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cHarTERO Antimalarials JOHN H. BLOCK Malaria, one of the most widespread diseases, is caused by a Plasmodium parasite. lts name is derived from mala aria (bad air), and it has been called ague, intermittent fever, marsh fever. and The Fever." ? The name is based on the carly knowledge that malaria was associated with swamps and badly draimed areas. The use of quinine for treating ma- laria has been known since the 17th century. While malaria is an ancient disease, its upsurge seems to coincide with the advent of farming about 20,000 years ago. The clearing of land provided areas for ponds containing still water. The Anopheles gambiae mosquito uses sull water that sits in ponds and containers to breed, The gathering of humans in farming communities provided the necessary concentration of people to form a reservorr of hosts for the parasite and “food” for the mosquitos breeding in the ponds.'* Proof that the Anopheles mosquito is the camer of the causative protozoa was obtained by Dr. Ronald Ross, who was recognized in 1902 with the Nobel Prize in Medicine. In a seenario somewhar similar to that in which definitivo proof that yellow fever was transmitted by the Aedes aegypti mosquito was required, Dr. Ross strongly argued that ma- laria was transmitted by an insect vector and finally demon- strated that the parasite was carried in the stomach and sali- vary glands of the Anopheles mosquito, The latter discovery was important because it helped resolve the dispute about whether malania was spread by the bite of the mosquito or by drinking water contuning mosquito cggs and larva” Because malaria has been eliminated from North America, 1 only becomes a potential problem when citizens of this continent travel into an area where malaria is endemic. With international travel so common, Americans receive prescrip- tons to take an antimalarial drug prophylactcally when trav- eling to, and living in, arcas where malana is endemic* Frequently, U.S, citizens returning to the United States from areas where malana 15 endemie and citizens of those coun- tries who are coming to the Umited States have malaria and need antimalaria drugs. In 2002, two cases of malaria were reported in Virginia, Neither patient had any of the risk faç- tors, including international travel, blood transfusion, organ transplantation, or needie sharing. Both lived in the same general geographical area. Examination of ponds in the area found Anopheles mosquitoes that initially tested positive for one of the malaria parasites, Plasmodium vivax (see below), The hypothesis was that infected mosquitoes had entered the United Siates through Dulles Intemational Airport or Virginia seaports, possible in cargo. Surveys of surrounding medical facilities showed no recent cases of intemational travelers who had malária. Follow-up testing of the mosqui- toes, using more precise methods, disputed the initial finding that mosquitoes in the ponds that were tested carried Plasmo- elium spp. This finding is still in dispute. 282 Malaria, which infects several hundred million people each year, resulting in several million deaths annually, isa complex disease to treat. The causative agent is a group of parasitical protozoa of the Plasmodium genus transmitial by the female Anopheles mosquito. The impact of malariaos the human species continues to be devastating. The impactol diseases such as smallpox, plague, yellow fever, and pole on human history às fascinating but, fortunately, is mogi historical. The later three diseases do reappear. but ihe case are isolated. Plague is treated effectively with antiblotio, and there are vaccines for yellow fever and polio. The public is aware of acquired immunodeficiency sy drome (AIDS) because it is a discase that “travels” by human carriers and has infected and killed prominent people who are citizens in economically developed countries Nevertheless, compare the 2001 figures for AIDS and me lara. After approximately 20 years, 40 million people have been infected with the human immunodeficiency vin (HIV),0f whom 5 million were infected and 3 million del in 2001, For North America, 940,000 have become infedie in lhe past 20 years, of whom 45,000 were infected 20,000 died in 2001, In contrast, approximately 109% ofie world's population has malaria (300 to 500 million) DM these, about | million will die anmually; most are childes In comtrast, there are only about 1,500 new cases of malink annually in the United States, and nearly all of these ou from travelers arriving from areas where malaria is € Most prescriptions for antimalarial drugs are for prophylas of travelers going to, and coming from, areas 0f the won where malaria is endemic. There are three potential ways to control malaria: clim tion of the vector. drug therapy, and vaceination. Eli of the vector currently às the simplest and most costa tive. Drug therapy has the same challenges as the devedor ment of antibiotics (e.g... resistance to the drug). The cut antimalarial drugs, while effective against certain spo also have significant adverse reactions, and resistance HE creasing. Thus far, no vaccine has been developed (ha effective in vivo. The malaria parasite does elicit um iu response, evidenced by the fact that children with an Intl exposure are more likely to die than adults who have ring attacks. A T-cell response that includes both CDE CD8* T cells, production of interferon gamma, and oxide synthase induction is added evidence that theh immune system does detect the parasite and responhed cordingly” An ideal vaccine should, at a minimum, be tive against both P, falciparum and P, vivax, the wo responsible for 90% of malária cases, The Anopheles mosquito has adapted very well tol habitats. As pointed out above, it requires still waterim its eggs. wait for them to hatch, and then Jet the MEO A sm ER Eme feed on microscopic organisms in still water. mature. Ent still water is ideal because it likely will not contain tut would feed on the eggs and larvae. In general, es need | to 2 weeks to develop into mature insecis. E polly is enough time before predators begin 10 popu- E sai] water. rentty, there are two ways to control the mosquito = One às to prevent contact between humans and the Because the Anopheles mosquito is a noctumal dtis casier to control than the Aedes aegypti mosquito, su day feeder and carries dengue and yellow fever. lp soreens on windows and using mosquito netting in are very elfective. Second, elimination of the Anopheles mosquito, usually E application of insecticide and destroying its breeding Bu e the most effective way to eliminate (as opposcd to Himalaria. Areas that have been successful at eliminat- anleciod mosquitões include North America, Europe, and sia To do this, the adult female mosquito must be killed, ! ing areas (still water) drained, One of the most i insecticides has been DDT. Dr. Paul Muller re- mei he 1948 Nobel Prize in Medicine for discovering WE DOT kills the malaria-carrying Anopheles mosquito, DE is long lasting and, unfortunately, accumulates in the mament. While being long lasting is beneficial from Ipoint of mosquito control, it also means that ihese pides get into lhe food chain and can affect both ani- and humans. Indeed, use of DDT has been banned in Msconomically developed countries. Untortunately, the gl ihe world where malaria is endemic are economi- E poor and cannot (4) afford the newer insecticides, must be reapplicd because they degrade; (b) fund and the infrastructure to eliminate breeding areas; and ke medical facilities, staff, and drugs to treat their Cei, | DDT Ew antimalarial drugs must be developed constantlv, be- Elhe protozoa develop resistance by a variety of mecha- pise discussions of mechanisms with the different Bd and there are a wide variety of adverse reactions. inibination 0! (he cost of the drugs and their adverse os can make patient compliance difficult. Four differ- les of protozoa cause malaria, and unfortunately, no iarial drug às effective against all four species. atremendous need for effective antimalarial agents. ATION OF ANTIMALARIAL CH BY WAR 444 to 1946 (World War 11, more than 15,000 sub- ls were synthesized and sercened as possible antimalar- enis by the United States, Australia, and Great Britain. my increased again during the Vietnam War, especially Chapter 9 = Antimalarials 283 because of the increasing problem of resistance to commonly used antimalarials. During the decade 1968 to 1978, more than 250,000 compounds were investigated as part of a U. S. Army research program!” Department of Defense funding of this rescarch has continued. In addition to human intervention, there is evidence for at least five mutations in the human species that provide protection against malaria. These predominate in popula- tions who historically lived and continue to live in areas endemic with malaria, The five mutations are sickling dis- case (formerly sickle cell anemia), glucose-6-phosphate de- hydrogenase deficiency, hemoglobin €, various thalassem- ius, and increased production of nitric oxide (NO). Sickling disease can be fatal in homozy gotes, Heterozygotes usually are asymptomatic and show a 90% decrease in the chance of dying from P. falciparum.!! Homozygotes with hemoglo- bin € usually are asymptomatic.” Erythrocyte glucose-6- phosphate dehydrogenase deficiency (actually, 10 to 15% of normal activity in the erythrocyte) can cause hemolyiic anemia and prehepatc jaundice when the patient takes cer- tain drugs or is exposed to some viral infections. Ironically, some of the antimalarial drugs must be used with caution in patients with erythrocytic glucose-6-phosphate dehydrogen- use deficiency to minimize the risk of hemolytic anemia. The increased levels of oxidized glutathione in the erythro- cytes thai are deficient in this enzyme may prevent the para- site from maturing in the erythrocyte, The significance of thalassemia varies with the type of anemia and whether the patient is homozygous or heterozygous. The most recent of the mutations to be identified is the ability of certain populations to increase their production of NO. The site is in the promoter region of the gene for nitric oxide synthase 2, which generates NO from arginine, and involves a mutation changing a cytosine residue to thymine. The result is higher circulating levels of NO, lt is not known how increased NO provides this protection, because lhere appears to be no significant difference between blood levels of the parasite in individuals with the mutation and those with “normal” NO synthase. The protection may be from complications seen with malaria that give lhe patient's im- mune system time to respond to the parasite.! Malaria Malária is caused by four species of a one-cell protozoan of the Plasmodium genus: P. falciparum: This species is estimated to cause approximately 50% of all malaria. causes the most severe form and the most debilitating form vf the disease, because patients feel ill between acute atincks. One reason why it leaves the patient so weak is lat if infects up to 65% of the patent's erythrocytes. P. vivax: This species is the second most common species, nº- counting for about 40% of all malaria cases, H can be very chronic, because il can reinfect liver cells. P. malariae: While causing only 10% of all malarial cases, re- lapses are very common, P. ovales This species is the least common. Figure 9-1 outlines the stages of the parasite after it is injected into the victim and indicates where drug therapy might be eflective. The mosquito stores the sporozoite form of the protozoan in its salivary glands. Upon biting the pa- tient, the sporozoites are infected into the patients blood. the gametocytes before they can enter the mosquito and De into rygotes. Some have argued that the focus at this RR should be on the male gametocyies. This would block the gametocrvies from mating =. eonversion of merozoites results in male and female es. Aller entering the mosquito, they “mate,” pro- ay potes in the mosquito stomach. The latter reside to's stomach endothelium oocysts, Eventually, ds sporozoites to the mosquito”s salivary gland, re the eycle begins again when the mosquito bites a Wan So, in effect, there are two reservoirs or vectors for te: lhe mosquito that infects humans and humans mosquitos. There have been some attempis at E prophylactic agents that would be in the blood fed by the mosquito. These drugs would stop further Mopment of the parasite in the mosquito and prevent the rom being a carrier. Cenome as deciphering the human genome may lead to new es, elucidating the genome (genomics) of pathogens he proteins made by their genes (proteomics) may pro- Eleads for targeting new therapeutic entities, The £, falci- m genome consists of 30 million base pairs and 5,000 NH genes, It is nearly 80% adenine (A)=thymine (T) making it difficult to tally base pairs on the parasite's nsomes.'* ** (In contrast, the human genome is 59% A=T.) The high A-T content made the Plasmo- E Benome difficult to sequence because (a) it was more Eu to slice the chromosomal DNA strands into smaller Eetsegments that make it casier to sequence the nucleo- Band then reassemble them into chromosome and (b) software would fail and had to be modified. 'º are at least two goals in decoding the parasite”s & One is to find a protein that is unique to Plasmo- Hpposo lhata drug is selectively toxic to the protozoan. in lhe discussion of antimalarial drugs, all have Nel alverse reactions. A second goal is to understand changes that lead to drug resistance, One of the sons for the increase in malaria since the late 1990s loping resistance to chloroquine, an antimalarial beca widely used against P. falciparum. This resis- Eis blamed for the increasing mortality rates in Africa Eresurgence of malaria. Vaccines early 1980s, there has been a tremendous effort de to design malaria vaccines, largely based on cell apelos bÍ sporozoites, merozoites, or sehiz- The use of recombinant DNA techniques to deter- siucture of these proteins and to direct their synthe- ns been the foundation of most of these studies. Most ipmental vaccine work with malaria has centered on Wopurim because it is the primary cause of malaria ty worldwide. ee primary lines of research include nelopent of sporozoite=merozoite vaccines to block clini- E stages of the discasc Eelopment of sporozoite vaccines to stop infection and d of the disease Chapter 9 = Antimalarials 285 * Development of vaccines that inactivate or block specific met- abolic steps in the parasite after infecting humans A small field trial of irradiated P, falciparum sporozoites produced 90% protection for 10 months. In addition to the fact that plasmodia go through antigenic changes, the para- se is very polymorphic. There is real concern that a vaccine that did not include a spectrum of Plasmodium variants could cause development of parasites of even greater virulence, Polymorphism in the human leukocyte antigen (HLA) system also may be an obstacle to producing an effective vaccine. À potential model for this problem is the observa- tion that T cells, including the eytotoxic T Iymphocytes, in patients with HLA-B35 do not respond to certain strains of the parasite. It appears that the combination of certain pro- teins produced by Plasmodium strains with HLA-B35 pre- vents à normal T-cell response. In other words, the immune system of these patients will respond to some Plasmodium strains and not others. The implication is that an effective vaccine will have to be very polyvalent. That an effective vaccine, even one that only responds to certain Plasmodium strains, has not been developed has been puzzling. in that the human immune system does adapt with immunoglobulin-producing B cells and 'T cells that respond to processed antigen. The innate side of the immune system also responds, In other words. the human immune system responds to the various forms of the Plasmodium parasite just as it does to other parasites. It has been suggested that Just as the Plasmodium genus has adapted to humans, hu- mans have adapted to the parasite. The five human mutations mentioned above are one example. There may be others. Proper nutrition is important in surviving a malaria attack. The patient must replace the destroyed erythrocytes and, depending on lhe species of Plasmodium, hepatocytes. This requires calories from à high-quality diet that provides essen- tial nutrients including amino acids, lipids, and trace min- erals, The severity of malaria às greatest in the areas of the world with malnourishment, poor samitation, lack of infra- structure to eliminate the mosquito breeding areas, and lack of drugs to treat the sick. The World Health Organization's 2002 Werld Health Report scored countries on the basis of their lifestyles and availability of resources. Proper food is one of those resources.” In other words, just as the pathol- ogy of malaria is complex, so is its control and treatment. dE css au coma e e a DRUG THERAPY Antimalarial drugs (sec Table 9-1 on pages 296=297) ure good examples of anti-infective agents with poor selective toxicity. Contrast them with the antibiotics (Chapter 10). Tetracyelines, chloramphenicol, and aminoglycosides act against bacterial ribosomes, but not mammalian ones. Peni cillins and cyclosporines inhibit bacterial cell wall cross- linking, and mammals have cell membranes, not cell walls. The fluoroquinolones inhibit bacterial gyrase, but not mam- malian topoisomerases. The biochemistry of Plasmodium spp. is similar to that of mammals, making it difficult to design drugs that will not affect the patient adversely. In- deed, some have indications beyond treating and preventing malaria. 286 ssa) CINCHONA ALKALOIDS The cinchona tree produces four alkaloids that were, until recently, the prototypical molecules on which most antima- larial drugs were based. These alkaloids (Fig. 9-2) are the enantiomeric pair quinine and quinidine and their desmeth- oxy analogues, cinchonidine (for quinine) and cinchonine (or quinidine). (Unfortunately, the nomenclature for the two sentes of alkaloids is inconsistent.) Their numbering system às based on rubane, The stereochemistry differs at positions 8 and 9, with quinine and cinchonidine being $,R and quini- dine (cinchonine) being R.S. Historically, quinine was the main treatment for malaria until the advent of World War H, when battle in areas where malaria was endemic led to the search for more effective agents. Quinine and Quinidine. Quinine has been used for “fevers"” in South America since the 16005. The pure alka- loids quinine and cinchonine were isolated in [820. The stereoisomer, quinidine, is a more potent antimalarial, but it HO tm R “sá Ses N Quinine R = OCH, Figure 9-2 = Cinchona alkaloids Cinchonidine R = H Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry CH R O dito casi E do : N H N R s HOu ] NS] also is more toxic (less selectively toxic). Quinine is lethal for all Plasmodium schizonts (site 2 in Fig. 9-1) and the gametocytes (site 4) from P. vivax and P. malariae but not for P. falciparum. Today, quinine's spectrum of activity is considered t00 narrow for prophylactic use, relative to lhe synihetic agents. The mechanism of action is discussed under “Chloroquine and Chloroquine Phosphate.” The mechanism of resistance to quinine is poorly understood and varies with the susceptibility of the parasite to other amino- quinoline antimalarial drugs. Quinine still is indicated for malaria caused by P. falciparum resistant to other agents including chloroquine. Many times it is administered in com- bination with pyrimethamine and sulfadoxine, doxyeyeline, or mefloquine, depending on the specific form of malas and geographical location. Cinchonism is a toxic syndrome. Symptoms start wih tinnitus, headache, nausea, and disturbed vision. If adminis tration is not stopped, cinchonism can proceed to involve ment ofthe gastrointestinal tract, nervous and cardiovascular systems, and the skin. Quinine also is indicated for nocturnal leg cramps, bu N Quinidine R = OCH, Cinchonine R = H - o. O = ds mdiass [E De + 288 the main antimalarial drug used both for prophylaxis and treatment. Note that the list of indications for many of the other drugs in this chapter includes Plasmodium spp. resis- tant to chloroquine. Tt is indicated for P. vivax, P, malariae, P. ovale, and susceptible strains of P. falciparum. Chlo- roquine belongs to the 4aminoquinoline series, of which hundreds have been evaluated. but only about three or four are still in use. Even though this drug has been used for many years, its mechanism of action às st] not known. lts main site of action appears to involve the Iysosome of the parasite-infected erythrocyte. The following actions have been suggested on the basis of experimental evidence. À very complex mecha- nism is based on ferriprotoporphyrin IX. which is released by Plasmodium-containing erythrocytes, acting as a chlo- roquine receptor. The combination of ferriprotoporphyrin IX and chloroquine causes lysis of the parasite's and/or the erythrocyte's membrane. Finally, there is evidence that chlo- roquine may interfere with Plasmodiwm's ability to digest the erythrocyte hemoglobin or the parasite's nucleoprotein synthesis. The mechanism is based on the drug entering the erythrocyte's Iysosome, which has am acid environment, where it becomes protonated. The protonated (positively charged) chloroquine now is trapped inside the Iysosome because the pore that leads out of the Iysosome also is posi- tively charged. This leaves chloroquine bound to the pa- tent's hemoglobin, preventing the parasite from processing it properly.” In general, chloroquine and the other 4-aminoquinolines are not effective against exoerythrocytic parasites. Note that cach of the mechanisms requires that the parasite be inside the ervthrocyte. Therefore, chloroquine does not prevent re- lapses of P. vivax or P. ovale malaria, The drug also is indi- cated for the treatment of extraintestinal amebiasis Effecuve as chloroquine has been, it is a poor example of selective toxicity. Adverse reactions include retinopathy, hemolysis in patients with glucose-6-phosphate dehydrogen- ase deficiency (same mutation that confers resistance against malaria), muscular weakness, exacerbation of psoriasis and porphyria, and impaired liver function, Further examples of poor selective toxicity include off-label indications such as rheumatoid arthritis, systemic and discoid lupus erythemato- sus (possibly as an immunosuppressant), and a variety of dermatological conditions. If the increase in resistance to chloroquine continues, this “reliable” antimalarial drug may no longer be the mainstay of malaria treatment. The increase in P. faleiparum resistant to chloroquine is considered one ol the main reasons for the increases in both incidence and deaths from malaria, Remember that chloroquine resistance is à recent phenome- non that became significam in the mid-1990s, The key Plas- modium gene that confers resistance appears to be the pferr gene. which codes for a transporter protein. The result of the changes in the gene is that the pore through which chlo- roquine might exit the Iysosome no longer is positively charged, allowing protonated chloroquine to exit the Iyso- some.» At least eight mutations have been identified in the pfcrt gene, and itis postulated that resistance occurs because of an accumulation of these mutations. Chloroquine remains effective when there are fewer mutations in the pfort gene. Once the critical number of mutatons has occurred, the para- Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry site spreads over a broad geographical area, rendering chlo- roquine ineffective. Hydroxychloroquine. In most ways, hydroxychior oquine (Plaquenil) parallels chloroquine. Structurally, it dils fers solely in having a hydroxy moiety on one of the N-ethyl groups. Like chloroquine, it remains in the body for overa month, and prophylactic dosing is once weekly. The other indications, both FDA approved and off-label, are very sim ilar. Amodiaquine. Amodiaquine is listed in USP 25 (2007 but is not covered in the USP-DI for Health Professionals, nor is it on the list of antimalarial drugs recommended by the Centers for Disease Control and Prevention. Mechanistk cally, itis very similar to chloroquine and does not have any advantages over the other 4-aminoquinoline drugs. When used for prophylaxis of malaria, it was associated with a higher incidence of hepatitis and agranulocytosis than was chloroquine. There is evidence that the hydroquinone (phenol) amine system readily oxidizes to a quinone-iminé (Fig. 9-3), antioxidatively and/or metabolically, and this product may contribute to amodiaquine toxicity. The qui none-imine system is similar to the acetaminophen toxic me tabolite (Chapters 4 and 22). Mefloquine HCI. The newest of the 4-aminoquinolines, mefloquine (Lariam), is marketed as the R,$ isomer. It was developed in the 1960s as part of the U.S. Army's Walter Reed Institute for Medical Rescarch antimalarial research program. kt differs significantly from the other agents in this class by having two trifluoromethyl moieties, at positions 7 and 8”, and no clectronegative substituents at either position 6º (quinine) or 7º (chloroquine). Mefloquine also differs from chloroquine and its analogues by being a schizonticide (sie 2in Fig. 9-1), acting before the parasite can enter the ervyihro: cvte. Some evidence indicates that it acts by raising the pH ip the parasite"s vesteles, interfering with its ability to proces heme, Mefloquine-resistant strains of P. falciparum huve appeared. Relapse can oceur with acute P. vive Ural has been treated with mefloquine, because the drug does no eliminate the hepatic phase of this species, which cam reli fect the liver. Mefloquine is teratogenic in rats, mice, and rabbits. Them is an FDA-required warming that this drug can exacerhals mental disorders, and it is contraindicated in patients with active depression, a recent history of depression, generalizal) anxiety disorder, psychosis, schizophrenia, and other majir psychiatric disorders or a history of convulsions. 8-Aminoquinolines The other major group of antimalarial drugs based on lhe cinchona alkaloid quinoline moiety is the substituted & aminoquinolines (Fig. 9-4), The first compound introduced in this series was pamaquine. During World War Il, pes taquine, isopentaquine, and primaquine became available Only primaquine, used during the Korean War, is in wide use today, All of the 8-aminoquinolines can cause hemolvie anemia in erylhrocytic glucose-6-phosphate dehydrogem ase-deficient patients. As pointed out above, this is a com mon genetic trait found in populations living in arcas demic with malania, and it provides some resistance lo lis mechanism of action and spectrum of activity issed under “'Primaquine.” nations are seen in the structure=activity relation- 1 this series. AI four agents in Figure 9-4 have a 6- 7 ) motety like quinine, but the substituents on quino- fe located! at position 8 rather than carbon-4 as found E cinchona alkuloids. All agents in this series have a E om alky] linkage or bridge between the two With the exception of pentaquine, the other three pimolines have one asymmetric carbon. While erences occur in the metabolism of each stercoiso- of adverse response, there is little difference lana activity based on the compounds” stercochem- | Primaquine is the only 8-aminoquinoline Win use for the treatment of malaria. Tt is not used laxis. ts spectrum of activity is one of the narrow- curently used antimalarial drugs: tt is indicated exvervihrocytic P. vivax malaria (site 2 in Fig. 9- endoerythrocytic P. vivax, chloroquine or a drug for chloroquine-resistant P. viva is used with pri- In addition to its approved indication, it also is E auuinst lhe exoerythrocytic stages of P. ovale and perythrocytic stages of P. faleiparem, Primaquine ts lhe gametocyte stage (site 4 in Fig. 9-1), which tes the form required to infect the mosquito carrier. and in vivo studies indicate that the stereochemistry Eesymmetno carbon is not important for antimalarial here appears to be less toxicity with the levorota- 4 buu this às dose dependent and may not be that ai the doses used to treat exoerythrocytic P. vivax H CH CH | ds | Primaquine Hal Hs ei N CHa CHa> N A Pa A nº em; CH; OH H Pentaquine Chapter 9 = Antimalarials 289 HCO Re A N N CH CH CH aa A â 2 H E cai Se a CH “ N a a CHs Ha = *cH Pamaquine he HaCo RS Er N N CH CH H Cá A nem >CHa 7 IR da E ias isopentaquine Hs CH Figure 9-4 = 8-Aminoquinolines Although structurally related to the cinchona alkaloids, the S-aminoquinolines have a different mechanism of action. Primaquine appears to disrupt the parasite's mitochondria. The resultis disruption of several processes, including matu- ration into the subsequent forms. An advantage is destroying exoeryihrocytic forms before the parasite can infect eryihro- cytes, the step in the infectious process that makes malaria so debilitating Fixed Combinations Because resistance is à frequent problem in the prophylaxis and treatment of malania, combination therapies thal use two Q N=— HN Ls N RN, [a] HC— O O—cH, Sulfadoxine HiC—CH; N à / Des == HaN Pyrimethamine Figure 9-5 = Sulfadoxine and pyrimethamine Thymidylate Synthase ymidylate Syn à Chapter 9 m Antimalarials 291 o Deoxyuridine 5-Monophosphate; dUMP NºÉN'O.CH-EH4 Emfolic acid and tetrahydrofolic acid; PABA is the ml part of the folate structure. Normally, sulfonamides il excellent selective toxicity because humans do not ne the vitamin folic acid. Nevertheless, there are a Of severe to fatal occurrences of erythema multi- + Sjevens-Jobnson syndrome, toxic epidermal necro- Emnd serum sickness syndromes attributed to the sulfa- imethamine, developed in the 1950s. inhibits the re- am of folic acid and dihydrofolic acid to the active tetra- plate coenzyme form. Although the latter is required fundamental resctions involving pyrimidine bio- the focus in the parasite is regeneration of Nº,N'O. tetrahydrofolate from dihydrofolate (Fig. 9-7). ests of thymidine 5'-monophosphate from deoxy- E S“monophosphate is a universal reaction im all cells DNA. There are enough differences between this r Ne and dihydrofolate reductase found in mammalian. À. und plasmodial cells that folate reductase inhibitors o E ipi that show reasonable selective toxicity. ke malaria parasite, the intimate relationship between mayo synthase and dihydrofolate reductase means that ne can inhibit both enzymes. s combination is indicated for prophylaxis and treal- Dl chloroquine- -pesistant P, falciparum and may be used atom with quinine. Although indicated only for P. m the combination is active against all the asexual Hc forms. lt has no activity against the sexual ga- form. The fixed combination contains 500 mg of ne and 25 mg of pyrimethamine. A wide number mides could be used in combination with pyni- The usual approach is to use a sulfonamide that jnetic properties like those of the dihydrofo- e inhibitor. For this combination, the peak ay [CH FHs Thymidine 5'-Monophosphate; TMP; dTMP FHs Dihydrofolate Reductase FH, = Dihydrofolate; FH, = Tetrahydrotolate Figure 9-7 = Thymidylate synthase Atovaquone HN q à CHs e] 4 CNH Ná CH Proguanil Figure 9-8 = Atovaquone and proguanil, 292 plasma sulfadoxine concentration occurs in 2.5 10 6 hours, and the peak plasma pyrimethamine concentration occurs in [Sto 8 hours, Resistance has developed, much of it involv- ing mutations in either or both of the genes coding for dihy- drofolate reductase and thymidylate synthase Atovaquone and Proguanil HCI. Atovaquone and proguanil HCL (Fig. 9-8) are administered in combination (Malarone) in an atovaguone-to-proguanil HCI ratio of 2.5:1, measured in milligrams (not millimoles). Proguanil, developed in 1945, is an carly example of a prodrug. It is metabolized to cycloguanil (Fig. 9-9), primarily by CYP 2019. The polymorphic nature of this hepatic enzyme explains why certain subpopulations do not respond to pro- guanil; they cannot convert proguanil to the active cyclogu anil, The basis for this combination is two distinct and unre- lated mechanisms of action against the parasite. Atovaquone is a selective inhibitor of the Plasmodiwn's mitochondrial electron transpor system, and cvcloguamil is u dihydrofolate reductase inhibitor. Atovaquone's chemistry is based on it Húlsom and Gisvolel's Textbook of Organic Medicinal and Pharmaceutical Chemistry being a naphihoquinone that participates in oxidation=re- duction reactions as part of its quinone=hydroquinone sys- tem. Itis patterned after coenzyme Q, found in mitochondrial electron transport chains. The drug selectively interferes with mitochondrial electron transport, particularly at th site 's eytochrome be, site. This deprives the cell of needed ATP and could cause it to become anaerobic. Resis- tançe to this drug comes from a mutation in the parasite's cytochrome Cyeloguanil (proguanil) interferes with deoxythymidylat synthesis by inhibiting dihydrofolate reductase (see Fig. 94 and the pyrimethamine discussion). Resistance to proguamil! eycloguanil is attributed to amino acid changes near the diby- drofolate reductase binding site. lts elimination half-life (48 to 72 hours) is much shorter than that of the other antimalar- tal dihydrofolate reduciase, pyrimethamine (mean elimina ton half-life of 111 hours). The combination is cffective against both eryithrocytic and exoerythrocytic Plasmodium “This drug combination is indicated for malaria resistant to chloroquine, halofantrine, mefloquine, and amodiaquine. ls main site às the sporozoite stage (site | in Fig. 9-1) HH À H—N H No Na H H a Lu Rain to) " Lu | fica cypzc19 HO / — No NJ dd Nuga ' et dd A Proguanil (Chloroguanide) HO a O A ae " Fa u à a ( Vá -— ca Rs a e, N / e, tac” Nos Ei Si Tautomeric shitts H Ed H=N N —— D===N H c / im N / Vo/ y ed as Cycioguanil (active metabolite) Figure 9-9 = Conversion of proguanil to cycloguanil by CYP 2C19 294 Wilseom amd Cisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry onticidal (sites | and 2 àn Fig. 9-1) and has no effeci on lhe sporozointe, gamerocvie, or hepatic stages. The parent compound and the N-desbutyl metabolite are equally active im vitro. Halofantrine”s mechanism of action against the par asite 15 not known. There is contradictory evidence that ts mechanism ranges from requiring heme to disrupting the ettochondria. A prominent warming cautions that halofan- trine can affect nerve conduchon im cardiac tissue. Quinacrine HC]. Quinacrine às no longer available in he Umied States. It can be considered one of the most toxic of the antimalanal drugs, even though, at one time, it was commonty used. ltacts al many sites within the cell, includ- ing intercalation of DNA strands, succinic dehydrogenase, mitochondrial electron transport, and cholinesterase. H may be tumorigenic and mutagente and has been used as a sele- rosing agent. Because il is an acridine dye, quinacrine can cause vellow discoloration of the skim and unne Ha mv E) al [8] Clin tg ma Artemelhar (oil soluble) R = CHs Artemotil (Oll soluble) R = CHaCHs Hs HCO Simplified Aryitrioxanes R=-For-COOH times, ES New Antimalarial Drugs Artemisinin. Drugs in the artemisinin series (Fig. 9-1) are the newest of the antimalarial drugs and are structurally unique, compared with the compounds in current use. The parent compound, aremisimin, às a natural product extracted from the dry leaves of Artemísia anna (sweet wormwood) The plant must be grown cach year from seed because ma ture plants may lack the active drug. The growing conditions are critical to maximize artemisinin yield. Thus far, the bes vields have been olmained from plants grown in North Viel- nam, Chongging region in China. and Tanzania.“ Al of the structures in Figure 9-[ | are active against the Plasmodium genera that cause malaria, The key structure characteristic appears to be a “trioxane”” consisting of the endoperoxide and doxepin oxygens. This is shown by the somewhat simpler series of 3-aryltrioxanes ut the bottom of Figure 9-1 1, which are active against the parasite, Note (hat the stereochemistry at position 12 is not critical,” While in CH CHs [o C—(CH)h—C—o" Na” Artesunate (water soluble) Figure 9-17 = Artemisinin and ar temisinin-derived compounds Fosmidomycin á | OH o E Va Ei” rag N ! OH Ha FR900098 pe 9. 12 = Fosmidomycin and a fosmidomycin analoque 1CH | Chapter 9 = Antimalarials 295 the vietim's eryihrocyte, the malaria parasite consumes the hemoglobin consisting of ferrous (Fe *?) iron, converting it to toxic hematin containing fernie (Fe *) iron, then reduced to heme with its ferrous iron. The heme iron reacts with the inoxane moietyv, releasing reactivo oxygen and carbon radicals and the highly reactive Fe” = O species. The latter is postulated to be lethal to the parasite **º With lhe reduction of armemisinin to dihydroanemisinin, an asymmetric carbon forms, and it'is possible to form ail- soluble and water-soluble prodrugs. Both stereoisomers are active, justas with the simpler aryltroxanes. The chemistry forming each of the artemisinin prodrugs results in the pre- dominance of one isomer. The £ isomer predominates when producing the nonpolar methyl and ethyl ethers, whercas the o isomer is the predominant product when forming the water-soluble hemisuccinate ester. The latter can be adminis- tered as 10-mg rectal capsules for patents who cannot take medication orally and when parenteral treatment is not avail- able, Fosmidomycin. Fosmidomycin (Fig. 9-12) was iso- Iated from a Streptomyces fermentation broth in 1980, lts 3 o) HO-—CH 3 DOXP Synthase | = 4HMC—OH O .a = 5H4C—0—P— 0H OH 1-Deoxy--xylulose-5-phosphate (DOXP) 3 H0— 0H 1 HC—ç2—oH HO—CH4 o 5 CH ——P—— OH OH Figure 9-13 = Nonmevalonate 2-C-Methyl-o-erythritol-4- phosphate pathway 298 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry selective toxicity is based on inhibiting a biochemical path- way not found in humans and mammals in general-—the nonmevalonate pathway to form isoprenoids. Mammals, in- cluding humans, form their isoprenoids solely by the meva- lomic acid pathway. Many microorganisms have both path- ways. Whereas the mevalonate pathway starts with three molecules of acety-CoA forming 3-hydroxy-3-methylglu- tarvl coenzyme A (AMG-C6A) followed by reduction to mevalonic acid by HMG-CoA reductase (site of the statin drugs), the nonmevalonate pathway is carbohydrate based (Fig. 9-13). Condensation of pyruvate und glyceraldehyde à-phosphate by I-deoxy-D-xylulose-5-phosphate (DOXP) synthase produces the five carbon DOXP, which undergoes a complex reduction and isomerization to form 2-C-methyl- p-erythritol-d-phosphate. The enzyme for this reaction, DOXP reductoisomerase, às inhibited by fosmidomyein. The basic five-carbon isoprene umit. isopenteny] diphosphate, concludes the pathway. The atoms have been numbered to help follow the isomerization of the deoxy-xylulose interme- diate to form the erythritol compound, The malarial parasite only has the nonmevalonate pathway, and initial studies show that fosmidomyein is relatively nontoxic in humans. Replacement of fosmidomycin's N-aldehyde with an acetate produces a very active antimalarial agent that has been desig- nated FR900098.*! As this chapter went to press, fosmido- mycin and analogues were in phase E and 1 trials. REFERENCES | Editors: Sei, Am. 286:8, 14, 38-45, H02- 103, 2002 2. 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