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Or· 8-Annoquriioltlmb WITH. NIT~~~OI,4 BIBIUD.~; TliE REACTION 8-AnNOQuriiOLtlmB WITH. NIT~~~OI,4 •' >'•' • or·I,' ",i. by Hugh Bu:rknla·p.·,:Ilona.hoe B.s.• ,. Rookhurst College, 194.3 M.A.,, Univ&rESi.ty of ICansas, · 1947 . Submitted to the Department of ·chemistry and the Faculty. of. the . G:raduate School or the University of Kansas in partial fulfillment ot the ?'equirements for the de• gree of Doctor ot Philosophy. Advisory Committee · May, 19.$0 AOKNOWLEOOMENT The author wishes to ex.press his thanks and appreciation to Dr. J. H. Burokhalter,, who suggested this problem, and Dr. a. A. Vanderwerf for ·their helpful suggestions and guidance during the course of this work. H.B.D. TABLE OF OONTEN'TS Chapter Page I • THE PROBLE?i Olr MALARIA. A. Introduction • • • • • . • • 1 B. The types of malaria. • • • • • • •• 2 O. The biology of malarial infection • • 3 D. The prophylaxis and treatment of malaria: •. ;•' •. • • •. • . ;.. • • : •••• ·• • • ., 6 II. ·Atfl'IMALARIAL ·:DRUGS. :· • · ,, A. Olassific at ion and. screening of antimalarial drugs • • . ,, . .. ' . • • • • 12 B. Historical • • • • • • • • • • • • • 1~ c. Quinine • .. • • • .. • • • • • • • • • 16 D. Synthetic substitutes • • • • • • • • 19 l. Plasmochin • • • • • .. • • • • • 19 2 •. Quinaorine • • • • • .. • • • • • 21 3. Ohloroquine • • • • • • • • • •• 21 q.. Pentaquine •• • • • • • • • • • 23 s. Paludrine • • • • • • • • • • • • 2q. E. Me(lhanism ot action of antimalarial drugs • • • • • • • •• • • • • • • • 2$ 1. The metabolite-antimetaboli te relationship • • • • • • • •• • 2.$ 2. The quinoid•Quinonimine theory • 26 3. Conclusions • • • • • • • • • •• 28 · -Ohapter III.· THE ANTIMALARIAL PROGRAM 1941-1945 . .A. The overall program • • • • • • • • • 30 .a. :._ Tb(j ·4•aminoquinolinea • • • • • • • • .32 · <h ·. The 8-aminoqu.inolines • : • . • • • • • • 34. IV. • DISCUSSION Of THE PROBLEM ) • • • • • .• • • • .38 ·V. · DISCUSSION OF· RESULTS. · - . A.;, Unsymmetrical hybrids related to '. propanediemine * • • • • •. • • • • • 46 B. ··Symmetrical: hybrida related to prc,pan~di8J1iinet ~d methanediamine • • S2 . a. Theoret_~cal oonsidere.tions • • • . • • . 61 VI. EXPERIMENTAL.· Pota·ss!um ·Phthalim1de • • • • • • • • . 69· l-Phthal!mido-2~ .3-epoxypropane · • · • • • · • - 71 · l-Phthalimido-3 .. ohloropropanol-2 · • · • • · • 73 · l~Phthalimido•·J-iodopropanol-2 • · • · • · • · • .15 l-Phthal1mido•3•p-ohloran1lino•· propanQl•2 • • • .. • • • • • • 76 '· • • • • • l•(p•Nitrof;Ulilino)•3-phthalimido- prope.nol•2. · • • ·• · ~ · • • ~ · • : • • • • • • • 80 l•{p•Aoetam1doanil1no)-3-phthal1mido- propanol•2. • • : " .•.• · • · • ·~- • • · • • • ·• • 81 8-(3•Phthal1m1do•2•hydroxypropylamido)- 6-mathoxy-qu.1nol1ne ~- ·• • • · ·• • • · ·• • · • • -- 82 l•Amino-3.·p-chloranilinopropanol-2 • • • Sq. 8~(3-Amino-2-hydroxypropylamino)-6- m,thoxyquinoline • • • • •. ;J •. ~ • •••• 86 7•0hloro-4• ( 3-p-ehl~ranil111-o-2•_. , hydroxyp~opylam1no)•qu1nol1ne. • • • • • • 87 ·7 ~Ohloro-4- (3~ '( 6-methoxy-8..;·qu'inolyl- ·. a:mino}·2~hydroxypropylamino )-qu.inoline • • 89 .: ; .. ~ .. : ' ( - . ' ' . ' ' . ' •' ,, ~ Attempts to react the hydroxyl group of .th~ atroctur.al type. RNHOH20H(OH)O.H2NHR' · with halogenating agents ~- ·• · • ~ · • • • • • 91 2~Ethyl~2-n!tro-l,3'.""propanediol • • • • • 93 2•~ethyl-2~n.1tI'0•l,.3-propaned.iol. • • . • • • 9.5 N,Nt ..-I)1•p•chlorphen:,l•2•ni tro-1, 3~ · . pJ'?plll:lediami11e • • .•. ·• • • : • • , .• • • • • 96 .. .'; .. : ' . ' ' ~ . ' . N,N'-D1•p•chlo:rphenyl~2 .. methyl•2•n1tro- l,3•Propaned1amine •. ·• • , • • • • .• • • • • 98 N•N•-D1·p-ohlo:rphanylmethe.ned1amine • • • 101 · N,N' •Di•P•Ohlorphenyl-2-amino-l, 3• propan.ediamine • • .• ·· • • • • • • • • • • • 102 N,.N• ""'Di-(6-methox.r-8•quinolyl) •2• nitro•l,3•propaned1am1ne (attempted) •••. 103 ••• I ' \ N•N'•Di .. (6-methoxy-8-qu1nolyl)-2-methyl- l,.3•Pt-Opanediamine (attempted) • • •. • • • 10.$ N,.N•-Di-(6-methoxy .. 8-quinolyl)•2-ethyl- l,3•propanediamine. (attempted) . • ••• • • 107 N.N•-D1(6-methoxy-8 .. quinolyl)• methaned1amine • ·• · ·~ • • • • , • • • • • • 108 ·, Di-( a~a.mino-6-methoxy-S.) •Q.uinolyl• methane (pre>bable) • • • • • • · • · • • • • • 109 8•Amino•$•chloro-6~methoxyquinoline. • • • 110 N,N'-Di-($-chloro-6-methoxy-8.:. q_""°inolyl)•methanediamine • ·• • • .• • • • 112 / . oh~pter· N• Nt •Di ... '( .S•ehloro ~6-methoxy-.,.8..- .; quinolyl)•2,•me~hyl-2-nltro-:l,.3• . •. • ... : • 113 (attempted) ' ' pl'opa~ed!~irie.- .' ' . ' ' . .. ... : ~ . ' . ' ' • • ••• OF,FUTU:REWORK- • ' ', : ' . ,. ' - :, .,_, f :· l ' : VII. DISCUSSION• ' ~ : . • • • • • •• • • • • 114 4t • OONOLUSIONS,,. ' - ·'· •., 116 VIII. ; • • . • • .• •. • • • • • • BIBLIOGRAPHY • • • • ... • • • • • .. • • • • • • • 119 1. CHAPTER I THE PROBLEM: OF MALARIA' A. INTRODUOTION. Malaria is one of the oldest diseases known to man, and, even today, with the great advances in medical science, it atf'l1ots a large percentage of the human race. It has been estimated (1,.3) that.the disease attacks several hundred million people evet7 year and that it accounts for three million.fatalities in the same period ot time. Approximately twenty•tive per cent ot the hospital admissions among United States tl'Oops stationed at Vera Oroz in the Mexican war was due to malaria and there were · 1,213,685 cases among the white troops on the Union side during the 01 vil War ( 66). The disease prevented action by both Allied and Central Powers in the Near East 1n World War I, and it· has been reported ( 111) that the incidence of malax-ia in the Pacific reached 750 per thousand per annum in the early years ot the Seoond World War. In the United States, which is in a temperate zone, an estimated one million persons are infected and it has been found in every state 1nthe Union. A neve~ ending search for more potent and less toxic antimal~rials has continued and will undoubtedly do so until this scourge is no longer of importance. \ J/ 2. B. THE 'l'Y.PES OF MALARIA. There are tour organisms which cause human · malaria Plasmodium falciparum Plasmodium vive.x Plasmodium malariae Plasmodium ovale but only Pk falcipaxtwn and t£ vivax are of importance, the latter two being rare and mostly of academic interest. ~ talciparum is the causative para.site in malignant tertian malaria. It shows a rise in temperature 'every .36~q.8 hours and frequently causes fatalities unless a . Sl,litable.drug·is administered promptly attar the initial symptomsof.the disease are ;ioted. Nevertheless, if the attack has been adequately treated, recurrence ot clinical symptoms>are unlikely. It is during the time or initial infectton that the plasmodia .are· most easily destroyed. It 1s prevalent 1n the tropics. 1n the Medita~ranean, and in sub-·tropical American .regions • .L. vivax is the o·iusative agent in ]:>enign ~ertian malaria. This disease is ra~ely ~atal and shows regular 36 hour rises in temperature or an intermittent nature •. In most cases attacks will recu:r periodically even when,: by the use of proper drugs, the clinical symptoms of an acute attack .3. are removed.. This parasite is found all over the world. L.· malariae ca.uses quartan malaria. This disease is not very common. The fever is manifested by a 72 hour period between rigors. J::. ovale causes a mild tertian infection. It recurs every q.8 hou-rs. It is rare and not found in temperate zones. Being a tai:rly mild form,. it yields satisfactorily to prope~ medication. 0. THE BIOLOGY OF MALARIAL.INFECTION. Human malaria is a protozoon disease caused·by four species of plasmodia, which to:rm one ot the families of the suborderhemos;eor1dia. These are sporozoa which possess an asexual cyclical existence in circulating red blood cells ot certain vertebrates and a sexual cycle in the anopheline species of mosquito •.. Laveran discovered the parasite causing malaria in 1880 and eighteen years later Ross showed that the anopheles mosquito ear~ied it from man to man. To understand the disease and what is required with respect to a chemotherapeutic agent, the life cyole and reproduction or the plasmodia m:ust be briefly considered. Man 1s the intermediate host in which the parasite completes its asexual cycle and reproduces by a process or schizogony. The anopheles mosquito is the vector and definitive host in which the sexual oyole is completed and· reproduction is aooomplished by sporogony. lt.- ill.! Oy;ol e !!! !!all• , When an infected mosquito bites a victim, sal1 va containing slender organisms called sporozo!tes are injected into the blood stream. In man the plasmodia live as :-·"'' . parasites in or on the surface of red blood corpuscles which are eventually discharged by the growth and division ot the paras! te. A short time after.the bite of an infected mosquito, the ring·torm-or trophozoite appears and attaches itself to the red blood cell. It grows at the expense of the·cell until it reaches maturity and becomes a schizont, the asexual form of the parasite. The soh1zonte then undergo asexual reproduction (sohizogony) With the formation or a numbett ot merozoi tes. The cell now ruptures and discharges the merozoites into the blood stream! It is this periodic breaki'ng of red cells which causes the typical attacks characteristic or malaria •. ·The·fever -which follows the chill is due to the ' . liberated foreign protein and cell products. In a single ·attack.as many as one-fifth of the circulating red-blood cells n1ay be destroyed. The free-swimming merozoites again attach t~!rti~.tt+ves to blood c-.orpuscles to become t~opo toi tes and to repeat once more the p:rooess ot echizogony. After several of
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