A Comprehensive Review of 4(1H)-Quinolones and 4(1H)-Pyridones for the Development of an Effective Antimalarial

Abstract

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.

Antimalarial Drugs with Quinoline Nucleus and Analogs

“…Replacing the quinoline ring with tricyclic isosteres such as a pyridoquinoline (Aza-acridine) or fluorene ring in compounds like pyronaridine and lumefantrine (Figure 5) has led to increased antimalarial activity. The presence of these isosteric nuclei gives these molecules special features in terms of their mechanism of action [2,4,13,16,18].…”

“…• The pyronaridine is an aminoalkoxy derivative having an aza-acridine core that would act as a facilitator of pi-pi interactions, helping to block the biopolymerization of β-hematin into hemozoin, and thus facilitating the accumulation of toxic hematin in the digestive vacuole of the parasite [2,4,13,16,18].…”

“…• The fluorene ring of lumefantrine would play a key role by increasing the solubility of the molecule in lipids, which facilitates its incorporation into the membranes of the parasites responsible for malaria. This interaction with parasitic membranes contributes to its accumulation in fatty tissue and prolongs the half-life of lumefantrine to 4-6 days [2,4,13,16,18].…”

“…This molecule exhibits improved pharmacokinetic properties, such as better absorption and a longer half-life than chloroquine. It is used in combination with artemether as a first-line treatment for uncomplicated malaria [2,4,13,16,18].…”

Theoretical investigation of tautomerism of 2- and 4-pyridones: origin, substituent and solvent effects

“…24 2-Pyridone is also a constituent of many biologically active natural products and pharmaceuticals, 25 DNA base analogue, 26 an important building block in synthesis 27 and shows the potential to direct molecular association by formation of hydrogen bonds. 28 The 4-pyridone structure can also be found in biologically active compounds, 29 in synthetic building blocks 30 and self-assembling building blocks, forming hydrogen bonds with extraordinary stability. 31…”