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ANNUAL REPORTS IN MEDICINAL CHEMISTRY-I5
Chapter 13.
Antiparasitic Agents
Leslie M. Werbel and Donald F. Worth Warner-Lambert Company, Ann Arbor, Michigan, 48105 Protozoal Disease General - In view of the increasing role of the W.H.O. in research on tropical diseases, an article on their new policies in research for new tools to control six major tropical diseases is of interest.l A fascinating summary has appeared on the philosophy of a pharmaceutical company towards involvement with tropical diseases. Malaria - A review on new experimental antimalarial drugs3 and a volume on "New Trends in Malaria Chemotherapy" have appeared.4 An overview of the literature indicates an encouraging trend towards the application of more basic science and thus a more rational approach to drug development in this area. An increase is a parent in papers dealing with the basic biochemistry of the parasite,5-i the mode of drug action9-11 and in the application of contemporary uantitative structure activity relationships (QSAR) technology12-12 towards the design of better agents. Drug delivery systems have also received attention,15-17 although it is still not clear that major improvements could be expected in malaria chemotherapy in this fashion. The need is well defined as the scourge of chloroquine resistance spreads slowly into areas such as Africa which have as yet remained untouched. 18-22 Moreover, it has been concluded recently that malaria and beriberi were the unresolved military medical problems contributing to the fall of Cambodia. 23 New therapeutic entities are sorely wanting and the recent literature has dealt mainly with further study of those agents revealed previously. Additional information is available on mefloquine (L), perhaps the most important new entity to appear in recent years. Stuaies on its clinical ef fi ~ a c y pharmacokinetics, ~ ~ 25-28 as well as on a pyridine methanol analog have appeared. 299 3o The therapeutic superiority of mefloquine may be explained by the fact that it, like amodiaquine, is undiminished in accumulation by erythrocytes infected with chloroquineresistant p. berghei.3l The novel acridinedione, 2,reported last year has now acquired a name (floxacrine), and a detailed evaluation of its biological activity has appeared. 32 U s e of this compound in combination with antimalarial agents such as chloroquine, quinine, pyrimethamine, etc., has been claimed to result in synergistically increased activity against the normal and chloroquine-resistant erythrocytic forms of p. berghei. 33
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Copyrisht 0 1980 by A d e m i s Press, Inc All rights of reproduaion m any form mervcd. ISBN 0-12-000515-6
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Complete primate data has been published on a number of the very potent 2,4-diaminoquinazoline antifol antimalarials. 34-36 The need for an improved tissue schizontocide continues to stimulate substantial effort. Synthetic efforts have been unrewarding thus far,37-40 as have efforts to understand the toxicity of primaquine, the best currently available drug.41-42 An effort to overcome drug toxicity by utilizing a lower dose via a slow release preparation was also unsuccessfu1.43 The enantiomers of chloroquine have been separated, and it was shown that the (+) isomer was some three times more active against2. vinckei than the (-) isomer. No correlation was observed between the antimalarial One novel structure activity and the DNA binding of the enanti~mers.~~ reported recently to have substantial curative activity in the p. berghei mouse screen is the pyridine thiosemicarbazone 2.45 An a-aminocresol derivative (9has been shown to be more active46 in-the primate model than in the mouse model, with efficacy against both normal and resistant parasites very similar to that of mefloquine.
3 =
--4
C(CH3) 3
Leishmaniasis - Little has appeared which would suggest that major therapeutic advances are forthcoming for this disease entity, or even that new approaches are available worthy of further study. As Marsden puts it, the need is for a cheap, non-toxic, orally administered drug and no prospect is in sight.47 He compares our current knowledge of the disease to that of malaria at the end of World War 11. Once again expanded interest in the biochemistry of the parasite is e ~ i d e n t . ~ ~ -Hope$~ fully, with time this may be translated into useful drug discovery results. The antileishmanial effect of allopurinol
(2) - on
the parasite
5 in vitro has been demonstrated at concentrations comparable to those --
achieved in human plasma. Work has continued in an effort to understand the actions of this drug and the unique aspects of its metabolism in the para~ite.~~-~ It’ is suspected that activation within the cells to an active form is required, but as yet it is not clear how a useful drug may result from these observations. To our knowledge, no in vivo test system can demonstrate antiparasitic activity for this compound.
Nifurtimox was evaluated in 2 6 patients with mucocutaneous disease. Only limited response was obtained when the drug was given in a daily oral divided dose of 10 mg/kg for 30 days and the drug was not recommended for routine use in the disease.58 Three other observations are worthy of follow-up, however. Oral administration of 150 mg/kg/day for 30 days of amphotericin B inhibited the
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development of symptoms in mice and hamsters.59 Rifampicin given at 600 mg daily for periods from 2 weeks to 2 months to 10 patients with cutaneous disease afforded disappearance of the lesions, but no parasitic evaluation was presented. 6o In 12 adult patients with Leishmania tropica, levamisole treatment at 150 mglday for 2 days for 3-7 weeks was said to be effective.61
(r.
r.
Trypanosomiasis - A review on the human cruzi, T. gambiense, rhodesiense) and animal brucei, vivax, congolense, 2. evansi, T. equinum, T. e ui erdum) trypanosomiases as world public health problems -6 as well as one on the present status of chemotherapy and has appeared, chemoprophylaxis of human trypanosomiasis in the Western hemisphere. 63
(z.
z.
r.
Nitroheterocycles continue to be a fertile field for investigation.
The nitroimidazole 5 was active againstz. cruzi, and a study of its
metabolites in the Tog led to the 6,7-cis dihydroxy compound which had greater trypanocidal activity in vivo than = 6 . 64
An interesting non nitroheterocycle, acridine 1,is reported in a recent patent to be a trypanosomicide, but details are not available.65 Two babesicides, amicarbalide (Diampion; 3,3'-diamidinocarbanilide diisethionate) and imidocarb (Imezol; 3,3'-bis(2-imidazolin-2-yl) carbanilide, dihydrochloride) were reported to cure 2. brucei infections in mice when given ip at 10 mg/kg for 3 days starting 24 hours post infection.66
Rats infected with 2. brucei were cured with just sublethal doses of salicylhydroxamic acid plus glycerol. It was thought that this was a result of the inhibition of L-glycerol-3-phosphate oxidase, which was also thought to be one of the principal sites of action of suramin. However, treatment with glycerol did not affect the mobility of the trypanosomes nor the survival of infected rats after treatment with suramin.67 Antitrypanosomal activity was reported for several benzyltriphenylphosphonium salts against rhodesiense infections in mice. 68
r.
Both African trypanosomes and some tumor cells undergo a high rate of aerobic glycolysis as a result of inefficient or nonfunctional mitochondria1 systems and in each the key "pacemaking" glycolytic enzymes are hexokinase, phosphofructokinase and pyruvic kinase. Using this as a rationale, 49 compounds known to have antitumor properties were screened against rhodesiense infections in mice. Six were found active with the most interesting being 5-(3,3-dimethyl-l,1t riazeno)imidazole-4-carboxamide. 69
r.
Studies to reexamine the synthesis of purines and pyrimidines in
T. -cruzi indicate that no form of the parasite can synthesize substantial
quantities of purine de novo and that therefore dependence is on salvage. Moreover, it seems that amastigotes and trypomastigotes will depend on -de novo synthesis for their pyrimidines and thus, drugs that can block this are likely to be trypanocidal. 70
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Benznidazole (N-benzyl-2-nitro-1-imidazoleacetamide) has been reported to be a very efficient agent a ainst Chagas disease, and its pharmacokinetics have been reviewed. 7f Trichomoniasis - Discussions as to the potential toxicity of metronidazole continueiLSl3 as the drug continues to be used as very likely the best available agent for this infection. Two separate publications have indicated that there is no evidence for cancer due to its use,74 and that it is safe for short-term treatment.75 Moreover, it was reported that the mutagenic effects of the drug can be dissociated from its antiparasitic properties in experimental models by pretreatment of 2(3)-pbutyl-4hydroxyanisole or administration of erythromycin. 7 6 An interesting anaerobic metabolite of metronidazole, N-(2-hydroxyethyl)oxamic acid has been reported. 7 7 Other than nitroheterocycles, little of interest against trichomonal infections has appeared, and as a matter of fact, not much of anything appears ready to compete with metronidazole as the drug of choice. Toxicological and teratological studies appeared on azanidazole (8), - a new systemic trichomonacide. 78 .
N
8
=
Another nitroheterocyle, of more unusual structure, is the imidazo[l,2-b]p ridazine 2, which is apparently being readied for clinical trial. v9 Nitro-T,8-naphthyridines such as 10 were reported to have nearly the same activity as metronidazole agxnst vaginalis infections. 80 0
r.
In vitro studies among a wide range of structural types revealed -activity with saponins, such as leontoside,81 and 3-hydroxymethylenepyrazoltetradecanoic acid picrate. 82 Tricandil (mepartricin) , a polyene antibiotic has been introduced into Brazil by Searle for the treatment of trichomoniasis and candidiasi~.~~ Amoebiasis - The literature on this disease area remains sparse. A belated summary on all aspects of amoebiasis research up to 1977 reported at the Seventh Seminar on Amoebiasis at Mexico City in November of 1977 has been published.84 A progress report on all intestinal protozoa has also appeared.85 The need for a cheap, non-toxic agent in rural environments has led to a recommendation for a diiodohydroxyquinoline-oxytetracycline combination86 the tetracycline acting presumably on the gut flora and thus indirectly on the infectious organism.87
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The classic drug in this area, emetine, has been shown to be amoebicidal by inhibiting protein synthesis.88 It has been the subject of this of two stereoselective total s y n t h e s e ~ . ~ Application ~,~~ technology may allow the syntheses of less complex structural analogs.
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The imidazo[l,2-b]pyridazine mentioned previously as a trichomonacide is also reported to be a potent agent against cecalE. histolytica in rats and hepatic 5. histolytica in hamsters. A recent patent claims still another dichloroacetamide (11)as a potent amoebacide in vitro.91 The amidines represented by 12 continue under investigation and 12 is reported to have no teratogenF effect, to be as potent as metroniGole against cecal amoebiasis (albeit with a lower safety margin) and to be more potent than metronidazole against the hepatic infection.92
Giardiasis - A thorough review of the infection of the human gastrointestinal tract by Giardia lamblia, known both as giardiasis or lambliasis, has appeared.yj The use of nitroimidazoles as therapy is stressed. In a comparison of metronidazole and quinacrine in 160 cases of infants and children, the low failure rate, minimal side effects and more tolerable flavor favored metronidazole given at 15-25 mg/kg/day for 5 days.94 A newer nitroimidazole, ornidazole (Tiberal) was studied in children and found to be effective in a single dose. It was preferred to metronidazole. 9 5 Another nitroimidazole, tinidazole, was also used successfully in children in a single dose treatment.96
Toxoplasmosis - Several reviews have appeared dealing with the disease and its treatment. 97-100 Therapeutic emphasis continues to center around combinations of pyrimethamine and a long-acting sulfonamide. Coccidiosis - Commercial potential for the control of this resistanceprone parasite continues to spark research interest. For example, of the approximately 130 million cattle in the United States, about 77 million are susceptible to coccidiosis each year. Of these, some 3,850,000 are treated and about 180,000 die.lol Ionophorous antibiotics recently have been found effective in poultry and mammals. Lasalocid added to feed in a dose to produce the equivalent of about 3.0 mg/kg has been found effective in controlling clinical coccidiosis in calves.lol A review of a variety of drug types has appeared. lo2 Studies are ongoing with arprinocid [ 9-(2-chloro6-fluorobenzyl)adenine]. Mode of action studies have led to the tentative conclusion that inhibition of hypoxanthine transport may play a critical role in its action on the parasite.lo3,104 A recent study has concluded that its anticoccidial activity is due to a metabolite in the chick. 1°5 Modification of the 6-azauracil structure resulted in 1(3',5'-dichlorophenyl)-6-azauracil. Further modifications have apparently resulted in the separation of potency from the undesirable persistence of these compounds and also prevent emergence of resistant strains. lo6 N,N'-bis(3,4-ditrifluoromethylphenyl)methylmalonamide has been shown to be effective vs. amprolium, zoalene, aklomide or nicarbazine resistant strains of 2. tenella. 107
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Helminth Diseases General - Recent articles and reviews consider a wide range of subjects includin the problem of resistance of animal helminths to current chemotherapy,?08 parasitic zoonoses109 and the complex interrelationships of the variety of disciplines contributing to human health.l1° Two provocative articles outlining broad biochemical strategies toward parasite chemotherapy appeared recently. 7 l2 Filaria - Basic biochemical studies with this parasitic group seem to be increasing, with work bein reported on comparative metabolism of different genera of adult and effects of larval forms in infected Methods of cryopreservation and in vitro cultivation mosquitoes. 114-116 may allow improved studies with the human parasite, Onchocerca v o l ~ u l u s . ~ ~ ~ Clinical trials with a variety of anti arasitic drugs, such as metronidazole,118 nifurtimox,119 mebendazole,1 2 9 7 122 amodiaquine,121 and levamisole121,122 gave marginally promising results at best with the possible exception of mebendazole against Dipetalonema perstans. 122 An interesting approach uses electron microscopy of skin snips to evaluate the effect of metrifonate on onchocerciasis atients. 123 Recent reviews of both the clinical124 and laboratoryP25 work on filariasis chemotherapy are available. Other Nematodes - An exciting new group of compounds, known collectively as avermectins was isolated from fermentation of Streptomyces avermitilis.126 This group consists of at least 8 disaccharides of 16membered pentacyclic lactones. The compound designated avermectin Bla has demonstrated a broad spectrum of activity at single oral doses of 0.1 mglkg or less,127 including a 95% reduction of Haemonchus contortis, Ostertagia circumcincta and Cooperia oncophora in sheep, E. placei, 0. ostertagi and C. punctata in cattle at 0.1 mg/kg, and Ancylostoma caninum in dogs. It was also effective a ainst Capillaria obsignata, but not Heterakis gallinarum, in poultry. 158 Activity was also seen against the pre-cardiac stage of Dirofilaria immitis in ferrets. 129
130 has shown an Amidantel, a new phenylenediamine derivative (131, interesting anthelmintic spectrum includin Hymenospis diminuta in rats,130 and Ancylostoma caninum in dogs. 191 It was also effective against both the microfilaria and adult Dipetalonema witei, but only the microfilaria of Litomosoides carinii in Mastomys natalensis. l30 St ill 1 4 ) , has been shown another new phenylenediamine structure, febantel (-
0Sq
N
H
C /MIC02CH3 'NCO, -CH,. NHCOCH20CH3
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highly effective a ainst various nematodes and cestodes in rodents, dogs, sheep and cattle. 132 A new benzimidazole derivative, (15), given to = SCN
-
sheep naturally infected with intestinal nematodes at 50 and 200 mg/kg gave complete reduction in fecal egg count despite a lack of activity against Nematospiroides dubius in mice. 133y Results from a doubleblind clinical study comparing ciclobendazole (16)and mebendazole, indicate that the two drugs are equally effective for treating ascaris and hookworm infections and that mebendazole is significantly better against trichuriasis. Both drugs were well tolerated. 134 A variety of other structures including 17 135 and 18 136 have appeared in the recent patent literature claimxg nematoc=l;ial activity.
Schistosomiasis - The first clinical reports using praziquantel appear promisin The pharmacokinetic behavior was dominated by rapid metab01ism.l~~No clinically relevant changes were found for any of the laboratory parameters measured in healthy volunteers given total doses as high as 7 5 mg/kg. In initial multicenter clinical trials,138-142 the drug was found effective against Schistosoma haematobium, & mansoni, andS.japonicum infections in Africa, South America, and Asia at total doses of 60 mg/kg or less. Further studies on the carcinogenic potential of hycanthone in rodents were conducted.143,144 The absence of mutagenic activity for prazi uantel was confirmed in several systems, including mammalian cells. 142 An interesting mechanized in vitro screening approach was developed using several known schistosomicides. 146
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s,
K. E. Kinnamon, E. A. S t e c k a n d D. S. Rane, Antimicrob. Agents Chemother., 157 (1 979). W. E. G u t t e r i d g e a n d M. Gaborak, I n t . J. Biochem., 10,4 1 5 ( 1 9 7 9 ) . J. R i a f l a u b , W. H. Z e i g e r , A r z n e i m i t . F o r s c h . , 29, 1 6 1 1 ( 1 9 7 9 ) . B. Hartley-Asp, L a n c e t 1?_ (8110) 2 7 5 ( 1 9 7 9 ) . C. M. Voogd, J. J. v a n d e r S t e l a n d J. J. J. A. A. J a c o b s , Mut. Res., 66, 207 (1979). C. M. Beard. K. L. N o l l e r . W. M. O ' F a l l o n , L. T. K u r l a n d , a n d M. B. D o c k e r t y , N. Engl. J. Med., 301, 5 1 9 ( i 9 7 9 ) . A. B. H a r t l e y , L a n c e t , 8110, 275 ( 1 9 7 9 ) . D. A. B r u c k n e r , E. Buedine. a n d M. VoRe, J. P a r a s i t o l . , 6 5 , 474 ( 1 9 7 9 ) . R. L. Koch a n d - P . Goldman; J. Pharmacol. Exp. T h e r . , c c 4 0 6 ( 1 9 7 9 ) . R. Tammiso, G. O l i v a r i , C. C o c c o l i , G. G a r z i a a n d G. V i t t a d i n i , Arzneim-Forsch, 28, ( I I ) , 2251 ( 1 9 7 8 ) . P. F. F a b i o , A. E. L a n z i l o t t i a n d S. A. Lang, J r . , J. L a b e l l e d Cpds. Radiop h a r m a c e u t . , 15,407 ( 1 9 7 8 ) . N. S u z u k i , M. Kato a n d R. Dohmori, Yakugaku Z a s s h i (J. Pharm. S c i . J a p . ) 99, 1 5 5 (1979). Kh. A b d u l l a e v , Farmakol. P r i r . V e s c h i s t v , 1978,1 0 3 (C.A. 91, 49295 ( 1 9 7 9 ) ) . Kh. A b d u l l a e v , i b i d . , 139, C. A. 3 151104 ( 1 9 7 9 ) . F. D. C. R e p o r t s "The P i n k S h e e t " , May 2 1 , 1979; U.S. P a t e n t 3 , 7 8 0 , 1 7 3 t o S. P. A., December 18, 1973. Arch. I n v e s t . Med., Suppl. 1, 8 5 ( 1 9 7 8 ) . R. K n i g h t a n d S. G. W r i g h t , &, 19, 9 4 0 ( 1 9 7 8 ) . D. K. Masters a n d A. D. Hopkins, J. Trop. Med. Hyg., 82, 9 9 ( 1 9 7 9 ) . W. A. Roemer, I n t e r n i s t , 19, 6 8 0 ( 1 9 7 8 ) . N. E n t n e r , J. P r o t o z o o l . , 26, 324 ( 1 9 7 9 ) . T. Kametani, Y. S u z u k i , M. Terasawa a n d M. Imara, J. Chem. SOC. P e r k i n . T r a n s . I., 1 9 7 9 , 1211. T. F u j i i , a n d S . Y o s h i f u j i , Chem. Pharm. B u l l . , 27, 1486 ( 1 9 7 9 ) . German P a t e n t No. 2 , 8 4 2 , 7 5 2 , t o C a r l o E r b a , A p r i l 5 , 1979. E. J. Burden, S. G. C a r v a j a l , P. F. F a b i o , T. L. F i e l d s , Yans-I L i n , K. C. Murdock, S . A. L a n s , J r . , E x p e r i e n t i a 3 5 , 3 3 ( 1 9 7 9 ) . H. J. S p e c h , Deut. Med. Wochenschr, 103,2 0 0 8 ( 1 9 7 8 ) . S. K a v o u s i , Am. J. Trop. Med. Hyg., 28, 1 9 ( 1 9 7 9 ) . N. I y n g k a r a n , E. L. Lee, a n d M. L. Robinson, Scand. J. I n f e c t . , D i s . , 1 0,2 4 3 ( 1 9 7 8 ) . G. C. L e v i , V. Amato Neto, H. N. V. S t e f a n i , N. A. Romero a n d N . L. Neto, Rev. I n s t . Med. Trop. Sao P a u l o , 21, 26 ( 1 9 7 9 ) . V. Maternova a n d E. A. Shevkunova, K l i n i c h Med., 57, 2 1 ( 1 9 7 9 ) . 1. T. E l D a s o u q i , J. Egypt SOC. P a r a s i t o l . , 9 , 8 9 ( 1 9 7 9 ) . R. J. S c o t t , Trop. D i s . B u l l . , 75, 8 0 9 (1978). J. v a n d e r Veen, Ned. T i j d s c h r . Geneesk., 123,564 ( 1 9 7 9 ) . P. R. F i t z g e r a l d a n d M. E. M a n s f i e l d , J. P a r a s i t o l . , 65, 8 2 4 ( 1 9 7 9 ) . K. I m a i a n d T. Matsuno, F a r u m a s h i a , 14,6 7 6 ( 1 9 7 8 ) [C. A., 90, 8 0 4 4 1 ( 1 9 7 9 ) l . C. C. Wang, P. M. S i m a s h k e v i c h a n d R. L. S t o t i s h , Biochem. Pharmacol., 28, 2241 (1979). C. C. Wane. R. L. Tolman. P. M. S i m a s h k e v i c h a n d R . L. S t o t i s h . Biochem. Pharmacol.. 28, 2249 ( i 9 7 9 ) . V. S. L a t t e r a n d R. G. Wilson, P a r a s i t o l . , 79, 1 6 9 ( 1 9 7 9 ) . M. W. M i l l e r , B. L. M y l a r i , H. L. Howes, J r . , J. E. Lynch, M. J. Lynch a n d R. C. Koch, J. Med. Chem., 22, 1 4 8 3 ( 1 9 7 9 ) . F. P a n i t z , P a r a s i t o l . , 78, 3 3 ( 1 9 7 9 ) . J. D. K e l l y a n d C. A. H a l l , Adv. Pharmacol. Chemother., 16,8 9 ( 1 9 7 9 ) . Tech. Rept. S e r . 6 3 7 , World H e a l t h O r g a n i z a t i o n , Geneva, 1979. W. S. B a i l e y , Am. J. Trop. Med. Hyg., 2 7 , 4 4 1 ( 1 9 7 8 ) . T. E. Mansour, S c i e n c e , 205, 462 (1979). S. S. Cohen, S c i e n c e , 205, 964 ( 1 9 7 9 ) . K. R. M i d d l e t o n a n d H. J. S a z , J. P a r a s i t o l . , 65, 1 ( 1 9 7 9 ) . J. J. J a f f e a n d L. R. C h r i n , J. P a r a s i t o l . , 65, 226 ( 1 9 7 9 ) i b i d . , 550 ( 1 9 7 9 ) . M. G. Simpson a n d B. R. L a u r e n c e , J. P a r a s i t o l . , 65, 732 ( 1 9 7 9 ) . J. J. J a f f e a n d L. R. C h r i n , Biochem. Pharmacol., 28, 1 8 3 1 ( 1 9 7 9 ) . E. L. S c h i l l e r , V. M. T u r n e r , H. F. M a r r o q u i n a n d R. D'Antonio, Am. J. Trop. Med. Hyg., 28, 997 ( 1 9 7 9 ) . V. P. Sharma, H. S. R a t h o r e , and M. M. Sharma, Am. J. Trop. Med. Hyg., 28, 6 5 8 (1979). H. F u g l s a n g a n d J. Anderson, Tropenmed. P a r a s i t . , 29, 3 5 5 ( 1 9 7 8 ) . J. M. Golsmid a n d S. R o g e r s , C e n t r a l Afr. J. Med., 25, 3 ( 1 9 7 9 ) . J. E. McMahon, Ann. Trop. Med. P a r a s i t . , 73,4 6 5 ( 1 9 7 9 ) . M. U. V. L. Narashinham, S. P. Roychowdhury, M. Das a n d C. K. Rao, S. E. A s i a n , J. Trop. Med. Pub. H e a l t h , 9 , 5 7 1 ( 1 9 7 8 ) . G. D. B u r c h a r d , E. J. A l b i e z a n d M. B i e r t h e r , Tropenmed. P a r a s i t . , 30, 9 7 ( 1 9 7 9 ) . F. Hawking, Advan. Pharmacol. Chemother., 16, 1 2 9 ( 1 9 7 9 ) . D. A. Denham, J. Helminth., 53, 1 7 5 (1979).
Chap. 13 126.
127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146.
T. W.
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J . C o l e , L. J. C o l e , J. E. F l o r , R. T. Goegelman, V.
P.
Gullo, H. J o s h u a , A. J. Kempf, W. R. K r e l l w i t z , R. L. Monaghan, R. E. Ormond, K. E. Wilson, G. Albers-Schonberg a n d I. P u t t e r , A n t i m i c r o b i a l Agents a n d Chemother., 15,
638 (1979). W. Burg, B. M. M i l l e r , E. E. Baker, J. Birnbaum, S. A. C u r r i e , R. Hartman, Y. Kong, R. L. Monaghan, G. O l s e n , I. P u t t e r , J . B. Tunac, H. W a l l i c k , E. 0. S t a p l e y , R. O i w a , a n d S . Omura, A n t i m i c r o b i a l Agents a n d Chemother., 15,3 6 1 (1979). J . R. E g e r t o n , D. A. O s t l i n d , L. S . Blair, C. H. E a r y , D. Suhayda, S. C i f e l l i , R. F. R i e k a n d W. C. Campbell, A n t i m i c r o b i a l Agents a n d Chemother., 15, 372 (1979). L. S. Blair a n d W. C. Campbell, J . P a r a s i t o l . , 64, 1032 (1978). H. Wollweber, E. Niemers, W. F l u c k e , P. Andrews. H. S c h u l t z and H. Thomas, Arzneim. F o r s c h . , 29, 3 1 (1979). H. Thomas, Tropenmed. P a r a s i t . , 30, 404 (1979). H. Wollweber, H. K o l l i n g , A. Widdig, H. Thomas, H. S c h u l t z a n d P. Murmann, Arzneim. F o r s c h . , 28, 2193 (1978). R. D. Haugwitz, B. V. Maurer, G. A. J a c o b s , V. L. Narayanan, L. C r u t h e r s a n d J . S z a n t o , J. Med. Chem., 22, 1113 (1979). R. Guggenmoos, K. M. Akhtaruzzaman, F. Rosenkaimer, W. Gaus, U. B i e n z l e a n d M. D i e t r i c h , Tropenmed. P a r a s i t . , 29, 423 (1978). U.S. P a t e n t 4021570 t o S c h e r i n g Corp., May 3, 1977; D. Loebenburg, M. M. N a f i s s i V o r c h e i , B. A n t o n a c c i a n d J . A. W a i t z , J. P a r a s i t o l . , 65, 823 (1979). U.S. P a t e n t 4154835 t o Merck L Co., May 15, 1979. G. Leopold, W. Ungethum, E. G r o l l , H. W. Diekmann, H. Nowak and D. H. G. Wegner, Eur. J . C l i n . Pharm., 14,281 (1978). A. D a v i s a n d D. H. G. Wegner, B u l l . W. H. O . , 57, 767 (1979); A. D a v i s , J. E. B i l e s 773. a n d A. M. U l r i c h , N. K a t z , R. S . Rocha a n d A. Chavas, %, 781. T. I s h i z a k i , E. Kamo a n d K. Boehme, 787. A. T. S a n t o s , B. L. B l a s , J . S . Nosenas, G. P. P o r t i l l o , 0. M. O r t e g a , M. H a y a s h i a n d K. Boehme, i b i d . , 793. J. E. McMahon a n d N. K o l s t r a p , B r i t . Med. J . , 2, 1396 (1979). 0. Bulay, H. Urman, K. P a t i l , D. B. C l a y s o n a n d P. S h u b i k , I n t . J. C a n c e r , 23, 97 (1979). H. Tsuda, D. S. R. Sarma, S. R a j a l a k s h m i , J. Z u b r o f f , E. F a r b e r , R. P. B a t z i n g e r , Y. Cha a n d E. Bueding, Cancer R e s . , 39, 4491 (1979). R.
x,
x,
H. B a r t s c h , T. K u r o k i , C. M a l a v e i l l e , N. L o p r i e n o , R. Barale, A. Abbondandolo, S. B o n a t t i , G. R a i n a l d i , E. Vogel a n d A. D a v i s , M u t a t i o n R e s . , 58. 133 (1978). M. C. Brown, D. F. Norman, D. R. B e l l a n d C. J . Chavasse, Med. B i o l . Eng. Cornput., 16, 408 (1978).
ANNUAL REPORTS IN MEDICINAL CHEMISTRY-I5
Chapter 13.
Antiparasitic Agents
Leslie M. Werbel and Donald F. Worth Warner-Lambert Company, Ann Arbor, Michigan, 48105 Protozoal Disease General - In view of the increasing role of the W.H.O. in research on tropical diseases, an article on their new policies in research for new tools to control six major tropical diseases is of interest.l A fascinating summary has appeared on the philosophy of a pharmaceutical company towards involvement with tropical diseases. Malaria - A review on new experimental antimalarial drugs3 and a volume on "New Trends in Malaria Chemotherapy" have appeared.4 An overview of the literature indicates an encouraging trend towards the application of more basic science and thus a more rational approach to drug development in this area. An increase is a parent in papers dealing with the basic biochemistry of the parasite,5-i the mode of drug action9-11 and in the application of contemporary uantitative structure activity relationships (QSAR) technology12-12 towards the design of better agents. Drug delivery systems have also received attention,15-17 although it is still not clear that major improvements could be expected in malaria chemotherapy in this fashion. The need is well defined as the scourge of chloroquine resistance spreads slowly into areas such as Africa which have as yet remained untouched. 18-22 Moreover, it has been concluded recently that malaria and beriberi were the unresolved military medical problems contributing to the fall of Cambodia. 23 New therapeutic entities are sorely wanting and the recent literature has dealt mainly with further study of those agents revealed previously. Additional information is available on mefloquine (L), perhaps the most important new entity to appear in recent years. Stuaies on its clinical ef fi ~ a c y pharmacokinetics, ~ ~ 25-28 as well as on a pyridine methanol analog have appeared. 299 3o The therapeutic superiority of mefloquine may be explained by the fact that it, like amodiaquine, is undiminished in accumulation by erythrocytes infected with chloroquineresistant p. berghei.3l The novel acridinedione, 2,reported last year has now acquired a name (floxacrine), and a detailed evaluation of its biological activity has appeared. 32 U s e of this compound in combination with antimalarial agents such as chloroquine, quinine, pyrimethamine, etc., has been claimed to result in synergistically increased activity against the normal and chloroquine-resistant erythrocytic forms of p. berghei. 33
0
0
-1
CF3
Copyrisht 0 1980 by A d e m i s Press, Inc All rights of reproduaion m any form mervcd. ISBN 0-12-000515-6
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Complete primate data has been published on a number of the very potent 2,4-diaminoquinazoline antifol antimalarials. 34-36 The need for an improved tissue schizontocide continues to stimulate substantial effort. Synthetic efforts have been unrewarding thus far,37-40 as have efforts to understand the toxicity of primaquine, the best currently available drug.41-42 An effort to overcome drug toxicity by utilizing a lower dose via a slow release preparation was also unsuccessfu1.43 The enantiomers of chloroquine have been separated, and it was shown that the (+) isomer was some three times more active against2. vinckei than the (-) isomer. No correlation was observed between the antimalarial One novel structure activity and the DNA binding of the enanti~mers.~~ reported recently to have substantial curative activity in the p. berghei mouse screen is the pyridine thiosemicarbazone 2.45 An a-aminocresol derivative (9has been shown to be more active46 in-the primate model than in the mouse model, with efficacy against both normal and resistant parasites very similar to that of mefloquine.
3 =
--4
C(CH3) 3
Leishmaniasis - Little has appeared which would suggest that major therapeutic advances are forthcoming for this disease entity, or even that new approaches are available worthy of further study. As Marsden puts it, the need is for a cheap, non-toxic, orally administered drug and no prospect is in sight.47 He compares our current knowledge of the disease to that of malaria at the end of World War 11. Once again expanded interest in the biochemistry of the parasite is e ~ i d e n t . ~ ~ -Hope$~ fully, with time this may be translated into useful drug discovery results. The antileishmanial effect of allopurinol
(2) - on
the parasite
5 in vitro has been demonstrated at concentrations comparable to those --
achieved in human plasma. Work has continued in an effort to understand the actions of this drug and the unique aspects of its metabolism in the para~ite.~~-~ It’ is suspected that activation within the cells to an active form is required, but as yet it is not clear how a useful drug may result from these observations. To our knowledge, no in vivo test system can demonstrate antiparasitic activity for this compound.
Nifurtimox was evaluated in 2 6 patients with mucocutaneous disease. Only limited response was obtained when the drug was given in a daily oral divided dose of 10 mg/kg for 30 days and the drug was not recommended for routine use in the disease.58 Three other observations are worthy of follow-up, however. Oral administration of 150 mg/kg/day for 30 days of amphotericin B inhibited the
122
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development of symptoms in mice and hamsters.59 Rifampicin given at 600 mg daily for periods from 2 weeks to 2 months to 10 patients with cutaneous disease afforded disappearance of the lesions, but no parasitic evaluation was presented. 6o In 12 adult patients with Leishmania tropica, levamisole treatment at 150 mglday for 2 days for 3-7 weeks was said to be effective.61
(r.
r.
Trypanosomiasis - A review on the human cruzi, T. gambiense, rhodesiense) and animal brucei, vivax, congolense, 2. evansi, T. equinum, T. e ui erdum) trypanosomiases as world public health problems -6 as well as one on the present status of chemotherapy and has appeared, chemoprophylaxis of human trypanosomiasis in the Western hemisphere. 63
(z.
z.
r.
Nitroheterocycles continue to be a fertile field for investigation.
The nitroimidazole 5 was active againstz. cruzi, and a study of its
metabolites in the Tog led to the 6,7-cis dihydroxy compound which had greater trypanocidal activity in vivo than = 6 . 64
An interesting non nitroheterocycle, acridine 1,is reported in a recent patent to be a trypanosomicide, but details are not available.65 Two babesicides, amicarbalide (Diampion; 3,3'-diamidinocarbanilide diisethionate) and imidocarb (Imezol; 3,3'-bis(2-imidazolin-2-yl) carbanilide, dihydrochloride) were reported to cure 2. brucei infections in mice when given ip at 10 mg/kg for 3 days starting 24 hours post infection.66
Rats infected with 2. brucei were cured with just sublethal doses of salicylhydroxamic acid plus glycerol. It was thought that this was a result of the inhibition of L-glycerol-3-phosphate oxidase, which was also thought to be one of the principal sites of action of suramin. However, treatment with glycerol did not affect the mobility of the trypanosomes nor the survival of infected rats after treatment with suramin.67 Antitrypanosomal activity was reported for several benzyltriphenylphosphonium salts against rhodesiense infections in mice. 68
r.
Both African trypanosomes and some tumor cells undergo a high rate of aerobic glycolysis as a result of inefficient or nonfunctional mitochondria1 systems and in each the key "pacemaking" glycolytic enzymes are hexokinase, phosphofructokinase and pyruvic kinase. Using this as a rationale, 49 compounds known to have antitumor properties were screened against rhodesiense infections in mice. Six were found active with the most interesting being 5-(3,3-dimethyl-l,1t riazeno)imidazole-4-carboxamide. 69
r.
Studies to reexamine the synthesis of purines and pyrimidines in
T. -cruzi indicate that no form of the parasite can synthesize substantial
quantities of purine de novo and that therefore dependence is on salvage. Moreover, it seems that amastigotes and trypomastigotes will depend on -de novo synthesis for their pyrimidines and thus, drugs that can block this are likely to be trypanocidal. 70
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Benznidazole (N-benzyl-2-nitro-1-imidazoleacetamide) has been reported to be a very efficient agent a ainst Chagas disease, and its pharmacokinetics have been reviewed. 7f Trichomoniasis - Discussions as to the potential toxicity of metronidazole continueiLSl3 as the drug continues to be used as very likely the best available agent for this infection. Two separate publications have indicated that there is no evidence for cancer due to its use,74 and that it is safe for short-term treatment.75 Moreover, it was reported that the mutagenic effects of the drug can be dissociated from its antiparasitic properties in experimental models by pretreatment of 2(3)-pbutyl-4hydroxyanisole or administration of erythromycin. 7 6 An interesting anaerobic metabolite of metronidazole, N-(2-hydroxyethyl)oxamic acid has been reported. 7 7 Other than nitroheterocycles, little of interest against trichomonal infections has appeared, and as a matter of fact, not much of anything appears ready to compete with metronidazole as the drug of choice. Toxicological and teratological studies appeared on azanidazole (8), - a new systemic trichomonacide. 78 .
N
8
=
Another nitroheterocyle, of more unusual structure, is the imidazo[l,2-b]p ridazine 2, which is apparently being readied for clinical trial. v9 Nitro-T,8-naphthyridines such as 10 were reported to have nearly the same activity as metronidazole agxnst vaginalis infections. 80 0
r.
In vitro studies among a wide range of structural types revealed -activity with saponins, such as leontoside,81 and 3-hydroxymethylenepyrazoltetradecanoic acid picrate. 82 Tricandil (mepartricin) , a polyene antibiotic has been introduced into Brazil by Searle for the treatment of trichomoniasis and candidiasi~.~~ Amoebiasis - The literature on this disease area remains sparse. A belated summary on all aspects of amoebiasis research up to 1977 reported at the Seventh Seminar on Amoebiasis at Mexico City in November of 1977 has been published.84 A progress report on all intestinal protozoa has also appeared.85 The need for a cheap, non-toxic agent in rural environments has led to a recommendation for a diiodohydroxyquinoline-oxytetracycline combination86 the tetracycline acting presumably on the gut flora and thus indirectly on the infectious organism.87
-
The classic drug in this area, emetine, has been shown to be amoebicidal by inhibiting protein synthesis.88 It has been the subject of this of two stereoselective total s y n t h e s e ~ . ~ Application ~,~~ technology may allow the syntheses of less complex structural analogs.
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The imidazo[l,2-b]pyridazine mentioned previously as a trichomonacide is also reported to be a potent agent against cecalE. histolytica in rats and hepatic 5. histolytica in hamsters. A recent patent claims still another dichloroacetamide (11)as a potent amoebacide in vitro.91 The amidines represented by 12 continue under investigation and 12 is reported to have no teratogenF effect, to be as potent as metroniGole against cecal amoebiasis (albeit with a lower safety margin) and to be more potent than metronidazole against the hepatic infection.92
Giardiasis - A thorough review of the infection of the human gastrointestinal tract by Giardia lamblia, known both as giardiasis or lambliasis, has appeared.yj The use of nitroimidazoles as therapy is stressed. In a comparison of metronidazole and quinacrine in 160 cases of infants and children, the low failure rate, minimal side effects and more tolerable flavor favored metronidazole given at 15-25 mg/kg/day for 5 days.94 A newer nitroimidazole, ornidazole (Tiberal) was studied in children and found to be effective in a single dose. It was preferred to metronidazole. 9 5 Another nitroimidazole, tinidazole, was also used successfully in children in a single dose treatment.96
Toxoplasmosis - Several reviews have appeared dealing with the disease and its treatment. 97-100 Therapeutic emphasis continues to center around combinations of pyrimethamine and a long-acting sulfonamide. Coccidiosis - Commercial potential for the control of this resistanceprone parasite continues to spark research interest. For example, of the approximately 130 million cattle in the United States, about 77 million are susceptible to coccidiosis each year. Of these, some 3,850,000 are treated and about 180,000 die.lol Ionophorous antibiotics recently have been found effective in poultry and mammals. Lasalocid added to feed in a dose to produce the equivalent of about 3.0 mg/kg has been found effective in controlling clinical coccidiosis in calves.lol A review of a variety of drug types has appeared. lo2 Studies are ongoing with arprinocid [ 9-(2-chloro6-fluorobenzyl)adenine]. Mode of action studies have led to the tentative conclusion that inhibition of hypoxanthine transport may play a critical role in its action on the parasite.lo3,104 A recent study has concluded that its anticoccidial activity is due to a metabolite in the chick. 1°5 Modification of the 6-azauracil structure resulted in 1(3',5'-dichlorophenyl)-6-azauracil. Further modifications have apparently resulted in the separation of potency from the undesirable persistence of these compounds and also prevent emergence of resistant strains. lo6 N,N'-bis(3,4-ditrifluoromethylphenyl)methylmalonamide has been shown to be effective vs. amprolium, zoalene, aklomide or nicarbazine resistant strains of 2. tenella. 107
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125
Helminth Diseases General - Recent articles and reviews consider a wide range of subjects includin the problem of resistance of animal helminths to current chemotherapy,?08 parasitic zoonoses109 and the complex interrelationships of the variety of disciplines contributing to human health.l1° Two provocative articles outlining broad biochemical strategies toward parasite chemotherapy appeared recently. 7 l2 Filaria - Basic biochemical studies with this parasitic group seem to be increasing, with work bein reported on comparative metabolism of different genera of adult and effects of larval forms in infected Methods of cryopreservation and in vitro cultivation mosquitoes. 114-116 may allow improved studies with the human parasite, Onchocerca v o l ~ u l u s . ~ ~ ~ Clinical trials with a variety of anti arasitic drugs, such as metronidazole,118 nifurtimox,119 mebendazole,1 2 9 7 122 amodiaquine,121 and levamisole121,122 gave marginally promising results at best with the possible exception of mebendazole against Dipetalonema perstans. 122 An interesting approach uses electron microscopy of skin snips to evaluate the effect of metrifonate on onchocerciasis atients. 123 Recent reviews of both the clinical124 and laboratoryP25 work on filariasis chemotherapy are available. Other Nematodes - An exciting new group of compounds, known collectively as avermectins was isolated from fermentation of Streptomyces avermitilis.126 This group consists of at least 8 disaccharides of 16membered pentacyclic lactones. The compound designated avermectin Bla has demonstrated a broad spectrum of activity at single oral doses of 0.1 mglkg or less,127 including a 95% reduction of Haemonchus contortis, Ostertagia circumcincta and Cooperia oncophora in sheep, E. placei, 0. ostertagi and C. punctata in cattle at 0.1 mg/kg, and Ancylostoma caninum in dogs. It was also effective a ainst Capillaria obsignata, but not Heterakis gallinarum, in poultry. 158 Activity was also seen against the pre-cardiac stage of Dirofilaria immitis in ferrets. 129
130 has shown an Amidantel, a new phenylenediamine derivative (131, interesting anthelmintic spectrum includin Hymenospis diminuta in rats,130 and Ancylostoma caninum in dogs. 191 It was also effective against both the microfilaria and adult Dipetalonema witei, but only the microfilaria of Litomosoides carinii in Mastomys natalensis. l30 St ill 1 4 ) , has been shown another new phenylenediamine structure, febantel (-
0Sq
N
H
C /MIC02CH3 'NCO, -CH,. NHCOCH20CH3
Sect. I11
126 -
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Chemotherapeutic Agents
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highly effective a ainst various nematodes and cestodes in rodents, dogs, sheep and cattle. 132 A new benzimidazole derivative, (15), given to = SCN
-
sheep naturally infected with intestinal nematodes at 50 and 200 mg/kg gave complete reduction in fecal egg count despite a lack of activity against Nematospiroides dubius in mice. 133y Results from a doubleblind clinical study comparing ciclobendazole (16)and mebendazole, indicate that the two drugs are equally effective for treating ascaris and hookworm infections and that mebendazole is significantly better against trichuriasis. Both drugs were well tolerated. 134 A variety of other structures including 17 135 and 18 136 have appeared in the recent patent literature claimxg nematoc=l;ial activity.
Schistosomiasis - The first clinical reports using praziquantel appear promisin The pharmacokinetic behavior was dominated by rapid metab01ism.l~~No clinically relevant changes were found for any of the laboratory parameters measured in healthy volunteers given total doses as high as 7 5 mg/kg. In initial multicenter clinical trials,138-142 the drug was found effective against Schistosoma haematobium, & mansoni, andS.japonicum infections in Africa, South America, and Asia at total doses of 60 mg/kg or less. Further studies on the carcinogenic potential of hycanthone in rodents were conducted.143,144 The absence of mutagenic activity for prazi uantel was confirmed in several systems, including mammalian cells. 142 An interesting mechanized in vitro screening approach was developed using several known schistosomicides. 146
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