A Glimpse at the Quinoline-Hybridization Approach for the Development of New Antimalarials

One of the most fatal infectious diseases, malaria, still poses a threat to about half of the world's population and is the leading cause of death worldwide. The use of artemisinin-based combination therapy has helped to significantly reduce the number of deaths caused by malaria, but the emergence of drug resistance threatens to undo this gain. In a bid to boost adherence, several new combination therapies with effectiveness against drug-resistant parasites are currently being tested in clinical settings. Nevertheless, notwithstanding these gains, malaria must be completely eradicated by a concerted international effort on several fronts. Quinoline-based compounds were the cornerstone of malaria chemotherapy until recently when resistance to these drugs severely hampered efforts to achieve a "Zero Malaria" world. The inappropriate use of available antimalarials is one of the factors responsible for resistance development and treatment failure, warranting the search for new chemical entities and alternative approaches to combat this threat. A vast number of solutions have emerged and one of them, quinoline-hybridization, is an effective method for introducing structural diversity, resulting in molecules with improved biological activities, reduced drug resistance, fewer drug-drug interactions, and improved safety and pharmacokinetic profiles. Choosing the ideal target combination and achieving a balanced activity toward them while preserving drug-like properties are the key challenges in the development of molecular hybrids. This review examines the highlights of quinoline hybridization, with some of the hybrids exhibiting remarkable in vitro and in vivo activities, emphasizing that it is a useful method for developing new anti-malarial lead compounds.