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The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
Phthalazine derivatives containing imidazole rings showed remarkable anti-T. cruzi activity in an immunodeficient-mouse model of infection (Sánchez-Moreno et al. 2012). The introduction of a nitro group on such derivatives led to the 8-nitrosubstituted compound (57) (Figure 14) which was more active in vitro against T. cruzi and less toxic against Vero cells than the reference drug benznidazole (9). The SI value was 47-fold better for (57) than the reference drug in amastigote forms. It also remarkably reduced the infectivity rate in Vero cells and decreased the reactivation of parasitemia in immunodeficient mice (Olmo et al. 2015). Structure and in vitro anti-T. cruzi activity of some nitroaromatics.
Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Cristiano Mota, Teresa Santos-Silva, Mineko Terao, Enrico Garattini, Maria João Romão, Silke Leimkühler
AOXs metabolize not only drugs, but also various molecules of toxicological interest, such as the environmental pollutants, phthalazines, which are classical AOX substrates. Different AOXs oxidize phthalazine into 1-hydroxy-phthalazine, which undergoes irreversible isomerization into 1-phthalazinone (Beedham et al., 1990; Coelho et al., 2015; Stubley et al., 1979). Phthalazine administration increases rabbit liver AOX activity, demonstrating that the compound is not only a substrate but also an AOX inducer (Johnson et al., 1984). Another example of toxicologically significant AOX substrate is caffeine (Castro et al., 2001) (Fig. 13.5). Vanillin, a sweetener, is an aromatic aldehyde which is oxidized into the corresponding carboxylic acid by AOXs (Fig. 13.5). A final AOX substrate is acetaldehyde, the primary ethanol metabolite, which is the reason as to why this class of enzymes has been implicated in the liver toxicity associated with alcohol consumption. The major mechanism deemed to be at the basis of AOX-dependent liver toxicity is the production of reactive oxygen species during acetaldehyde oxidation (Shaw and Jayatilleke, 1990). However, the results obtained in AOX deficient DBA/2 and AOX proficient CD1 mice are not consistent with this hypothesis. In fact, CD1 and DBA/2 livers do not contain detectable levels of AOX3 and show markedly lower amounts of AOX1 relative to CD1 animals. Yet CD1 and DBA/2 mice were endowed with the same amounts of liver acetaldehyde after ethanol administration (Vila et al., 2004). This supports the concept that neither liver AOX1 nor AOX3 contributes to acetaldehyde metabolism in mice. The finding is also in line with the fact that acetaldehyde is a poor AOX1/AOX3 substrate.
Genetic variants of aldehyde oxidase (AOX) 1 in cynomolgus and rhesus macaques
Published in Xenobiotica, 2021
Yasuhiro Uno, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki
Among the variants that were observed at relatively high frequencies, eight were selected for functional analysis. To assess the functional significance of non-synonymous variants, wild-type AOX1 and eight selected variant proteins (D138H, P605L, R688Q, I1105T, E1132D, V1139I, I1185T, and V1338I) were heterologously expressed in E. coli. Among these variant proteins, P605L and V1338I AOX1 variants showed substantially lower phthalazine and carbazeran oxidation activities than those of wild-type AOX1 (Figure 1(A,B)). Kinetic parameters for phthalazine and carbazeran oxidation by wild-type, P605L, and V1338I AOX1 (Figure 2(A,B)) were determined. The Km and Vmax values for phthalazine oxidations were 21 ± 3 µM and 0.49 ± 0.02 min−1 for wild-type AOX1, 17 ± 7 µM and 0.08 ± 0.01 min−1 for the P605L variant, and 76 ± 15 µM and 0.14 ± 0.01 min−1 for the V1338I variant, respectively. For carbazeran oxidations, the Km and Vmax values were 1.4 ± 0.8 µM and 0.019 ± 0.001 min−1 for wild-type AOX1, 3.6 ± 2.2 µM and 0.005 ± 0.001 min−1 for the P605L variant, and 1.5 ± 0.9 µM and 0.013 ± 0.001 min−1 for the V1338I variant, respectively. The amino acid substitutions in AOX1 affected the Km and Vmax values for phthalazine and carbazeran oxidations in different ways under the present conditions.
Methoxsalen as an in vitro phenotyping tool in comparison with 1-aminobenzotriazole
Published in Xenobiotica, 2019
Raghava Choudary Palacharla, Parusharamulu Molgara, Hanumanth Rao Panthangi, Rajesh Kumar Boggavarapu, Arun Kumar Manoharan, Ranjith Kumar Ponnamaneni, Devender Reddy Ajjala, Ramakrishna Nirogi
The inhibition potential of ABT and methoxsalen against AO enzyme was evaluated by using phthalazine oxidation as a marker reaction. ABT (1000 mM) and methoxsalen (300 mM) were prepared in water:acetonitrile (1:1 v/v) and DMSO, respectively. The incubation mixture contained phthalazine (substrate) in phosphate buffer (100 mM, pH 7.4) in an incubation volume of 178 µL. Serial dilutions (2 µL) of the inhibitors were added to the well designated for ABT and Methoxsalen in triplicates. Reactions were initiated by the addition of cytosol (0.5 mg.mL−1) to a final incubation volume of 200 µL such that the final protein concentration in the assay was 0.05 mg.mL−1). The incubations were conducted in triplicates and were commenced for 10 min. At the end of 10 min incubation, the reactions were terminated by adding 120 µL of the reaction mixture to 240 µL of acetonitrile containing 4-phenyl-1-phthalazone, the internal standard. The samples were centrifuged at 4000 rpm for 20 min and an equal volume (120 µL) of supernatants was mixed with equal volumes of 0.1% formic acid in water. All the samples were analyzed by LC-MS/MS for phthalazone formation.
Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Salwa Elmeligie, Asmaa M. Aboul-Magd, Deena S. Lasheen, Tamer M. Ibrahim, Tamer M. Abdelghany, Sohair M. Khojah, Khaled A. M. Abouzid
Eighteen of the submitted phthalazines (5b, 5d, 6b, 6e, 7b, 7e, 8a, 8d, 8f, 8g, 8h, 8i, 13a, 13b, 13c, 16a, 16d, and 17a) were selected by NCI under drug discovery programme for screening against the full NCI 60 cell panel at single dose 10 µM. Among the investigated 18 compounds, eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) were selected by NCI for further screening at 5-log dose molar range due to their prominent cell growth inhibition against various cell lines.