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Water-soluble oxadiazole-based HKT inhibitor library, comprising a new class of compounds for control of Aedes aegypti dissemination, act as competitive HKT enzyme inhibitors, promoting accumulation of the toxic metabolite 3-hydroxykynurenine in insect organism.

Arboviral infections such as Zika, chikungunya, dengue, and yellow fever pose significant health problems globally. The population at risk is expanding with the geographical distribution of the main transmission vector of these viruses, the Aedes aegypti mosquito. The global spreading of this mosquito is driven by human migration, urbanization, climate change, and the ecological plasticity of the species. Currently, there are no specific treatments for Aedes -borne infections. One strategy to combat different mosquito-borne arboviruses is to design molecules that can specifically inhibit a critical host protein. We obtained the crystal structure of 3-hydroxykynurenine transaminase (AeHKT) from A. aegypti , an essential detoxification enzyme of the tryptophan metabolism pathway. Since AeHKT is found exclusively in mosquitoes, it provides the ideal molecular target for the development of inhibitors. Therefore, we determined and compared the free binding energy of the inhibitors 4-(2-aminophenyl)-4-oxobutyric acid (4OB) and sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) to AeHKT and AgHKT from Anopheles gambiae , the only crystal structure of this enzyme previously known. The cocrystallized inhibitor 4OB binds to AgHKT with K i of 300 μM. We showed that OXA binds to both AeHKT and AgHKT enzymes with binding energies 2-fold more favorable than the crystallographic inhibitor 4OB and displayed a 2-fold greater residence time τ upon binding to AeHKT than 4OB. These findings indicate that the 1,2,4-oxadiazole derivatives are inhibitors of the HKT enzyme not only from A. aegypti but also from A. gambiae .

Diabetes is a chronic metabolic disorder characterized by insufficient insulin production, the cells’ inability to use this insulin, or a combination of both, leading to secondary complications such as diabetic neuropathy and retinopathy. One way to prevent or control such complications is the use of aldose reductase (AR) inhibitors. In this work, we synthesized and tested new candidates for human AR inhibition containing a 2-thiopyrimidin-4-one heterocycle as a central ring. The fifteen derivatives were tested in vitro and their binding modes were evaluated via molecular docking simulations. AR inhibition assays showed that all synthesized compounds were able to inhibit the AR enzyme at 50 μM. From these results, seven compounds were noteworthy and had their half maximal inhibitory concentration (IC50) values estimated, ranging from 2.0 to 14.5 μM. Molecular docking simulations showed that these compounds bind specifically to the catalytic subpocket and the results indicate a good association between in vitro and in silico studies.

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