The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).
A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC 50 values ranging from 3 -5 μM. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K I values ranging between 2 and 11 μM. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme.
The naphthoquinone ring is almost perpendicular [dihedral angle 71.02 (3)°] to the phenyl group of the title compound, C17H9Cl2NO3, while the dihedral angle between the amide group and the 4-chlorophenyl ring is 21.9 (2)°. The conformation of the N—H and C=O bonds are anti to each other. N—H⋯Cl hydrogen bonds link the molecules into chains in the a-axis direction. In addition, these chains are linked by weak intermolecular C—H⋯O interactions.
In the title compound, C18H18ClNO4, the imide group with its two alkyl substituents is approximately perpendicular to the plane of the naphthoquinone ring system [dihedral angle = 78.5 (1)°]. Further, the imide carbonyl groups are oriented in an anti sense. In the crystal, the substituted naphthoquinone rings form π–π stacks in the a-axis direction [perpendicular centroid–centroid distance = 3.209 (2) Å and slippage = 4.401 Å].
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