Antimalarials targeting different forms of parasite.
Malaria is a global public health issue. Despite the efforts in malaria prevention, nearly half the world’s population is at risk of infection. Until present-day, researchers are struggling to design and discover an efficacious antimalarial. In comparison to most common antimalarial chemotypes that eliminate erythrocytic stages of P. falciparum, 4(1H)-quinolones and 4(1H)-pyridones exhibit antimalarial activity against multiple stages of the parasite. They have potential to treat blood stages of multidrug resistant P. falciparum malaria, eradicate dormant exoerythro stages of relapsing malaria species (P. vivax), and prevent transmission of infectious gametocytes to mosquitoes. However, thus far, the advancement of these chemotypes towards pre-clinical and clinical development has been impeded due to poor physicochemical properties, poor oral bioavailability, and poor dose-proportionality limiting preclinical safety and toxicity studies. Despite all these challenges, 4(1H)-quinolones and 4(1H)-pyridones continue to be at the forefront for the development of the next-generation antimalarials as they would have tremendous global public health impact and could significantly enhance current malaria elimination efforts.
Malaria is a global, mosquito-borne, parasitic disease that is serious and fatal, putting people of 87 countries at risk. The population with the highest risk of infection are young children under the age of five and pregnant women living in the sub-Saharan Africa. In 2020, the World Health Organization (WHO) reported an estimate of 229 million malaria cases, with approximately 409,000 deaths in 2019 alone . This is a significant decrease from that of ten years ago, where the global number of malaria cases and deaths were 243 million and 863,000, respectively. The increased efforts in malaria prevention had led to these decreases in cases .
Malaria is a disease caused by a protozoan parasite of the genus
To develop efficacious antimalarial drugs, it is important to understand the
Once inside the erythrocytes, the parasites can hide from the hosts’ immune response. These merozoites begins to enlarge and become a uninucleate cell termed trophozoite. The nucleus of the trophozoites divides asexually to produce a schizont. The schizont then divides and produces merozoites. These merozoites can invade other erythrocytes and continue replicating. The clinical symptoms of malaria appear when these erythrocytes rupture and releases merozoites .
After many rounds of schizogony in the erythrocyte, some merozoites, rather than replicating, enter a sexual phase, where they develop into male and female gametocytes. Erythrocytes containing gametocytes do not rupture. Gametocytes are incapable of forming gametes within their hosts and form only when they are taken up by a mosquito. The importance of sexual differentiation is that it is responsible for the transmission from host to the
Opposed to the common
Unfortunately, this infection follows a vicious, never-ending cycle between human and mosquito, if a cure is not discovered for all forms of the parasite. Hence, the life cycle dictates design consideration from the onset of the discovery, optimization, and development of a new antimalarial agent.
1.2 Past and present antimalarial drugs
Decline in malaria cases are being observed due to the increased efforts in preventing, controlling, and treating malaria . Still, chemotherapy is the most common method of prevention and treatment utilized for this infection. Of course, given the complex nature of the parasite, these drugs act differently towards different stages of the parasite. For this reason, antimalarials are categorized by their activity – blood schizonticidal, tissue schizonticidal, gametocytocidal, and sporontocidal drugs. Blood schizonticidal drugs are antimalarials that target the asexual erythrocytic stages of the parasite. Tissue schizonticidal drugs are antimalarials that target hypnozoites. Gametocytocidal drug are antimalarials that targets the sexual erythrocytic forms of the parasite in the blood. Lastly, sporontocidal drugs are antimalarials that prevent formation of malarial oocytes and sporozoites in infected mosquito (Table 1) [9, 10].
|Classification via Activity|
|Blood Schizonticidal||Tissue Schizonticidal||Gametocytocidal||Sporontocidal|
Currently, the majority of drugs target the asexual blood stages of the parasite. The most utilized drugs are chloroquine (
Not only is the inadequate number of antimalarials that are active against the different life stages of parasite an issue, the development of resistance towards currently available drugs is a major concern. Resistance towards current antimalarial drugs are usually a result of a point mutation that can decrease drug accumulation through altered influx/efflux mechanism or change the affinity of the drug to its’ validated targets [18, 19]. Actions have been taken by the WHO to act against resistance. Originally, artemisinin (
Despite these efforts, increased resistance from mutant strains of
1.3 Recommended candidate profiles for the next generation of antimalarials
We are currently facing issues with current antimalarials due to resistant strains and lack of antimalarials to combat this problem. To develop the next generation of antimalarials, a description of the desired drug profile has been summarized in a Target Product Profile (TPP). TPPs are divided into different target candidate profiles (TCPs) since malaria chemotherapies will exist as combination therapy, containing more than one active ingredient. The main considerations across all TCPs are that these drugs are safe, affordable, and efficacious against multi-drug resistant
2. Development of 4(1
H)-quinolones and 4(1 H)-pyridones
Abiding to the TCPs to develop a novel class of antimalarials is the current measure taken to assist in the eradication of malaria. 4(1
Previously discovered 4(1
To improve physicochemical properties, it is necessary to scrutinize the properties, such as molecular weight, polar surface area, rotatable bonds, hydrogen bond acceptors and hydrogen bond donors as introduced in Lipinski’s paper introducing Rule of Five and other subsequent papers [27, 28]. Another key feature to consider is the complexity of the molecule via Fsp3, which measures saturation of the compound. It has been observed that increase saturated carbons leads to higher aqueous solubility – a major downfall in 4(1
2.1.1 Optimization of clopidol
An anticoccidial drug clopidal (
After several decades, scientists at GlaxoSmithKline (GSK) exerts efforts to optimize clopidal (
Variations to the C-2, C-3, and C-6 position were made and further improvements could not be observed (Figure 6). Variations on the aryl group made a major impact on the
To improve the physicochemical properties of GW844520 (
Recently, various linkers and heteroaromatic rings have been investigated. Compounds with rigid linker (alkyne) are still active; however, relative to their flexible linker (ether and alkane) counterparts, their potency decreases by a ten-fold. They anticipate that the flexibility allows the compound to mold into the active site with correct hydrophobic interactions. Another observation was that replacing the proximal phenyl ring with a pyridine ring maintains the activity and improves pharmacokinetic profiles. This demonstrates the potential of analogues of
With renewed efforts to optimize 4(1
The balance amongst these three qualities are necessary for the development of a potent, orally bioavailable antimalarial quinolones.
2.2.1 Optimized of floxacrine
In 1974, an evaluation of floxacrine (
Due to limited exploration of THAs since the discovery of WR243251, Manetsch and Kyle initiated a structure–activity relationship (SAR) and a structure–property relationship (SPR) studies to better understand THAs and its ability to exert activity towards both the blood and liver stage of the parasite.
Altering the number of carbons on the saturated ring system significantly reduced the activity and the aqueous solubility. Here on out, the scientists modified the 5-, 6-, 7-, and 8- position of the benzenoid ring with the 6-membered saturated ring. It became evident that the 6- and 7-position are key positions for antimalarial activity, which also affected the RI. The electronics on the 6-position did not significantly alter the activity. However, the 7-position was more sensitive, as it displayed preference for electron donating groups to retain potency and maintain the RI between 0.3 and 3. Furthermore, an inverse relationship was observed between potency and aqueous solubility. Substituting either or both the 5-position and 8-position, decreased activity and increased solubility. With this, THA-114 (
2.2.2 Optimization of ICI56,780
Scientists at Imperial Chemical Industries (ICI) developed ICI56,780 (
Manetsch and Kyle initiated work on SAR to optimize
Given the necessity to improve aqueous solubility, ionizable piperazinyl-substituted analogues were developed. The linker length between the piperazine moiety and the benzenoid ring was investigated, along with the various piperazinyl-substituent. Ethylene linker analogues were found to diminish blood stage activity, while methylene linker analogues were most active. Amongst the
2.2.3 Optimization of endochin
The two groups worked together to synthesize a series of compounds, termed ELQ for
2.2.4 Optimization of TDR molecules
The Guy laboratory is also one of the various groups that are working to optimize quinolones to develop a potent antimalarial; however, their approach was slightly different. Rather than utilizing the older antimalarials, this group utilized two compounds that had confirmed antimalarial activity through the WHO’s Special Programme for Tropical Disease Research (TDR). TDR42098 (
Findings from the initial SAR study prompted the Guy laboratory to further investigate 3-carboxy-4(1
7-position was also investigated, where findings also displayed that small hydrophobic electron-donating group improves potency, while an electron withdrawing group diminishes the potency .
Multi-substituted benzenoid ring was investigated to observe if there are any synergistic effect of varying substituents. 5,7- and 6,7- dihalogenated compounds were inactive towards multidrug-resistant (MDR) strains. Similar results were observed from 6,7-dimethoxy analogues. Simultaneous incorporation of a methoxy and halo group was investigated, where it exhibited sub-micromolar to nanomolar activity when the halogen was on the 6 position and the methoxy was on the 7 position. When installing a methoxy group on the 6 position and the halogen on the 7 position, antimalarial activity against all strains were lost .
Finally, the carbonyl substituent on the 3-position was investigated. Varying chain lengths and incorporation of morpholinyl, pyrrolidinyl, and
13 compounds that had an appropriate balance amongst activity, solubility and permeability were selected by the Guy laboratory to test for microsomal activity. Compounds
2.2.5 Optimization of HDQ
Similar to the Guy laboratory, the O’Neill and Ward utilized a unique approach that led them to study quinolones to treat malaria. Originally, hydroxy-2-dodecyl-4(1
Initially, the quinolone core was modified. Installing a 8-aza-4(1
To improve solubility properties, heterocyclic substituents were introduced to the quinolone core. It was observed that the distal ring is most favorable as a phenyl ring; however, a pyridine ring for the replacement of the proximal aromatic ring demonstrates great potency, reduced ClogP, and improved solubility. However, even with the improved solubility, the
The most recent attempt to improve solubility was to utilize a bioisostere of benzene rings. Pyrazoles have been well-documented to improve solubility by reducing ClogP. The optimization of the other substituents follows their previous findings (Figure 17) .
While malaria remains to be a global health threat, developing a novel class of drugs has become essential to treat and prevent the spread of this disease. 4(1
The frontrunner compound for 4(1
Since many research teams focus solely on the activity against the blood stage, compounds
Nevertheless, one major downfall with the development of 4(1
Thankfully, by early 2000s, the field of medicinal chemistry advanced, where researchers could optimize historical quinolones to develop them into drug-like molecules. Even with the variety of chemotypes, the approach towards optimization is quite similar amongst the various research teams.
Despite these obstacles, 4(1
We would like to thank Medicines for Malaria Venture and the National Institutes of Health for supporting our efforts in developing 4(1H)-quinolones with antimalarial activity. In particular, we are grateful for MMV awards 08/0068, 11/0022 and 16/00421 and NIH awards GM097118 and AI144464.
Conflict of interest
The authors declare no conflict of interest.