Desscription

The development of antimalarial drugs has traditionally focused on quinoline derivatives because of its strong ability to combat Plasmodium species, which cause malaria. Mefloquine, quinine and chloroquine are among the medications that have been essential in the fight against the illness for many years. To improve their effectiveness, reduce toxicity and get around resistance mechanisms, quinoline derivatives must be structurally optimized in light of the rise of drug-resistant strains of Plasmodium falciparum and Plasmodium vivax. Quinoline-based antimalarials are based on their core structure, which offers a framework that may be altered chemically. In order to improve biological activity and pharmacokinetic characteristics, the optimization procedure frequently concentrates on changing substituents at strategic locations in the quinoline nucleus. For example, one of the first and most effective quinoline derivatives, chloroquine, works against malaria by preventing the Plasmodium feeding vacuole's heme detoxification.

The Parasite's Chloroquine Resistance Transporter (PfCRT) mutations, however, have been linked to widespread resistance to chloroquine. Therefore, structural optimization of chloroquine has sought to circumvent resistance by adding bulky groups or altering its side chain to avoid PfCRT identification. The creation of hydroxychloroquine and amodiaquine, which added hydroxyl and amino groups, respectively, at certain locations, represented a major advancement in the discipline. While keeping a good safety record, these changes increased their efficacy against strains that were resistant to chloroquine.

Similarly, it has been demonstrated that adding halogen atoms like fluorine or chlorine at certain locations improves the quinoline derivatives' lipophilicity and membrane permeability, which increases their capacity to concentrate in the parasite's feeding vacuole. The popular quinoline-based antimalarial drug mefloquine serves as an example of how resistance and side effects may be addressed by structural optimization. Mefloquine's effectiveness against multidrug-resistant Plasmodium strains was enhanced by the addition of a trifluoromethyl group and changes to the basic amine moiety. Using hybrid structures has become a viable way to increase the antimalarial properties of quinoline derivatives. In order to create synergistic effects, hybrid compounds mix the quinoline nucleus with different pharmacophores. As an illustration, quinoline-artemisinin hybrids combine the heme-binding qualities of quinolines with the strong antimalarial action of artemisinin. These hybrids' diverse mechanisms of action not only increase efficacy but also lessen the possibility of resistance development. The combination of quinolines with other bioactive scaffolds, including triazoles or aminoquinolines, has also produced variants that are more effective against resistant bacteria.

Antimalarial medication research has expanded due to the investigation of non-classical quinoline derivatives, including azaquinolines and quinoline-carboxamides. These derivatives add nitrogen atoms or other connections to improve activity and decrease cross-resistance, departing from the conventional quinoline structure. Beyond increasing effectiveness and overcoming resistance, structural optimization plays a more significant function. Additionally, it includes the creation of derivatives with more extensive medicinal characteristics. The development of quinoline compounds that exhibit action against several phases of Plasmodium life, such as the liver and gametocyte stages, might greatly improve attempts to eradicate malaria. Global health programs also depend on compounds that are compatible with vulnerable groups, such children and pregnant women and have lower toxicity profiles.

In conclusion, the development of antimalarial drugs continues to rely heavily on the structural optimization of quinoline derivatives. The development of next-generation antimalarial drugs that can tackle the urgent problems of resistance and treatment accessibility is made possible by the combination of hybrid structures, prodrug methods and innovative scaffolds. The improvement of quinoline derivatives will surely be essential in the continuous battle against malaria, which continues to pose a danger to world health.