. The constant, K , describes the ratio of concentrations of un-ionized quinone distributed between the ether and aqueous phases. The critical extraction value, pE, is defined as
+
0
I
pE = PH - 2 log { [ H + ] ( K / K a ) } (1) where K connotes [,AIether/ [HAIUater. I t follows that,
0 I1
The 2-acylhydrazino-l,4-naplithoqui1iones [11, R = alkyl or (CH2).cycloalkyl] are a class of compounds marked by an acidity constant (pK,’) of about 8.0-8.5.j It was of interest to probe whether some degree of antiplasmodial activity would be obtained from analogs of 11, particularly in instances where the proper “hydrophilic-lipophilic balance,” as defined by a p E value of 10-12, was incorporated into 11. We report here the p E data and some biological data of two series of 2-acylhydrazino-l,4-naphthoqui1io1ies (11). Related data for certain analogs of I are included for comparison.6 Methods and Results Except for IIg and IIh, the two series of 2-acylhydrazino-1 ,4-naphthoquinones (11)reported in Table I (1) This investigation was supported under Contract No. DA-49-193-AID2862 with t h e Department of Army and t h e U. S. Army Research and Development Command. This paper is Contribution K o . 239 from the .Army Research Program on Malaria. (2) Present address: Center for Research in Pharmacology and Toxicology, School of hledicine, University of North Carolina, Chapel Hill, N . C. 27514. (3) (a) L. F. Fieser, J . P. Schirmer, S. Archer. R. R . Lorenz, and P. I. Pfaffenbach, J . .Wed. Chem., 10, 513 (1967) and references therein; (b) L. F. Fieser, “The Scientific Method,” Reinhold Publishing Corp., New York, N. T., 1964, pp 163-191. (4) L. F . Fieser, AI. G . Ettlinger, and G. Fawae, J . Amer. Chem. S o c . . 7 0 , 3228 (1948). (5) K . H. Dudley, H. IT. hliller, P. TV. Sclineider, and R. L. 1 l c K e e . J . Ory. Chem.. 34, 2T50 (1969). ( 6 ) \Ye thank Professor Fieser for use o f these data. T h e d a t a n e r e kindly searched and talmlated 11s I l r . R . E. Strube t i t \VR.AIR,
($3
+ 2 ) - pKa
log K
(2) A rough value of log K can be estimated for each arialog of series of I and I1 by assuming pKuHZoof 5.5 for I7and pKaHZoof 8.5 for 1I.j Comparison of calculated log K values for specific analogs of related series of I4 and I1 indicated that, for comparable analogs, a distribution ratio of un-ionized I (i.e., log K ) exceeded that for a corresponding analog of I1 by an exponential factor of roughly 2.52. Biological Data.-The 2-acylhydrazino-1,i-naphthoquinones, IIa-IIn, ere evaluated as antimalarial agents against lethal Plasmodium berghei infections in mice [Walter Reed Army Institute of Research (WRAIR) screening program] .8 Compounds were administered subcutaneously as oil suspensions to lots of 5 mice a t dosages of 40, 160, and 640 mg/kg. All analogs of I1 in Table I were n o n t ~ x i cand ~ inactive. The mean survival time (AMST) of treated over control animals ranged from 0.1 to 1.3 days, but AMST of less than 2 days was considered insignificant. Berberian arid Slighter’O have recently reevaluated the efficacy of series of hydroxymphthoquiriones (I) as antimalarial agents against blood-induced P. berghei infections in mice; the screening procedure differed, however, from the standard WRAIR assay. Regarding =
( T ) L. F . Fieser and h I . Fieser, J. Amer. Chem. S o c . , 6 6 , 1565 (1934). (8) T. S. Osdene, P. 13. Russell, and L. Lane, J . M e d . Chem., 10, 431 (1967). (9) Printout interpretation for rodent antimalarial test results, Walter Reed Army lnstitute of Research. ( I O ) 1).;\. Berberian and R . G . Slighter. J . f’rirnsiloi., 64, Y Y Y (1968).
Journal of Xcdicinal Chemistrg, 1910, Vol. 12, S o . 3 537
NOTES
In the case where a hydrazide.HC1 was employed (ix.,IIl), an equiv quantity of Et3N was added to the condensing medium. Thnj, a suspension of cyclopentylpropionic acid hydrazide. HCl (6.3 g, 33 mrnol) and 2-hydroxy-l,4-napthoquinone(5.0 g, 29 mmol) in 807, HOBc (200 rnl) containing E t J (3.3 g, 33 rnrnol) was stirred at 25” for 26 hr. The solvent was stripped in oacuo and the bright orange residue was freed from excess hydrazide arid Et& .HC1 using a wash solution of EtOH-KnO-concd HC1 (10: 10: 1). Additional successive washings with EtOH-H20 (1: l), AleaCO, and Et20 gave a crude product (4.6 g) which afforded after two recrystallizations 2.73 g of 111, mp 174-179”. Critical Extraction Values (pE).-Extraction const,ants, pE, were determined using the standard procedures described as A and B by Fieser, c f Procedure B4 was required only for IIf. Initial concentrations of naphthoquinone in Et20 were in the order of 30-60 mg =k 0.01 mg/2d0 ml; which is approximately 0.4 that generally employed for the 2-hydroxy-3-alkyl-l,4naphthoquinone~.~This deviation from the standard procedure was necessary because of the lesser solubility of the lower rnolecular weight, analogs of 11. The concentration of naphthoquinone in the alkaline buffer was determined by measuring the absorbance at 533 mk uit,h a IIodel 2400 Beckman DU Spectrophotometer.
standard route from G,S-dichloroquinoline-5-carboxylic acid, which in turn was prepared from 5-amino-2,4dichlorobenzoic acid by a Slcraup reaction.
I
,.
HOCHCH,N( TL-CJH,)~
I
Ll
Ci I1
Ill
Pharmacology.-Several major revien s of druginduced p h o t o t ~ x i c i t y ~are - ~ available. It is apparent that phototoxic compounds fall into two classes, depending on whether the changes they evoke in tissues are oxygen-dependent or oxygen-independent. The EDJ\IRD R. ATKINSON. W D ASTHONY J. P U T T I C K best known oxygen-independent drugs are the furocoumarins (psoralens) Recent workB shows that the .Arthur D.Little, Inc., Cambridge, Massuchusefts 09140 phototoxic quinolinemethanol drugs are definitely oxyReceived Sovember 29, 1969 gen-dependent . The photosensitizing furocoumariris are known to react with DNA in a photochemical reaction, We have reported2 that no significant decrease in which has been studied in detail;g no mechanism has phototoxicity was observed when the structures of yet been proposed for the photosensitizing action of the certain 2-phenyl-4-quinolinemethanol antimalarials quinolinemethanols. were modified by replacing chlorine by fluorine, or by The possible role of long-lived triplet states in the changing the nature of the S-containing side chain. phototoxic action of drugs4 was the basis of our study We now report the results of a study of four addiof the iodine compounds 1-6. It is known that molecules tional structural modifications, three of which might that contain atoms of large atomic number have a be expected, on theoretical grounds, to cause a signifisignificantly decreased triplet state lifetime.I0 Excant decrease in phototoxicity. The fourth modificaamples of the effect of iodine as a “heavy atom” are tion involved the synthesis of a 2-phenyl-5-quinolineavailable in which iodine functions in a n intramolecumethanol drug, a structure not reported previously. lar” and intermolecular12way. Chemistry.-The synthesis route to compounds conThe antimalarial activity of the iodine compounds taining iodine or free phenolic groups (Table I ) n as the (Table 11)was equal or superior to that of analogous C1 same as that used previously.2 Six novel oxides were and F compounds studied earlier. I n the standard test prepared from the appropriate cinchoninic acids and the of phototoxicity, in which the drug mas administered ip, compounds in Table I ere prepared by the reaction of there was a significant decrease in phototoxicity (Table these oxides with the appropriate amine. During the 111) when iodine was at the 3’ or 4’positions, but little preparation of oxides having free phenolic groups it was or no decrease when iodine mas a t the 7 position. Hownecessary to protect the latter by acetylation a t the ever, when any of these compounds mas administered cinchoninic acid stage; the protecting group was reorally, the minimum effective phototoxic dose was 30 moved during the reduction of the bromomethyl ketone mg/kg or less. The high phototoxicity of the 4’,6-diintermediate by SaBH+ iodo compound 6 seems anomalous. 6,S-Dichloro-2-phenyl-a-(2-piperidyl)-l,2,3,4-tetra- The phenolic compounds 7-9 were prepared a t a time hydro-4-quinolinemethanol (I) was prepared by catalwhen the differences in mechanism of phototoxic ytic reduction of the well-known antimalarial 6,sdichloro-2-phenyl-CY(2-piperidyl)-4-quinolinemethanol. ( 4 ) 11. -4. Pathak. in “Drugs and Enzymes,” 11. 11. I1rodie and J . R . The 3-quinolinemethanol 111 was prepared by way Gillette, E d . , Pergamon-hlacmillttn. S e w York. N . I-., 1965, pp 419-440. ( 5 ) 11,I. Simon. C o m p . Biochem., 27, 137 (1967). of I1 so that the antimalarial activity and phototoxicity (6) T. B. Fitupatrick, .\I. .4, Pathttk, I. .4, hfapnus, and \V. L. Curwen, of I1 could be measured also. I1 was prepared by our Annu. Reu. ,Wed., 14, 195 (1963). Antimalarials. 11. Quinolinemethanols with Decreased Phototoxicity’
.’
T.0 . Soine. J . I’hiirm. Sci., 63, 231 (1964). (8) I. G. Fels. J . .\fed. Chem., 11, 8 8 i (1968). (9) G. Rodighiero. L. hlnsajo, F. Dall’hcrlua, S. hlarciani, G. Caporale, and 11. L. Ciavatta, E r p e r i e n t i n . 26, 479 (1969). ( 1 0 ) S. P. AfcGIynn, T. .\zumi. and A I . Kastia, J . Chem. Phya.. 4 0 , 307 (7)
(1) This n o r k \ \ a s performed under Contract Di-49-193-hID-2901 \\it11 the U k r m i Medical Research and Deielopment Command Office of the Surgeon General Contrilmtion N o 736 of t h e i r m i Research Program on hlaldria ( 2 ) E R itkinuon and 4 J Puttick J ’Wed Chem 11, 1223 (1968) ( 3 ) E R Duclirnan H Sargent T C hlvers and D R H o n t o n J d m e , C h e m S O L 68, 2710 11946)
(1964). (11) I,. S. Foster and D. Dudley, J . f’hy.,. Chem.. 66, 838 (1962). (12) H. Van Z w e t , K e c . T r m . Chim. P o ~ A - B Q 67, . s . 1201 (1968).
