Chapter 9 Antimalarials CHAPTER ANTIMALARIALS 1. INTRODUCTION Malaria is one of the most widespread diseases caused by the protozoan parasite of the genus, Plasmodium. These parasites spend an asexual phase in the man and sexual phase in female anopheles mosquito. Malaria is caused by four species of one-cell protozoan of the Plasmodium genus: P. falciparum, P. vivax. P. malariae and P. ovale. No single antimalarial drug is effective against all four species. FEMALE ANOPHELES MOSQUIT( SPOROZOITES (SOBER, a "peal Ext, —emeRozorTES. t en ee in ‘Schizonts (Liver)" i MEROZONTES tes Zygotes Insect bite {5 ‘Mutpication and development of marozoites o gametoyies cient ‘Somachh Fig. 9.1 Diagrammatic Representation of Life Cycle of Plasmodium 127Chapter 9 Antimalarials The mosquito stores the sporozoite form of the protozoan in its salivary glands. Malarial infection is initiated through the bite of infected mosquito into the human blood stream. The sporozoite in the blood stream enters into the parenchyma cell of host liver, where they become primary schizonts and then merozoites. Depending upon the plasmodium the merozoites either rupture the infected hepatocytes and enter the systemic circulation or infect other liver cells. Merozoite now enters into the circulation and invades erythrocytes, where they reside for 3 to 4 days and reproduce. The reproduction stage in the erythrocyte can produce either more merozoites or another form called gametocytes. Due to this repeated multiplication erythrocyte may rupture and release merozoites into the circulation. Each merozoite again invades fresh erythrocytes and the cycle of asexual multiplication is repeated again. This stage is known as schizogony phase of infection which causes severe fever and chills. When such infected blood was ingested by female anopheles mosquito, the gametocytes (male and female) undergo sexual reproduction within the gut of the insect. The resulting zygotes through various stages of development migrate as sporozoites to the mosquito salivary gland. The cycle begins when a mosquito bites a human. Site of antimalarial agents: (Fig. 9.1) a) Kills the sporozoites injected by the mosquito and / or prevail the entering of sporozoites entering the liver. The drugs used in this stage in known as prophylactic agent. Since no drug is effective in this stage, true prophylaxis does not exist for malarial parasites. b) Drug active against erythrocytic phase. These drugs are known as schizonticidal agents eg. Amodiaquine, Chloroquine, Quinine, Pyrimethamine. c) Kills the merozoites in the blood and / or prevent their multiplication known as suppressive agent eg. Chloroquine, Amodiaquine. d) Kill the gametocytes before they enter the mosquito and reproduce into zygotes. eg. Primaquine. 2. CLASSIFICATION Antimalarial agents are chemically classified as 128Chapter 9 Antimalarials i) Cinchona alkaloids: eg. Quinine, Cinchonine. ii). 4-Amino quinolines: eg. Chloroquine, Amodiaquine, Hydroxy chloroquine. & 7 iii) 8- Amino quinolines: eg. Primaduine, Pamaquine. iv) 9 - Amino acridine: eg. Mepacrine. v) _ Biguanides: eg. Proguanil, Cycloguanil. vi) Pyrimidine analogue: eg. Pyrimethamine. vii) Polycyclics: eg. Doxycycline, Halofantrine. viii) Miscellaneous: eg. Metaloamine, Sulphadoxine, Mefloquine. ix). Newer antimalarial agents: eg. Artemisinin, Fosmidomycin. 2.1 Cinchona Alkaloids Quinine was the first known antimalarial. It is a 4-quinoline methanol derivative bearing a substituted quinuclidine ring. Four stereo isomeric chemical centers exist in the molecule at C-3, C-4, C-8 and C-9. Quinine absolute configuration of 3R: 4S: 8S: 9R and their optical isomers have antimalarial activities. The dextro isomer of Quinine is Quinidine which is used as antiarrhythmic drug. A. Quinine It is a di-acid tertiary base and its forms salts with two equivalents of an acid, ts ‘CH=CH, (Ba, 9R)-6 - Methoxy cinchonan - 9 - ol Use: It is used to treat Chloroquine-resistant strains of Plasmodium falciparum, 129Chapter 9 Antimalarials 22 4-Amino Quinolines The 4 - substituted quinoline rapidly acts against Plasmodium in the erythrocytic stage. They act by intercalating into the DNA of the parasite. ‘A. Chloroquine , / x Z | 7 Chloro ~4~ {[~ (diethy lamina) 1+ methy] butyl] ‘anino} quinoline The phosphate salt is used in oral dosage form and hydrochloride salt is used in parenteral formulation. Synthesis Step -I: Preparation of 4, 7 - Dichloro quinoline wepec,_£000 oO Be CHYACOOC;Hy), + Js we Biel yo a a anime * a cron fern a on NH a conc 7 =O) = CoO [ — = aa Wi of A -CH,CH (CH,),C1_ + HN(C2Hs)2 Tye tH (CHa N= Cat, 5-Chioro-2- ™ — $-Chloro-2- _Diethylamine ~ 5-(N, N'- diethyl Pentane pentanol amino) - 2 - pentanol soBr,} ~HBr -SO, Br (CH CH (CHg)3 - N - (Cals) 4- Bromo - |- diethyl amino pentane 134er ne eens ne nenccncinncccrancra creer ere 7 chapter 9 i Antimalarials step - I: Condensation of step -1 sn 1 pro duct 300 B S Hyco ~S A 7 SIEM, Nate, Seteeon SN ‘ef Bromo 1. a Tu dicthylamino pentane 7 8 Amino -6- methoxy NHLCH. (CHAN Caps quinoline . Pamaguine se: It is used as suppressive agent in malaria, B. Primaquine H,co. Y 7 D4 Ww NHLCH-(Ci) Nt, cH 8-[(4- Amino ~ 1- methyl butyl amino} ~6 methoxy quinoline synthesis Method - I Step - I: Preparation of 8 - Amino - 6 - methoxy quinoline (Refer to the synthesis of : Pamaquine) Condensation of 4 - Chloro pentylamine with 8 - Amino - 6 - methoxy quinoline HCO NN 7 Condensation + CHCHICH),NH, SEE co. SS “uct ZA _4-Chloro WN pentyl amine 2 Nt N 8~ Amino - 6 - NHCH- (CH) NI methoxy quinoline 1 oH Primaquine 135