We present a novel series of quinolin-4(1H)-imines as dual-stage antiplasmodials, several-fold more active than primaquine in vitro against Plasmodium berghei liver stage. Among those, compounds 5g and 5k presented low nanomolar IC50 values. The compounds are metabolically stable and modulate several drug targets. These results emphasize the value of quinolin-4(1H)-imines as a new chemotype and their suitable properties for further drug development.

Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including the obligatory developmental phase in the liver, which precedes the erythrocytic stage. We have previously reported that N-Mannich-based quinolon-4(1H)-imines are potent antiplasmodial agents but present several stability liabilities. We now report our efforts to optimize quinolon-4(1H)-imines as dual-stage antiplasmodial agents endowed with chemical and metabolic stability. We report compounds active against both the erythrocytic and exoerythrocytic forms of malaria parasites, such as the quinolon-4(1H)-imine 5p (IC50 values of 54 and 710 nM against the erythrocytic and exoerythrocytic forms), which constitute excellent starting points for further lead optimization as dual-stage antimalarials.

The gas-phase behavior of 12 quinolon-4(1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold.

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In the present study, the levels of Total Phenols compounds (TPC) and the antioxidant capacity of different extracts from leaves of Cassytha filiformis (C. filiformis), Commiphora schlechteri (C. schlechterii), Ochna natalitias (O. natalitia) and Pavetta assimilis (P. assimilis) were evaluated by the Folin-Ciocalteu and ferric ion reduction methods, respectively. The extracts evaluated were prepared with solvents of different polarities (n-hexane, dichloromethane, ethyl acetate and aqueous methanol). The total phenols found in all samples increase with solvent polarity. The reduction power found was linearly proportional to the concentration and is greater the greater the content of total phenolics. All extracts of the species O. natalitia (DCM, EtAcO and MetOH) showed higher antioxidant capacity than the other species. Thus, the promising results found in the present study suggest a high potential of these species as a source for the development of therapeutically useful natural antioxidants.