Quinolin-(1H)-imines as a new chemotype against leishmaniasis: biological evaluation and mechanistic studies

Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC50 values against intracellular L. infantum parasites in the submicromolar range (1h: IC50 0.9 M and 1n: IC50 0.7 M) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.This work was funded by the Portuguese Foundation for Science and Technology (FCT, Portugal) under the scope of the strategic funding of UIDB/04469/2020 unit, by the BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte 2020 Programa Operacional Regional do Norte, and by Fundação para a Ciência e Tecnologia through project grants number UID/DTP/04138/2019, PTDC/QEQ-MED/7097/2014, PTDC/MED-FAR/30266/2017, and PTDC/MED-QUI/30021/2017. It also received support from NORTE-01-0145-FEDER-000012 Structured Program on Bioengineered Therapies for Infectious Diseases and Tissue Regeneration, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FCT provided additional support to H.C. and A.S.R. (Investigator FCT contracts number IF/01244/2015 and IF/01034/2014, respectively) and to A.G.G.A. (contract number 373 SFRH/BD/93766/2013). We acknowledge the support of the i3S Scientific Platform BioSciences Screening, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122) and PT-OPENSCREEN.