Quinoline-piperazine molecular hybrids as potential antimalarial agents

Malaria is one of the most prevalent infectious diseases worldwide, posing a significant threat in the malaria-endemic areas. The rapid emergence of Plasmodium strains resistant to the existing antimalarial drugs underscores the necessity for discovering the next generation of antimalarial drugs with reduced resistance and enhanced potency. Quinoline-based compounds have been long recognized for their remarkable antimalarial efficacy due to their ability to interfere with heme detoxification within the parasites and have been extensively modified to generate molecules with improved pharmacological potential and overcome the resistance. Among the various strategies employed, the incorporation of piperazine moiety has gained considerable attention, as it can improve pharmacokinetic properties, molecular flexibility, and target interactions. Consequently, quinoline-piperazine hybrids have emerged as promising candidates with enhanced antimalarial potential. This review underscores recent advances in the development of quinoline-piperazine hybrids as antimalarial agents, emphasizing their activity against chloroquine-sensitive and resistant Plasmodium falciparum strains. In addition, structure-activity relationship (SAR) trends influencing potency, selectivity, and resistance profiles are discussed. These insights will facilitate the rational design and development of novel chemical entities as next-generation antimalarials.