**3. Conclusion**

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*H*)-quinolones and 4(1*H*)-pyridones both display potential of developing into potent antimalarial agents due to recent re-evaluation of old 4(1*H*)-quinolones and 4(1*H*)-pyridones possessing antimalarial activity. These historical quinolones display promising activity against both erythrocytic and exo-erythrocytic stages of the parasite. Various research groups invested their efforts and resources to optimize these 4(1*H*)-pyridones or 4(1*H*)-quinolones since it is perfect for the malaria eradication initiative.

The frontrunner compound for 4(1*H*)-pyridone is **13**, which displayed singledigit nanomolar activity against the erythrocytic stage with excellent solubility. However, after entering first-time in human study, **13** displayed toxicity, which terminated the study.

Unlike 4(1*H*)-pyridones, 4(1*H*)-quinolones (P4Qs, ELQs, THAs, TDR analogues, and HDQ analogues) lack cytotoxicity. This is essential to develop a species-specific inhibitor. The frontrunner compounds for ELQ/P4Q are **22** and **23**, which displayed low nanomolar activity for both the erythrocytic and exo-erythrocytic stages. In addition to this, **22** and **23** displayed activity against the transmitting stages, making these molecules especially important. The frontrunner compounds for PEQ are **17**, **18,** and **32**, which displayed low nanomolar activity for both the erythrocytic and liver stages. Another molecule that is promising. The frontrunner compounds for THA are **15** and **16**, which displayed nanomolar activity for the erythrocytic stage. The frontrunner compound for TDR analogues are **26** and **27**, which displayed nanomolar activity for the erythrocytic stage. The frontrunner compound for HDQ analogues are **30** and **31**, which displayed nanomolar activity for the erythrocytic stage.

Since many research teams focus solely on the activity against the blood stage, compounds **22**, **23**, **17**, **18**, and **32** are especially promising, as these display exoerythrocytic activity, along with the erythrocytic activity.

Nevertheless, one major downfall with the development of 4(1*H*)-quinolones and 4(1*H*)-pyridones is the poor aqueous solubility. This prevents proper development of pharmacokinetic profiles for drug candidacy; therefore, failed clinical development and development was halted in the early 80s.

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*H*)-quinolones have a great potential of becoming the next class of antimalarials. These molecules lack toxicity and have acceptable physicochemical properties, aside from solubility. With increased understanding to improve aqueous solubility, it is recommended to continue research on antimalarial quinolones, as they have great potential of becoming orally bioavailable antimalarials.
