September l 9 6 i YH3 to.lo6,CH (CHd 3N(CzHs)z +0.019
0.000
c1 -0.214
-0.009
-0.036
+0.016
quinine
HOMO: +0.647 LEMO: -0.539 -0.096
+0.062
H 0.000
&
/
+
-0.269
chloroquine HOMO: +0.603 LEMO: -0.601
t0.049
:
. +o.oo> P
f0.011
+0.081 -0.006
t0.068
-0.003 -0.0a2
\
+0.050
-0.009 +0.104
- 3 -0.206
HN, +o,ogl'CH
(CHZ)~ N H z
I
CH3
t0.018
\ -0.013
N -0.216
quinoline HOMO: +0.703 LEMO: -0.527
primaquine HOMO: +0.524 LEMO: -0.578
NH2
+0.016
-0.041
+0.059
+0.106
+0.119
-0.015
-0.075
+0.042/
+0.017
+0.103
NHz -0.022
-0.267
4-aminoquinoline HOMO: +0.607 LEMO: -0.595
to.091
8-aminoquinoline
HOMO: +0.552 LEMO: -0.567
Figure l.--HMO charge densities and energy levels of the HOMO and L E N 0 of the quinoline antimalarials, quinine, chloroquine, and primaquine, and their parent compounds, quinoline, 4-aminoquinoline, and 8-aminoquinoline.
Results and Discussion Electronic Structures and Energy Levels of Antimalarial Molecules and Related Compounds.-Antimalarial drugs fall into several csategories:14 4-yuinolylcarbinols, -I-aminoyuinolines, 8-aminoyuinolines, 4yuinazolones, 9-aminoacridines, diaminopyrimidines, biguanides, 4,4'-diaminodiphenyl sulfones, and a new category, sydnones. We have selected representative ailtimalarial compounds from these classes for our cdculat'ions, with the exception of the sulfones. Sulfones were omitted because there is controversy over their molecular orbital description;'; we are studying this problem in more detail. It should be noted that sydriones are mesoionic caompourids16wild also present difficulties in their molecular orbital treatment. We recognize that the a h v e antimalarial agent may for some drugs be a metabolite of the administered drug. This is known to be true for proguanil." m e have t'herefore included an active m e t a b ~ l i t e 'of~ proguanil and an analog" of the met,abolite. -4lthough these antima,larial drugs are oftmenadministered in salt form, me have initially compared t'he (14) IT-. H. Nyberg and C . C . Cheng. J . .lltd. Chem., 8,531 ( 1 9 6 5 ~ . (15) G . Cilento, Chem. Rev.. 60, 117 (1960). (16) I\-. Baker atid IT-. 1).Ollis. Quart. Ret,. (London), 11, 1.5 (1957~.
( I T ) IH. C . Carrington, A . I:.
( ' r o w h e r , I). G I)avey, .i. -1. L P v i , ancl
1'. I.. R O ~ P.\.,~tuw, , 168, 1080 (l!J5l),
neutral forms. The effect of salt formation on some of these structures is considered in the latter part of this paper. The indices of electronic structure coilsidered are the net a-electronic charge densities'* and energy levels in units of Po (eq 1) of the highest occupied molecular orbital (HOMO) and the lowest empty molecular orbital (LEMO).l9 We have assigned a plus sign to those charge densities representing a deficit of electrons. The energy level of the HOMO is taken as a measure of electron-donor ability*O and that of the L E N 0 as a measure of electron-acceptor ability.?' These properties are of primary importance in influencing charge-transfer complex formation.'? ail interaction which is proving of interest in biologic*al s~.stems.*~The smaller the energy level of the HOMO, the lower the energy required to remove a a electrori from the molecule, and therefore the greater are the electron-donor properties. The closer to zero the (18) Reference 2, y 116. (19) I t should he kept in mind that the value of Bo is negative, a s a result
of which the energy values given by 11s have the opposite sign compared to the absolute values of tlieae energies. 'I'liroiighout this diwllssion t h e P I I P T vahirs ~ ~ are alxvays i i i uiiits of P o . 120) Reference 2 , p 128. (21) Reference 2, IJ 132. (221 K e f ~ r e n c e2. 1) 13.5. (2:O 1,; 11. I), ~,4'-diiriti,oc.tlrt)Riiilide ( I )KC), arid (xihaiiilide. interaction with the chloroquine riiig, even (.orisidwing the negative u charge which the chloro substituent should have. We were interested in (1) exploring fur-0.Sti5, does not indicate especially good electroiither the role of the 2-aniitio group of guanine, ( 2 ) Liccept()rproperties. c.omparing, with a consisteiit set of HA10 paramet,ers, We believe that the H l I 0 calculations indicate elec.tronic~properties of the DSA bases and of the stroligly th:it the attractive forces it1 the DKC-HDI' atitinialarials with which they interact, and (8) iiivest'icomplex arise in large part from a charge transfer :tiid gating the effecst) of salt formation at the amino group that the specificit?. of D S C as compared to carbaiiilide bonded to the ring o i i the electroiiic strwtiirr of the res.;UItsfrom the extraorditiarj. electroti-acceptor proper:intimalarials. ties of D S C . We would like to poiiit~out that HI\IO (dculations Electronic Aspects of the Interaction between on the DSA4 bases adenine, guanine, cytosine, arid Some Antimalarials and Deoxyribonucleic Acid.-Ai thymine, as well as t8hehydrogeii-boiided pairs adeniuemost interesting and valuable study by Hahn arid cothymine and guariine-c.\.tosine. have been carried out \\-orkeys*h a s 1)rovided convincing evidence that chloroby the PullmarisZ using their set of parameters. For cluirie, cluiiiacrine, and quinine romplex with native our c*alculatiotis,we employed hydrogen bonding paramI)SA\, bloc~kingenzymatic synthesis of DSA and riboet ers suggested by the Pullmans. 31 nucleic acid ( R S A ) i i L zitro atid the biosynthesis of Comparing the two pyrimidine bases, cytosine with I > S X und RS-1 in susce1)tible cells. The selectivity t>hymine, and t'he two purine bases, guanine with adeof these drugs for the malaria parasite is attributed iiine (Figure X), otie riot,es pronouwed charge-density t o the unusually high acc.umulation of the drug by thc differences. I r i part, these ditl'erericw are due to t,he 1):ir:tsit ized eryt hrovyt es. lie t.anc*et o the drugs is due t 1) :in inipairnient of the n c ~ c ~ ~ ~ m r ~ l ; ltne(*hHtiisni ~tiori or I )rrtiiwbili t y .
'9
+o*N,&ll&l&H
thymine
cy tosine HOMO: t 0 . 7 6 8 LEMO: -0.602
HOMO: +0.665 LEILIO: -0.597 - 0 6'1 I 0
0.157
-0.094
H . I
guanine HOMO: +0.481 LEMO: -0.754 10 108
NH, I
.
0 2ti6
0 149
guanine-c ytosine HOMO: S0.487 LEMO: -0.592 0..1%
adenine
HOMO: +0.640 LEMO: -0.772 -0.tit;k
0
10.131
inosine-cy tosine HOMO: +0.564 LEMO: -0.590 inosine
-'0.036
HOMO: S0.546 LEMO: -0.677 Figure 8.-HlIO charge detisities atid energy levels of the 1lOLLO and LIClIO (Jf cytoeiiie, thymiiip, giiatiiiis, :tderiitie, : I t i d iit osinr.
rhoice of the lac%mi arid itniiiio fornib, whicah have been shown to preponderate3? a s opposed to the lactim arid imino forms, of these molerulr~. Since the coiitribu-
tions, however, of the lnctini arid imino fornis are relatively the charge distributions of the molecule :is represented should be close t o that of the mole( d e :is it exiatb. The purines are better electron donors than the pyrimidines, arid guanine is, as indirated previously,230 far superior in this respect to adenine. We would expect that electrostatic interactions involving the five-membered purine ring would not be 1 3 2 ) Reference 2. i) 207
-0.664
-0.346 - 0 I€?,\
N
A/
-0274
-0.095
N H
t O 265
adenine-thymine HOMO: +0.605 LEMO: -0.584 Figure 9.--HllO charge densities and energy levels of i h t . IIOMO and LE110 of the hydrogen-bonded pair\ gtianinr LJ t w n e , adenine t h l mille, and inosine-cytosine, with h\ di rigt'ri lii~tid~iip trratsd i c w i i t f i r i g t o I'iillmnri anti I'iillmaii
N@
c1
-0,192
-0.023
f0.016
chloroquine (amine salt) HOMO: $0.719 LEMO: -0.486
N@ I
quinacrine (amine salt) HOMO: +0.507 LEMO: -0.291 -0.019
+0.063
0.000
+0.100
f0.032 -0.096
I
NQ primaquine (amine salt) HOMO: +0.682 LEMO: -0.511 4”
I -0.020
+0.006
t0.015
Consideration of hydrogen bonding for the pairs , guariine-cytosii~e, inosine-( h e , :tnd :idenine-th!.mine, does iiot change these general conclusions. It is found that charge densities vary somewhat for those atoms directly involved in the hydrogen bonding (F’g ’ 1 ure 9). The changes in HOAIO energy levels on hydrogen bonding bring the inosine-cytosine pair rloser in elevtroll-donor properties t o adenine-thymine than to g u a n i n e q tosine (l’igure 9), Ji-hich is iiiterestingly it1 acwrd n i t h the respective influeiicaes on the chloroquine spectrum by dIdC, d M T , and dGdC Since Hahii, et U Z . , ~ fouiid the interactions of chloroquine took place only iyith double-stranded (i.e., base-paired) DATApolymers, and since this base pairing does riot cause great differences in electronic properties, the hypothesis that chloroquine must interact simultaneously with both members of a base pair is attravtive. To take acrount of the proposed participation of the amine salt form of chloroquine in the Dl-A% we treated the protonated amino group according to S t r e i t ~ v i e s e r who , ~ ~ has indicated that an amine halt group may be considered purely inductive. We employed his auxiliary i i i d u r t i ~ eparameter of 0.lhl1l where hx i5 talien a b the 11 value of a positively charged nitrogen, ‘2.0,” giving us a n h value for the carbon bonded to the amine salt group of 0.2. Comparison of the calculation for the amine salt of chloroquine (Figure 10) with that for neutral chloroquine (Figure I) indicates that the quinoline nitrogeii is sensitive to this alteratioii; this charge for the salt is appreciably lon-er. Even more outstanding is the effect on the energy levels. There is a marked improvement in the elec,troii-:Lc,ceptor properties of the salt which should enhance interaction with the electrondonating purines. The effect of salt forniatioii (Figure 10) on quinacrine (1:igure 2 ) is in the same direction as for chloroquine and is even more pronounced. The amine salt of quinacrine should be by far the best electron acceptor of the antimalarials considered. Because the quinacrine salt is so much better a n electron acceptor than the chloroquine salt, it is reasonable that its complexation is observable spectroscopically n-ith dIdC and dAdT, poorer electron donors than dGdC and DSA, while the weaker electron acceptor, chloroquine salt, must interact with the better electron donors, dGdC and DSA, before the spectroscopic changes are observed. This explanation is an alternate to the conclusion that the compared effects of DSA, dGdC, d d d T , and dIdC on the spectra of chloroquine and quinacrine point t o the general interactions of quiiiacrine and the guanine-specific interactions of chloroquine with DXAk I t is interesting that quinine, which does not form an amine salt arid has poorer electron-acceptor properties than the salt forms of chloroquine and quinacrine, m s thought to involve hydrogen bonding8 in the DSA\ complex, in contrast to the “ionic” interactio~is~ suggested for chloroquine and quinacrine. We have also calculated the effect of salt formation (Figure 10) on primaquine (Figure 1). Surprisingly, the quinoline nitrogen’s charge density for the salt is raised slightly. Electron-acceptor properties are im-
uN,/ +0.043,
-0.009
+0.102
-0,190
4-aminoquinoline (amine salt) HOMO: +0.729 LEMO: -0.481 Figiire lO.--H3IO charge densities and energy levels of the IIOAIO and LE310 of the amine salt forms of chloroq~iine, quinacrine, primaquine, and 4-aminoqninoline, with the positive amine nitrogen treated as purely indiictive.
of the %amino group makes it important in influencing charge-transfer interactions, which may be observed spec,tro~copically.~~ We feel that this function of the %amino group of guanine may very well explain why the interaction of chloroquine and dGdC is observed spectroscopically, while that of chloroquine and dIdC is not, without involhig a specific electrostatic interltctioii involving the 2-amino group. Electrostatic interactions with the guanine ring should not be greatly different than those with the inosine ring, with the possible exception of those a t the 3-nitrogen, the charge density of whirh is influenced by the 2amino group. (33) L. J. Andrews and R. M . Keefer, “Molecular Complexes in Organic Chemistry,” Holden-Day, Inc., San I‘rancisco. Calif., 1961.
(34) Reference 11, p 231.
