Antimalarial drugs history, new antimalarial drugs and antimalarial vaccines

MALARIA

Malaria, one of the most infectious diseases of mankind in the world, is wide spread
in more than 90 countries and affecting around 40% of the world’s population. There
are some 300-500 million cases and between 1.5-2.7 million deaths each year from
malaria. It is a hematoprotozoan parasitic disease transmitted to humans by a
particular species of Anopheline mosquitoes.1 These insects inoculate Plasmodium
sporozoites to humans via a blood feeding process. The genus Plasmodium can be
classified into nine subgenera. Plasmodium falciparum, P. vivax, P. ovale and P.
malariae are the species that infect humans. Malaria caused by P. falciparum is most
critical and lethal. It accounts for 80% of all malaria infections and 90% of malaria
related deaths. Infection with this parasite can lead to death within hours to days.

HISTORY OF QUINOLINE ANTIMALARIAL DRUGS

A reliable treatment for malaria – powdered bark of the South American cinchona
tree, which contains the alkaloid quinine – has been available since at least the early
seventeenth century. According to legend, Peruvian Indians knew about the efficacy
of cinchona bark before the Spanish conquest. There have been many hypotheses
about the South American Indian’s knowledge and use of Cinchona bark. According
to one speculation, Indians used it while working in cold streams in Spanish-owned
mines in order to stop shivering.
The use of cinchona bark was firmly established in England by the activities of Sir
Robert Talbor (or Tabor). As a young man, Talbor was apprenticed to an apothecary
in Cambridge, where he learnt of Peruvian bark. He then studied at St John’s College,
and in 1671 moved to Essex, which was highly malarious, and later to London. Talbor
produced a secret and highly successful remedy for the ague.
Its value is said to have come to light when it was used to cure the wife of the
Spanish Viceroy in Lima, the Countess of Chincho´ n (in whose honor Linnaeus later
named the tree, though he spelt her name incorrectly), and she then broad cast the
virtues of the astonishing remedy on her return to Spain Various analogs of methylene
blue were synthesised by replacing one methyl group with basic alkyl side chain to
enhance activity. Figure 4: Chemical structure of pamaquine, primaquine,
chloroquine&amodiaquine Int. This compound was found too toxic to use therefore,
to overcome this problem primaquine was synthesised. Primaquine was comparatively
much less toxic analog of 8-amonoquinoline. Primaquine is still used to eradicate the
hypnozoites of P. ovale and P. vivax. 4-Aminoquinole Scientist at Bayer Institute in
Germany synthesized 4- aminoquinoline Resochin by altering the basic side chain.15,
Resochin was found to be safe for malaria treatment and renamed as chloroquine.
Chloroquine became popular for clinical use due to its effectiveness and low risk of
side effects. Unfortunately, chloroquine has not been used wisely and in early 1960s
the cases of chloroquine resistance emerged.24, 25 Amodiaquine was introduced as
an alternative and has been used for the prophylaxis of P. falciparum for almost 40
years. Upon oral intake of amodiaquine rapidly absorbs and metabolizes. Even though
AQ has a high absorption rate, it has a low bioavailability and is considered a pro-
drug for desethylamodiaquine. The formation of DEAQ is rapid and its elimination
very slow. In contradiction of the metabolism of CQ, AQ produces a toxic
quinoneimine metabolite. The metabolites have been detected in vivo by the excretion
of glutathione (GSH) conjugates (figure 5). Figure 5: Chemical reactions involve in
the formation of DEAQ and bis DEAQ CQ still remains the treatment of choice in a
few geographical areas where it can still be relied upon, although guidelines now
instruct the use of combination chemotherapy to slow the development of resistance
to the partner drug. In some resistance “hot spots”, CQ was completely abandoned for
a combination of Sulfadoxine - pyrimethamine almost two decades ago. In such cases,
there is evidence to suggest that CQ sensitivity can be restored. The failure rate of CQ
treatment can be decreased by giving the drug twice per day rather than as a once
daily treatment regimen. Doubling the dosing frequency in this way achieved a high
cure rate despite underlying CQ resistance and without any adverse side effects. This
increase in efficacy can be explained by the pharmacokinetics of CQ; the second daily
dose of CQ acting to raise plasma concentrations to levels where they have activity
against resistant parasites. It has also been shown that the use of this type of treatment
regimen can stabilize the spread of CQ resistance but major drawback in this is the
narrow therapeutic index for chloroquine. Quinoline methanol The most promising
compounds in this group were 4- aminoquinoline methanol structurally analogous to
quinine.21 These compounds were every effective for both P. falciparum and P. vivax
but exhibited strong photosensitizing actions. Figure 6: Chemical structure of
mefloquine and halofantrineMefloquine (figure 6) was synthesized afterwards which
was more potent with no appreciable photosensitizing effects.26 Mefloquine was used
in fields for almost 30 years especially for chloroquine resistant strains. But due to
resistance and toxicity associated these are now limiting in use.27-29 Another major
class of compounds emerged by replacing quinoline basic scaffolds of 4-
aminoquinoline to various aromatic rings. Halofantrine (figure 6) synthesized in this
class and used to treat chloroquine resistant malaria.30-32 However, its use has been
restricted due to serious cardiotoxic effects. 33, 34 Quinoline and its derivatives:
structure-activity relationship (SAR) Quinine has been used for centuries in the
treatment of malaria. It is a low-cost drug but has become limited due to a decrease in
its sensitivity by parasites. However, it is still used parenteral to control acute cerebral
malaria. The structure-activity relationships of chloroquine and related quinoline
antimalarial compounds have been reviewed extensively.35-38 Other derivatives of
quinine include chloroquine, amodiaquine, mefloquine and halofantrine. These drugs
act by decreasing the rate of hemozoin formation, rather than irreversibly blocking its
formation.39-41 An alternative mechanism of action of chloroquine has also been
hypothesized. It is believed that it works through the generation of highly reactive
radicals due to an electron transfer between the couple Fe II heme/Fe III heme and the
quinoline ring may be responsible for antimalarial action of chloroquine.42 The 7-
halosubstituted compounds are the most active antimalarials in the 4-aminoquinoline
series. Change of the halogen or disubstitution on the quinoline nucleus generally
lowers activity as in 9-aminoacridine series. The inter-nitrogen separation (the
molecular distance between the quinoline N and the alkylamino N) affects the level of
activity of 4-aminoquinolines43 and is important in defining the ability of drugs to
bind to heme.44 Structure-activity relationship studies of quinine analogs suggested
that a hydroxyl group on C-9 is necessary for activity. Erythro configurations at the
C-8 and C-9 positions of quinine analogs are more active than the threo isomers but
not in all cases.21 The orientations of the hydroxyl and amine groups of mefloquine
are critical to antimalarial activity. 4-Aminoquinoline nucleus of chloroquine and
related antimalarials is responsible for complexing free heme and the group at the 7-
position of the quinoline ring appears to be vital in determining the antimalarial
ability of 4-aminoquinolines to inhibit the formation of hemozoin. The aminoalkyl
side chain of quinoline drugs is also accountable for strong antiplasmodial activity.
However, change in the length of amino alkyl side chain has little influence on
activity against chloroquine-sensitive strain of P. falciparum but has an intense
influence on the activity especially against chloroquine-resistant strains.45 Quinoline
drugs lacking 7-chloro group do not inhibit hemozoin formation although forming
complexes with heme. Replacing 7-chloro group with a bromo or nitro group shows
the inhibition of hemozoin formation. If a chloro atom is introduced at the 6-position
on the quinoline ring, the interaction with hematin is completely disrupted.43-45 If 7-
chloro is replaced by 7-amino and 7- chloro derivatives, hemozoin formation is not
inhibited. Aminoquinolines inhibiting hemozoin formation must have aminoalkyl side
chain for its strong antimalarial activity. Replacement of aminoalkyl side chain to
hydroxyl or other group causes severe reduction in activity. 4-
Aminoquinolinedialkylamino side groups are liable for ideal activity.

Drugs Under Development

When a candidate antimalarial drug moves from being evaluated in animals to being
assessed in humans, the first step of the process —phase I testing—uses incrementally
increasing doses given to healthy volunteers in an effort to determine the drug's safety
and patients' tolerance for it. Once the drug's safety is assured, phase II testing is
conducted to judge its efficacy in volunteers or naturally infected patients with low-
level parasitemias and mild clinical illness. In phase III testing, the drug is initially
given only to patients hospitalized with moderately severe disease; later, wide-scale
use of the drug in a limited area, with careful monitoring to evaluate efficacy and
detect low frequency side effects, takes place. Following phase III, an application may
be submitted to FDA for licensure of the drug. Phase IV, post-marketing surveillance,
involves careful scrutiny for low-prevalence side effects (Fernex, 1984a,b). Although
there are several promising leads, few antimalarial drug candidates have reached
phase I testing.
Arteether
This ethyl ether derivative of artemisinin has been selected by WHO and the U.S.
Army for collaborative development as an intramuscular formulation to treat malaria.
It may have some advantages over artemether, another artemisinin analog, in terms of
toxicity.

WR 238605

Extensive primate studies suggest that this 8-aminoquinoline, a less toxic-

ity, better oral bioavailability, and a longer half-life than primaquine. Human testing
awaits the filing of an investigational new drug application with FDA. It is of
considerable interest that WR 238605 has also shown activity against the
opportunistic pathogen Pneumocystis carinii in rodents (Bartlett et al.,
1991). Pneumocystis carinii pneumonia is a common and serious infection in AIDS
patients. A partner for development of the drug has not yet been selected.

BW566c

This compound is a member of the hydroxynaphthoquinone class of compounds. The

antimalarial activity of these compounds was discovered in the 1940s, when they
were synthesized and tested as part of an effort to develop a synthetic replacement for
quinine. Several drugs in this class, including menoctone, have gone on to human
testing, but further development proved unwarranted.

BW566c was identified as an antimalarial candidate at the British drug company

Burroughs Wellcome (Gutteridge, 1989). Interest intensified when, like WR 238605,
it was found to possess anti-P. carinii activity. It is now in human trials for the
treatment of P. carinii pneumonia. Development of BW566c as an antimalarial agent
depends on the results of these studies; it is not likely to undergo further research and
development if it has only antimalarial potential, since Burroughs Wellcome, like
most other pharmaceutical companies, has terminated its antimalarial drug discovery
program.

There is some evidence that the hydroxynaphthoquinones act by inhibiting electron

transport at ubiquinone-sensitive sites in the parasite mitochondria. This inhibition is
coupled to inhibition of the enzyme dihydroorotate dehydrogenase, which is
necessary for pyrimidine (and thus nucleic acid) synthesis.

A Malaria Vaccine: An Immunological Approach Against the Parasite

The complicated life cycle of Plasmodium presents a challenge to malaria vaccine

development. Researchers must determine which life stage of the parasite to target, or
whether the vaccine needs to combine elements that target more than one life stage.
However, recent findings allow us to be optimistic about the possibility of an effective
malaria vaccine.
Current Research

Scientists have expanded on what was learned in the 2002 study to develop many
potential malaria vaccines. Instead of attempting a live attenuated vaccine, most
scientists today are using technologies to isolate and deliver specific antigens in a
vaccine. And because the parasite has three different life stages, there are three
distinct vaccines approaches being investigated.

Pre-erythrocytic vaccines target the infectious phase and aim either to prevent the
sporozoites from getting into the liver cells or to destroy infected liver cells. [15] The
most significant challenge for a pre-erythrocytic vaccine is the time frame:
sporozoites reach the liver less than an hour after being injected by the mosquito. As a
result, the immune system has a limited amount of time to eliminate the parasite.
Although most of the potential pre-erythrocytic vaccines are still in Phase I or Phase
II trials, one vaccine is currently in Phase III trials and is showing promise: the RTS,S
vaccine. (Note that Phase I studies evaluate for safety, Phase II tests evaluate dosing,
and Phase III tests assess overall efficacy. [16])

In order to develop the RTS,S vaccine, developers identified the protein that was most
responsible for protection in the irradiated sporozoite trial from 2002. This antigen is
known as the circumsporozoite protein, or CS protein. Although this antigen is
protective, it is not very immunogenic on its own, meaning that it is not good at
stimulating an immune response. Thus, scientists fused the Hepatitis B surface
antigen (the antigen responsible for providing protection in the Hepatitis B vaccine)
with an antigen from the CS protein. In order to stimulate the immune system even
further, scientists employed a compound called an adjuvant that boosts the immune
system’s response to the antigen. The goal is to induce high levels of antibodies to
both block the sporozoites from entering the liver cells and to tag specific infected
cells for destruction.

The RTS,S vaccine was tested in Phase III trials in 11 different African countries.
These trials have had some successes. The earliest results, released in October 2011,
showed that in children aged 5-17 months, vaccination with RTS,S reduced the risk of
clinical malaria and severe malaria by 56% and 47%, respectively.[17] However,
in results released in November 2012, the vaccine was less effective in infants aged 6-
12 weeks at first vaccination. In that group, vaccination with RTS,S led to one-third
fewer episodes of both clinical and severe malaria. Final results from the trial, which
followed young children for about three years, showed reduction in clinical malaria
cases by 26% for the youngest children to to 36% for children up to age 17 months at
first vaccination.[18] In July 2015, the European Medicines Agency recommended
that the vaccine be licensed for use in young children in Africa; the World Health
Organization is consider the recommendation on the vaccine. In the meantime, a
WHO advisory group has recommended pilot implementation of the vaccine in 3-5
sub-Saharan African countries.[19] The chief developer of RTS,S, the Malaria
Vaccine Initiative, a nonprofit based in Seattle, Washington, has hopes of developing
an even better vaccine that is 80% effective by 2025.[20]

Several other pre-erythrocytic vaccines are in trials but none have shown the promise
or success of RTS,S. Scientists are working on improving the efficacy of the RTS,S
vaccine to get it to be more than 50% effective by employing prime boost technology,
adjuvants, and antigen optimization.[21]

Erythrocytic vaccines, or blood-stage vaccines, aim to stop the rapid invasion and
asexual reproduction of the parasite in the red blood cells. Recall that the blood stage
is the time when symptoms appear and is also the most destructive to the patient due
to the bursting of red blood cells. Because of the huge number of merozoites produced
during this stage – 40,000 merozoites are released for each infected liver cell – a
blood-stage vaccine can aim only to reduce the number of merozoites infecting red
blood cells rather than completely block their replication.[22] Currently there are no
blood-stage vaccines that have had the success of the RTS,S vaccine and most are still
undergoing Phase I or II trials.

Finally, another type of vaccine targets the stage of sexual reproduction that occurs in
the mosquito gut. This approach is known as a transmission blocking vaccine
(TBV) because it aims to kill the vector, the Anopheles mosquito, to stop further
spread of the parasite. This is an indirect approach to a vaccine because it will not
directly protect an individual who gets the parasite but rather will stop the continued
spread.[23]
One TBV candidate vaccine is the Pfs25-EPA which is being developed by US
National Institute of Allergy and Infectious Diseases Laboratory of Malaria
Immunology and Virology and Johns Hopkins University Center for Vaccine
Research. The idea behind this vaccine is that if the body can develop antibodies
against the Pfs25 antigen, a mosquito taking a blood meal will take up some of these
antibodies into its stomach. There the antibodies will encounter the antigen, enabling
them to interfere with development and kill the parasite.[24]

Ultimately, many scientists think that the next step is to combine multiple approaches
to develop a malaria vaccine. But these individual stage vaccines must show efficacy
on their own before scientists can develop a vaccine combining approaches.
Moreover, the major challenge that scientists will face in the future is that there are no
known correlates for immunity, meaning that there is no method other than costly
clinical trials in humans to demonstrate a vaccine’s efficacy.[25] Thus although great
progress has been made, malaria vaccine development will continue to be a costly and
multidimensional effort.
References
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chemotherapy. The journal of the Royal College of Physicians of
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2. http://www.who.int/mediacentre/news/releases/2015/sage/en/
http://www.who.int/mediacentre/news/releases/2015/sage/en/
3. Camila Henriques Coelho, Justin Yai Alamou Doritchamou, Irfan Zaidi and
Patrick E. Duffy, (2017), “Advances in malaria vaccine development: report
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publications/world-malaria-report-2015/report/en/ (2015).
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(http://www.who.int/biologicals/vaccines/Malaria_Guidelines_TRS_980_Ann
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trial to evaluate the effcacy of the RTS,S/AS01 malaria vaccine in children
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