Antimalarial Moustafa K. Soltan Antimalarial drugs. Malaria has two hosts: 1) vertebral host (human). 2) Vector (mosquito). Classification of antimalarial drugs: according to chemical structure. 1) Cinchona alkaloids: quinine (-),while quinidine its isomer (+) is used as antiarrythmic. 2) 8-aminoquinolines: pamaquine, primaquine. 3) 4-aminoquinolines: chloroquine, hydroxychloroquine, Santoquine and amodiaquine. 4) Aminoacridine: quinacrine. 5) Biguanides: proguanil, chloroguanil, bromoguanil, and cycloguanil. 6) pyrimidines: pyrimethamine. 7) sulfonoes: sulfadoxine. 8-aminoquinoline pamaquine -[ -(N,N-diethylamino) - -methylbutyl]amino - - methoxy quinoline primaquine N,N-diethylamino is replaced by amino group only to give -[ -amino- -methylbutyl]amino - -methoxy quinoline Curative Exoerythrocytic schizonticides, but primaquine is 4-6 times as active as pamaquine and ½ toxicity, this is because of terminal 1ry amino gp in primaquine. SAR. 1)quinoline ring is important for activity, if reduced or changed into isoquinoline activity is lost. 2) 6-methoxy group is not essential for activity If changed into 6-hydroxy, activity increase if to 6-ethoxy or 6- methyl ,activity is lost. 3)the side chain in 8 show optimum activity if alkyl group C4-C6, if less than 4 or more than 6, activity decrease. 4) 2ry amino group at position 8 is active than 1ry or 3ry. 5) Terminal amino group show increase in activity from 3ry to 2ry to 1ry, so primaquine is 4-6 more active and ½ toxic than pamaquine . 1)skraup synthesis of quinoline ring: ( glycerol + H2SO4 = acrolein react with aniline dv). 1)glycerol 2)H2SO4 H3CO H3CO NH2 NO2 3) FeSO4 4)nitrobenzene H3CO N NO2 Sn / HCl reduction N (I) NH2 2)preparation of side chain: EtONa base -HI COCH 3 COCH 3 N I+ COOEt COOEt diethylamino ethylacetoacetae 1)hyd of ester ethyliodide 2)decarboxylation 1)reduction of C=O Br O to 2ry alc (II) N CH3 2)halogenation by PBr3 N CH N 3 3)condensation of (I) + (II) to give pamaquine. **synthesis can be modified to give primaquine 4-aminoquinoline chloroquine -[ -(N,N-diethylamino) - -methylbutyl]amino - -chloroquinoline R= Hydroxychloroquine -[ -(N-ethyl-N-( -hydroxyethyl) amino)- -methylbutyl] amino- -chloroquinoline R= amodiaquine R= -[( -hydroxy- -(N,Ndiethylamino)methyl)phenyl]amino - -chloroquinoline Chloroquine: 1) Suppressive erythrocytic schizonticide: inhibit development of schizonts during erythrocytic stage.2) concentrate in liver so used in hepatic amoebiasis. Hydroxychloroquine, Amodiaquine are also suppressive erythrocytic schizonticides SAR. 1)quinoline ring is important for activity, if reduced or changed into isoquinoline activity is lost. 2) introduction of 3-methyl group on quinoline ring of hydroxychloroquine give santoquine which is less active. 3) halogenation is restricted in 7- position if changed, lose activity, Chloride is the best halogen. 4)any substitution in 8- position like methyl, cancels activity. 5) introduction of hydroxyl group in the ethyl group of terminal amino group reduce toxicity and produce higher blood levels, increase activity. So hydroxychloroquine is more active, less toxic than chloroquine . 6) p-aminophenol derivatives in the side chain as in amodiaquine decrease activity and also decrease toxicity than chloroquine. (Hydroxychloroquine> Chloroquine>Amodiquine>Santoquine) in activity due to SAR. 9-aminoacridine derivatives H3C HN 8 9 7 6 N Cl 5 10 1 (CH2)3 N(C2H5)2 1 OCH 3 2 3 4 quinacrine 6-chloro-2-methoxy-9[4-(N,N-diethylamino) -1- methylbutyl]acridine. CH3 1)KMnO 4 2)NaOH Cl 2,4-dichlorotoluene Cl Cl COONa p-anisidine OCH3 H2N Cl H3C CH3 (CH2)3 N(C2H5)2 (CH2)3 NH2 HN H2N OCH3 Cl N -HCl Cl Cl N COOH N H OCH3 1)cyclization -H2O 2)POCl3 to convert OCH3 OH to Cl