Design, synthesis and biological evaluation of new quinoxaline 1,4-di-N-oxide and arylamino alcohols derivatives as antimalarial agents

Resum

Malaria continues to be one of the major tropical diseases affecting the entire world. Nearly half of the world's population, distributed in 91 countries, is at risk of being infected. In 2016 alone, 216 million cases and 445,000 deaths were reported globally, mostly those of small African children aged under five years. Most malaria cases were in WHO African Region representing the 90% of cases. P. falciparum and P. vivax are responsible for the most significant impact on public health, being P. falciparum the deadliest and the most prevalent malaria parasite in Africa. This work is an effort to contribute to the global fight against malaria disease. Due to high costs, high rates of failure and the considerable time it takes to develop new antimalarial drugs, the study of classic antimalarial drugs, or drug repurposing, is a valid approach. Based on the previous great results of quinoxaline 1,4-di-N-oxide (QdNO) and 1-aryl-3-substituted propanol derivatives (APD) obtained by our group and with the aim of exploring the scope of these derivatives as antimalarial drugs, we decided to focus our work on the development and optimization of potent antimalarial agents, by selecting these two chemical families. The extensive literature search about QdNO and APD, and their use against malaria, have guaranteed the development of active molecules. Throughout the present work, three design strategies have been applied: classical SAR exploration, hybridization concept, and bioisosteric replacements. In all cases, the strategies have been implemented taking into account the drug-likeness profile of the virtual candidates (in silico ADMET filters), their synthetic viability, and the cost-effectiveness of the reagents. The Beirut and Mannich reactions were adapted and optimized under microwave conditions, reducing costs and achieving time efficiency in comparison with the traditional reflux method. No product in this work has required more than 4 step reactions. In total, twenty-five QdNO and fifty APD were evaluated against chloroquine sensible (3D7 and D6) and multidrug resistance (FCR-3 and C235) strains of P. falciparum. Additional studies such as liver stage and sporogony inhibition, target exploration, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of QdNO and APD as promising antimalarial compounds. Final results are grouped into 5 scientific publications which can be consulted and examined