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Bisamidines
455
CHAPTER 19 BISAMIDINES 1.
INTRODUCTION
The introduction of amidines in the chemotherapy of protozoal diseases was based on the study of the biochemistry of protozoans. In 1925, Schern [1] observed that the motility of trypanosomes depends on extracellular supply of glucose. Later, Poindexter found that the multiplication of trypanosomes may be reduced by injecting insulin in the animal hosts [2]. This led yon Joncso' and yon Jancs'o [3] to evaluate the blood sugar lowering (hypoglycemic) agent, 1,10-bisguanidinodecane (1, synthalin) against T. brucei in experimented animals; in this in vivo test the drug was found to be active. Following this, a major break through regarding the activity of synthalin was achieved by Lourie and Yorke [4], who demonstrated that the drug was highly trypanosomicidal in vitro even in the presence of glucose. This observation clearly indicated the fact that the activity of synthalin was not due to its hypoglycemic properties, instead it had direct action on trypanosomes.
HN--C-- NH-- (CH2)1o~NH--C--NH I I NH2 NH2 I (Synthalin) The discovery of the trypanosomicidal efficacy of synthalin triggered the synthesis and biological evaluation of various diamidines (2), dithioureas (3) and diguanidines (4), whose two functional groups were linked through a long alkyl chain [5,6]. These compounds exhibited strong in vitro activity, but when tested against T. rhodesiense in mice, only moderate activity was observed in 2 and 4 (n=1014) and 3 (n=6). HN-----C--(CI-12)n--C---NH I I NI--12 NH2 2
S=C--NH--(CH2)n--NH--C=S I I NH2 NH2 3
HN=C--NH-- (CH2)n--NH--C=NH I I NI--12 NH2 4
456 A new horizon in the design of therapeutically useful diamidines was discovered when the alkyl chain in 2 was replaced by C6H5-X-C6H 5. The aromatic diamidines (5a-f), thus obtained, were found to exhibit varying degrees of antiprotozoal activities [7-9]. The first active member of this series was 5a, which was active when tested against T. equiperdum and T. rhodesiense in mice [10]. Later other effective aromatic diamidines were discovered, of which the most notable are pentamidine (5b), propamidine (5c), stilbamidine (5d), dimethyl stilbamidine (5e) and phenamidine (5f). One compound of this series, pentamidine, shows high trypanosomicidal and leishmanicidal activities and, therefore, finds use in clinical practice, especially as diisethionate salt (Pentam 300) [11,12]. Pentamidine has been used in the mass therapy of Gambian sleeping sickness [13] and is also the preferred drug for the treatment of visceral leishmaniasis in humans [11,12,14,15].
Nl"12
NH2 5
a b c d e f
X = -CH2X =-O(CH2)50X = -O(CH2)30X =-CH=CHX = -C(Me) = C (Me)X = -O-
(Pentamidine) (Propamidine) (StUbamidine) (Dimethylstilbamidine) (Phenamidine)
Another compound stilbamidine (5d) has been found to be highly effective against Leishmania donovani in experimental animals and humans [11,12,14]. Although this drug proved to be quite useful in the treatment of visceral leishmaniasis [11], its use in clinical medicine was limited due to its high toxicity. The toxicity of this drug was attributed to its facile photochemical dimerisation to form cis, trans,
cis, trans-l,2,3,4-tetra(4-guanylphenyl)cyclobutane (6) [16]. This limitation was overcome by synthesizing 2-hydroxystilbamidine (7), which was found to be stable to light and was also less toxic than stilbamidine [16]. 2-Hydroxystilbamidine (7) has been used to treat visceral and American cutaneous leishmaniasis in humans with good success [11]. Further work on the design of better antiprotozoals derived from aromatic diamidines has culminated in the synthesis of a series of novel compounds, of which diminazene (8) and HOE-668 (9) exhibited promising antiprotozoal activity. [17-19]. Both these compounds were found to be highly effective against L. donovani in hamsters. Diminazene (berenil) has been widely used to treat early stages of African try-
457
R OHLOH X" --R 5d
6 R =-C--NH I
OH
NH2
CH=CH H2N
\"-" /
C \~ /
\NH2
7 (Hydroxystibamidine) HN,, / ~ ~ ~NH '~C--'-(( "}~#---NH--N----N---(( ")Xt---C~. H2N/ \x,.j/ \',,,_t/ NH2 8 (Berenil) HNx ~ ~ / ~ ,~NH "2HCI '~C--'-~( ~)~k--NH--N--C---~("~k~'--O--(I( ")'kr--C" H2a / \M J / / \"--J/ \M.J/ "N H2 9 (HOE-668)
panosorniasis [11]. The drug has also been found effective against T. vivax and T.
congolense infections in cattle [20,21]. The antiprotozoal activity of aryldiamidines is believed to be due to their ability to bind to the parasite DNA [22,23]. The binding of diarnidines with DNA is mediated through the electrostatic interactions between negative phosphate groups on the DNA helix and the positive centre of protonated amidines [24]. The molecular models of diarylamidines indicate that such compounds may be broadly divided in two classes; one class in which two amidine groups are separated by 12 A and the other where the interamidine distance is about 20 A. These values correspond well with the distances between major and minor groups of DNA [25]. On the basis of these findings, the synthesis of a large number of aromatic diamidines (10-13) was carried out displaying the characteristic distance of 12-20/k between the two amidine functions [26-28]. All these compounds have been found to cause 71-93% inhibition of amastigotes in the macrophages in the spleen of hamsters infected with L.
donovani at an intraperitoneal dose of 2.5 rng/kg [26-28].
458 HN,,
(CH2)2---4N~,)//~---C,,NH2 10
O
11 HN% /C.
,~NH A
A
/N
,C
HN% H2N/C~
12
//NH C
13
It is also possible to link the two amidino functions through a heterocyclic ring. Accordingly a variety of heterocycles carrying 4-guanylphenyl groups have been synthesized [11]. Dann and coworkers [29-32] have carried out a detailed SAR study on diamidines derived from some benzoheterocycles. Among the several heterocyclic diamidines prepared, 2-(4-guanylphenyl)-6-guanylbenzothiophene (14a) and the corresponding indene analogue (14b) exhibited better activity than pentamidine (5b) or berenil (8) against T.b. gambiense. Similarly the indole and benzofuran derivatives (14c and 15) were found to possess high trypanosomicidal activity against T.b. congoliense and T.b. rhodesience respectively [32-34].
~
~
N
H
HN~c~X/ \~/ H2N/ 14a X = S b X=GH2 c X=NH
~~~~~/~~C "NH2 H N ~ c ~ O / / H2N
\x.~/
~NH \NH2
15
A series of aromatic diamidines wherein the two 4-guanylphenyl groups are attached at 2- and 5-positions of furan (16), thiophene (17), pyrrole (18), oxazole (19), thiazole (20) and thiadiazole (21) have been synthesized as possible antiparasitic agents [23,35-38]. The most effective compound was found to be 2,5-bis(4-guanylphenyl)-l,3-oxazole (19) and 2,5-bis(4-guanylphenyl)-l,3,4-thiadiazole (21), which exhibited high trypanosomicidal activity. The cure rates of these two compounds against T.b. rhodesiense in mice was comparable to pentamidine, stilbamidine and hydroxystilbamidine at a dose of 3 m g / k g [38].
459
/
16 X = O
H2N
\
17 X = S 18 X=NH
NH2
H2N/
H
H
\ NH2
22
Ph
- - h CI-
HNmc~
HN'~'C--/ ~ H2N/
C#NH
/
H2N
\
19 X = O 20 X = S
~N--N--N H 23
NH2
.NH2
N--N H2~C
N
N
C,,NH2
24
/ H2N
21
NH2
The other phenylamidines prepared to generate effective antiprotozoals include amicarbalide (22) [39], isometamidium chloride (23) [40] and the triazino compound (24) [41]. Of these, amicarbalide (22) and isometamidium chloride (23) are effective veterinary drugs for treating babesiosis and trypanosomiasis in domestic animals [42], while 24 exhibit trypanosomicidal activity against T. congotiense [10].
2.
SYNTHESIS
2.1
Pentamidine
Pentamidine has been synthesized by Qshley et al. [43]. A convenient route to obtain pentamidine isethionate from 4-hydroxybenzonitrile is outlined in scheme 1.
N C ~ O H
+ Br'(CH2)5"Br
25
b,c >
a
---~ NC~
O--(CH2)5--O
26
27
HN,, ~ ~ NH ~C---k,/(" "~X/--O--(CH2)5--O--~(" "~Xr--Cz"
H2N"
\"J/
\"J/
"NH2
Pentamidine isethionate
28
Scheme 1 Reagents: (a) K2CO3, (b) HC1, EtOH, (c) NH3, EtOH, (d) Isethionic acid.
CN
460
REFERENCES Schern, K., Zent. Bakteriol. Parasitenkd. Abt. I, Orig. 96, 356, 440 (1925). Poindexter, H.A., J. Parasitol. 21, 292 (1935). Von Joncso', N. and von Jancs'o, H., Z. Immunitaetsforsch. 86, 1 (1935). Lourie, E.M. and Yorke, W., Ann. Trop. Med. Parasitol. 31, 435 (1937). King, H., Lourie, E.M. and Yorke, W., Lancet. 2, 1360 (1937). ,
.
.
.
King. H., Lourie, E.M. and Yorke, W., Ann. Trop Med. Parasitol. 32, 177 (1938). Lourie, E.M. and Yorke, W., Ann. Trop, Med. Parasitol. 33, 289 (1939). Ashley, J. N., Barber, H.J., Ewins, A.J., Newberry, G. and Self, A.D.H., J. chem. Soc. 103 (1942). Fulton, J.D. and Yorke, W., Ann. Trop Med. Parasitol. 36, 131 (1942).
10.
Ross, W., In: Burger's Medicinal Chemistry, 4th ed., Part II ed. M.E. Wolff, John Wiley & Sons, New York (1979), pp 439-479.
11.
Sharma, S., Prog. Drug. Res. 35, 365 (1990).
12.
Katiyar, J.C. Anuradha and Sharma, S., Med. Res. Rev., 12, 473 (1992).
13.
Rew, R.S. In: Chemotherapy of Parasitic Diseases, eds. W.C. Campbell and R.S. Rew, Plenum Press, New York (1986), pp. 129-137.
14.
Steck, E.A., Prog. Drug. Res. 18, 289 (1974)
15.
Mc Greevy, P.B. and Marsden, P.D., In: ref. 13, pp. 115-127.
16.
Fulton, J.D., Ann. Trop. Med. Parasitol. 37, 48 (1943); Brit. J. Pharmacol. 3, 75 (1948).
17.
Meith, H., Z. Tropenmed. Parasitol. 12, 320 (1966)
18.
Raether, W., Seidenath, H. and Loewe, H., Ann. Trop. Med. Parasitol 72, 543 (1978).
19.
Jensch, H., Arzneim-Forsch. 5, 634 (1955); Med. Chem. 6, 134 (1958).
20.
Fussgaenger, R. and Baner, R., Med. Chem. 6, 504 (1958).
21.
Raether, W., In: Parasitology in Focus-Facts and Trends, ed. H. Mehlhorn, Springer Verlag, Heidelberg (1988), pp. 739-866.
22.
Festy, B., Sturm, J. and Daune, M., Biochem. Biophys. Acta 407, 24 (1975).
23.
Das, B.P. and Boykin, D.W.J. Med. Chem. 20, 1219 (1977).
461 24.
Waring, M.J., J. Mol. Biol. 54, 247 (1970).
25.
Wartell, R.M., Larson, J.E. and Wells, R.D., J. Biol. Chem. 250, 2698 (1975).
26.
Chauhan, P.M.S. and Iyer, R.N., Indian J. Chem. 22B, 898 (1983).
27.
Chauhan, P.M.S., Rao. K.V.B., Iyer, R.N., Shankhdhar, V., Guru, P.Y. and Sen, A.B., Indian J. Chem. 26B, 248 (1987).
28.
Chauhan, P.M.S., Iyer, R.N. and Bhakuni, D.S., Indian J. Chem. 27B, 144 (1988).
29.
Dann, O., Hieke, E., Hahn, H., Miserre, H.H., Lurding, G. and Roessler, R., Justus L~bigs Ann. Chem. 734, 23 (1970).
30.
Dann, O., Bergen, G., Demant, E. and Volz, G., Justus Liebigs Ann. Chem. 749, 68 (1971).
31.
Dann, O. Volz, G., Demant, E., Pfeifer, W., Bergen, G., Fick, H. and Walkenhorst, E., Justus Liebigs Ann. Chem. 1112 (1973).
32.
Dann, O., Fick, H., Pietzner, B., W alkenhorst, E., Fernbach, R. and Zeh, D., Justus Liebigs Ann. Chem. 16 (1975).
33.
Raether, W. and Seidenath, H., Trop. Med. Parasitol. 27, 238 (1976).
34.
Ogada, R., Fink, E. and Mbwabi, D., Trans. R. Soc. Trop. Med. Hyg. 67, 280 (1973).
35.
Steck, E.A., Kinnamon, K.E., Rane, D.S. and Hanson, W.L., Exp. Parasitol. 52, 404 (1981).
36.
Das, B.P., Zalkow, V.B., Forrester, M.L., Molock., F.F. and Boykin, D.W., J. Pharm. Sci. 71 465 (1982).
37.
Das, B.P. and Boykin, D.W., J. Med. Chem. 20, 531 (1977).
38.
Das, B.P., Wallace, R.A. and Boykin, Jr., D.W., J. Med. Chem. 23, 578 (1980).
39.
Ashley, J.N., Berg, S.S., and Lucas, J.M.S., Nature (London) 185, 461 (1960).
40.
Wragg, W.R., Washbourne, K., Brown, K.N. and Hill J., Nature (London) 182, 1005 (1958).
41.
Ashley, J.N., Berg. S.S. and MacDonald, R.D., J. Chem. Soc. 4525 (1960).
42.
Kuttler, K.L. and Kreier, J.P. In: ref. 13, pp. 171-191.
43.
Ashley, J.N., Barber, H.J. and Ewins, A.J., J. Chem. Soc. 103 (1942).
CHAPTER 19 BISAMIDINES 1.
INTRODUCTION
The introduction of amidines in the chemotherapy of protozoal diseases was based on the study of the biochemistry of protozoans. In 1925, Schern [1] observed that the motility of trypanosomes depends on extracellular supply of glucose. Later, Poindexter found that the multiplication of trypanosomes may be reduced by injecting insulin in the animal hosts [2]. This led yon Joncso' and yon Jancs'o [3] to evaluate the blood sugar lowering (hypoglycemic) agent, 1,10-bisguanidinodecane (1, synthalin) against T. brucei in experimented animals; in this in vivo test the drug was found to be active. Following this, a major break through regarding the activity of synthalin was achieved by Lourie and Yorke [4], who demonstrated that the drug was highly trypanosomicidal in vitro even in the presence of glucose. This observation clearly indicated the fact that the activity of synthalin was not due to its hypoglycemic properties, instead it had direct action on trypanosomes.
HN--C-- NH-- (CH2)1o~NH--C--NH I I NH2 NH2 I (Synthalin) The discovery of the trypanosomicidal efficacy of synthalin triggered the synthesis and biological evaluation of various diamidines (2), dithioureas (3) and diguanidines (4), whose two functional groups were linked through a long alkyl chain [5,6]. These compounds exhibited strong in vitro activity, but when tested against T. rhodesiense in mice, only moderate activity was observed in 2 and 4 (n=1014) and 3 (n=6). HN-----C--(CI-12)n--C---NH I I NI--12 NH2 2
S=C--NH--(CH2)n--NH--C=S I I NH2 NH2 3
HN=C--NH-- (CH2)n--NH--C=NH I I NI--12 NH2 4
456 A new horizon in the design of therapeutically useful diamidines was discovered when the alkyl chain in 2 was replaced by C6H5-X-C6H 5. The aromatic diamidines (5a-f), thus obtained, were found to exhibit varying degrees of antiprotozoal activities [7-9]. The first active member of this series was 5a, which was active when tested against T. equiperdum and T. rhodesiense in mice [10]. Later other effective aromatic diamidines were discovered, of which the most notable are pentamidine (5b), propamidine (5c), stilbamidine (5d), dimethyl stilbamidine (5e) and phenamidine (5f). One compound of this series, pentamidine, shows high trypanosomicidal and leishmanicidal activities and, therefore, finds use in clinical practice, especially as diisethionate salt (Pentam 300) [11,12]. Pentamidine has been used in the mass therapy of Gambian sleeping sickness [13] and is also the preferred drug for the treatment of visceral leishmaniasis in humans [11,12,14,15].
Nl"12
NH2 5
a b c d e f
X = -CH2X =-O(CH2)50X = -O(CH2)30X =-CH=CHX = -C(Me) = C (Me)X = -O-
(Pentamidine) (Propamidine) (StUbamidine) (Dimethylstilbamidine) (Phenamidine)
Another compound stilbamidine (5d) has been found to be highly effective against Leishmania donovani in experimental animals and humans [11,12,14]. Although this drug proved to be quite useful in the treatment of visceral leishmaniasis [11], its use in clinical medicine was limited due to its high toxicity. The toxicity of this drug was attributed to its facile photochemical dimerisation to form cis, trans,
cis, trans-l,2,3,4-tetra(4-guanylphenyl)cyclobutane (6) [16]. This limitation was overcome by synthesizing 2-hydroxystilbamidine (7), which was found to be stable to light and was also less toxic than stilbamidine [16]. 2-Hydroxystilbamidine (7) has been used to treat visceral and American cutaneous leishmaniasis in humans with good success [11]. Further work on the design of better antiprotozoals derived from aromatic diamidines has culminated in the synthesis of a series of novel compounds, of which diminazene (8) and HOE-668 (9) exhibited promising antiprotozoal activity. [17-19]. Both these compounds were found to be highly effective against L. donovani in hamsters. Diminazene (berenil) has been widely used to treat early stages of African try-
457
R OHLOH X" --R 5d
6 R =-C--NH I
OH
NH2
CH=CH H2N
\"-" /
C \~ /
\NH2
7 (Hydroxystibamidine) HN,, / ~ ~ ~NH '~C--'-(( "}~#---NH--N----N---(( ")Xt---C~. H2N/ \x,.j/ \',,,_t/ NH2 8 (Berenil) HNx ~ ~ / ~ ,~NH "2HCI '~C--'-~( ~)~k--NH--N--C---~("~k~'--O--(I( ")'kr--C" H2a / \M J / / \"--J/ \M.J/ "N H2 9 (HOE-668)
panosorniasis [11]. The drug has also been found effective against T. vivax and T.
congolense infections in cattle [20,21]. The antiprotozoal activity of aryldiamidines is believed to be due to their ability to bind to the parasite DNA [22,23]. The binding of diarnidines with DNA is mediated through the electrostatic interactions between negative phosphate groups on the DNA helix and the positive centre of protonated amidines [24]. The molecular models of diarylamidines indicate that such compounds may be broadly divided in two classes; one class in which two amidine groups are separated by 12 A and the other where the interamidine distance is about 20 A. These values correspond well with the distances between major and minor groups of DNA [25]. On the basis of these findings, the synthesis of a large number of aromatic diamidines (10-13) was carried out displaying the characteristic distance of 12-20/k between the two amidine functions [26-28]. All these compounds have been found to cause 71-93% inhibition of amastigotes in the macrophages in the spleen of hamsters infected with L.
donovani at an intraperitoneal dose of 2.5 rng/kg [26-28].
458 HN,,
(CH2)2---4N~,)//~---C,,NH2 10
O
11 HN% /C.
,~NH A
A
/N
,C
HN% H2N/C~
12
//NH C
13
It is also possible to link the two amidino functions through a heterocyclic ring. Accordingly a variety of heterocycles carrying 4-guanylphenyl groups have been synthesized [11]. Dann and coworkers [29-32] have carried out a detailed SAR study on diamidines derived from some benzoheterocycles. Among the several heterocyclic diamidines prepared, 2-(4-guanylphenyl)-6-guanylbenzothiophene (14a) and the corresponding indene analogue (14b) exhibited better activity than pentamidine (5b) or berenil (8) against T.b. gambiense. Similarly the indole and benzofuran derivatives (14c and 15) were found to possess high trypanosomicidal activity against T.b. congoliense and T.b. rhodesience respectively [32-34].
~
~
N
H
HN~c~X/ \~/ H2N/ 14a X = S b X=GH2 c X=NH
~~~~~/~~C "NH2 H N ~ c ~ O / / H2N
\x.~/
~NH \NH2
15
A series of aromatic diamidines wherein the two 4-guanylphenyl groups are attached at 2- and 5-positions of furan (16), thiophene (17), pyrrole (18), oxazole (19), thiazole (20) and thiadiazole (21) have been synthesized as possible antiparasitic agents [23,35-38]. The most effective compound was found to be 2,5-bis(4-guanylphenyl)-l,3-oxazole (19) and 2,5-bis(4-guanylphenyl)-l,3,4-thiadiazole (21), which exhibited high trypanosomicidal activity. The cure rates of these two compounds against T.b. rhodesiense in mice was comparable to pentamidine, stilbamidine and hydroxystilbamidine at a dose of 3 m g / k g [38].
459
/
16 X = O
H2N
\
17 X = S 18 X=NH
NH2
H2N/
H
H
\ NH2
22
Ph
- - h CI-
HNmc~
HN'~'C--/ ~ H2N/
C#NH
/
H2N
\
19 X = O 20 X = S
~N--N--N H 23
NH2
.NH2
N--N H2~C
N
N
C,,NH2
24
/ H2N
21
NH2
The other phenylamidines prepared to generate effective antiprotozoals include amicarbalide (22) [39], isometamidium chloride (23) [40] and the triazino compound (24) [41]. Of these, amicarbalide (22) and isometamidium chloride (23) are effective veterinary drugs for treating babesiosis and trypanosomiasis in domestic animals [42], while 24 exhibit trypanosomicidal activity against T. congotiense [10].
2.
SYNTHESIS
2.1
Pentamidine
Pentamidine has been synthesized by Qshley et al. [43]. A convenient route to obtain pentamidine isethionate from 4-hydroxybenzonitrile is outlined in scheme 1.
N C ~ O H
+ Br'(CH2)5"Br
25
b,c >
a
---~ NC~
O--(CH2)5--O
26
27
HN,, ~ ~ NH ~C---k,/(" "~X/--O--(CH2)5--O--~(" "~Xr--Cz"
H2N"
\"J/
\"J/
"NH2
Pentamidine isethionate
28
Scheme 1 Reagents: (a) K2CO3, (b) HC1, EtOH, (c) NH3, EtOH, (d) Isethionic acid.
CN
460
REFERENCES Schern, K., Zent. Bakteriol. Parasitenkd. Abt. I, Orig. 96, 356, 440 (1925). Poindexter, H.A., J. Parasitol. 21, 292 (1935). Von Joncso', N. and von Jancs'o, H., Z. Immunitaetsforsch. 86, 1 (1935). Lourie, E.M. and Yorke, W., Ann. Trop. Med. Parasitol. 31, 435 (1937). King, H., Lourie, E.M. and Yorke, W., Lancet. 2, 1360 (1937). ,
.
.
.
King. H., Lourie, E.M. and Yorke, W., Ann. Trop Med. Parasitol. 32, 177 (1938). Lourie, E.M. and Yorke, W., Ann. Trop, Med. Parasitol. 33, 289 (1939). Ashley, J. N., Barber, H.J., Ewins, A.J., Newberry, G. and Self, A.D.H., J. chem. Soc. 103 (1942). Fulton, J.D. and Yorke, W., Ann. Trop Med. Parasitol. 36, 131 (1942).
10.
Ross, W., In: Burger's Medicinal Chemistry, 4th ed., Part II ed. M.E. Wolff, John Wiley & Sons, New York (1979), pp 439-479.
11.
Sharma, S., Prog. Drug. Res. 35, 365 (1990).
12.
Katiyar, J.C. Anuradha and Sharma, S., Med. Res. Rev., 12, 473 (1992).
13.
Rew, R.S. In: Chemotherapy of Parasitic Diseases, eds. W.C. Campbell and R.S. Rew, Plenum Press, New York (1986), pp. 129-137.
14.
Steck, E.A., Prog. Drug. Res. 18, 289 (1974)
15.
Mc Greevy, P.B. and Marsden, P.D., In: ref. 13, pp. 115-127.
16.
Fulton, J.D., Ann. Trop. Med. Parasitol. 37, 48 (1943); Brit. J. Pharmacol. 3, 75 (1948).
17.
Meith, H., Z. Tropenmed. Parasitol. 12, 320 (1966)
18.
Raether, W., Seidenath, H. and Loewe, H., Ann. Trop. Med. Parasitol 72, 543 (1978).
19.
Jensch, H., Arzneim-Forsch. 5, 634 (1955); Med. Chem. 6, 134 (1958).
20.
Fussgaenger, R. and Baner, R., Med. Chem. 6, 504 (1958).
21.
Raether, W., In: Parasitology in Focus-Facts and Trends, ed. H. Mehlhorn, Springer Verlag, Heidelberg (1988), pp. 739-866.
22.
Festy, B., Sturm, J. and Daune, M., Biochem. Biophys. Acta 407, 24 (1975).
23.
Das, B.P. and Boykin, D.W.J. Med. Chem. 20, 1219 (1977).
461 24.
Waring, M.J., J. Mol. Biol. 54, 247 (1970).
25.
Wartell, R.M., Larson, J.E. and Wells, R.D., J. Biol. Chem. 250, 2698 (1975).
26.
Chauhan, P.M.S. and Iyer, R.N., Indian J. Chem. 22B, 898 (1983).
27.
Chauhan, P.M.S., Rao. K.V.B., Iyer, R.N., Shankhdhar, V., Guru, P.Y. and Sen, A.B., Indian J. Chem. 26B, 248 (1987).
28.
Chauhan, P.M.S., Iyer, R.N. and Bhakuni, D.S., Indian J. Chem. 27B, 144 (1988).
29.
Dann, O., Hieke, E., Hahn, H., Miserre, H.H., Lurding, G. and Roessler, R., Justus L~bigs Ann. Chem. 734, 23 (1970).
30.
Dann, O., Bergen, G., Demant, E. and Volz, G., Justus Liebigs Ann. Chem. 749, 68 (1971).
31.
Dann, O. Volz, G., Demant, E., Pfeifer, W., Bergen, G., Fick, H. and Walkenhorst, E., Justus Liebigs Ann. Chem. 1112 (1973).
32.
Dann, O., Fick, H., Pietzner, B., W alkenhorst, E., Fernbach, R. and Zeh, D., Justus Liebigs Ann. Chem. 16 (1975).
33.
Raether, W. and Seidenath, H., Trop. Med. Parasitol. 27, 238 (1976).
34.
Ogada, R., Fink, E. and Mbwabi, D., Trans. R. Soc. Trop. Med. Hyg. 67, 280 (1973).
35.
Steck, E.A., Kinnamon, K.E., Rane, D.S. and Hanson, W.L., Exp. Parasitol. 52, 404 (1981).
36.
Das, B.P., Zalkow, V.B., Forrester, M.L., Molock., F.F. and Boykin, D.W., J. Pharm. Sci. 71 465 (1982).
37.
Das, B.P. and Boykin, D.W., J. Med. Chem. 20, 531 (1977).
38.
Das, B.P., Wallace, R.A. and Boykin, Jr., D.W., J. Med. Chem. 23, 578 (1980).
39.
Ashley, J.N., Berg, S.S., and Lucas, J.M.S., Nature (London) 185, 461 (1960).
40.
Wragg, W.R., Washbourne, K., Brown, K.N. and Hill J., Nature (London) 182, 1005 (1958).
41.
Ashley, J.N., Berg. S.S. and MacDonald, R.D., J. Chem. Soc. 4525 (1960).
42.
Kuttler, K.L. and Kreier, J.P. In: ref. 13, pp. 171-191.
43.
Ashley, J.N., Barber, H.J. and Ewins, A.J., J. Chem. Soc. 103 (1942).