Abstract
AbstractThe fragmentation pattern of certain isatin-based compounds was carried out using collision-induced dissociation inside the triple quadrupole mass analyzer. These data were used as a clue for the identification of metabolites of the recently reported isatin-based antiproliferative agent, namely, N′-[5-bromo-1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-5-methoxy-1H-indole-2-carbohydrazide (1) in rat liver microsomes (RLMs) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Prediction of the vulnerable sites for metabolic pathways in compound 1 was performed by WhichP450 module of StarDrop software. In vitro metabolites for compound 1 were identified with the aid of rat liver microsomes. The in silico data were utilized as a guide for the practical work. Compound 1 was metabolized into three (hydroxylated, reduced and O-demethylated) metabolites in RLMs in the presence of NADPH. The chemical structures of those metabolites were elucidated, and the metabolic pathways were proposed by comparing the fragmentation pattern of the isatin–indole conjugates 1–7. The data presented in this paper provided useful information on the effect of different substituents on the ionization/fragmentation processes and can be used in the characterization of isatin derivatives. In silico toxicity assessments for the title compounds 1–7 and for the metabolites of compound 1 were conducted utilizing the deductive estimation of risk from existing knowledge (DEREK) module of StarDrop software.
Highlights
Cancer is a serious public health burden worldwide, and there is an increase in the mortality rate in less economically developed countries [1]
The outcomes were presented by the pie chart that was used for indication of the most likely CYP450 isoforms that have a principal role in the metabolism of compound 1
Fragmentation of isatin-indole conjugates 1–7 yielded the same fragmentation pattern as it gave one fragment ion at m/z = 174 that represented the breakage of the carbohydrazide bond
Summary
Cancer is a serious public health burden worldwide, and there is an increase in the mortality rate in less economically developed countries [1]. Isatin and indole are privileged scaffolds because they are incorporated in myriad compounds endowed with various bioactivities including anticancer agents [3,4,5] In view of these premises and as a part of our interest to develop new potent anticancer candidates, we were inspired to synthesize the isatin-based compounds 1–7 as potent antiproliferative compounds. The structural alerts in the chemical structures of compounds 1–7 and in the metabolites of compound 1 were obtained using deductive estimation of risk from the existing knowledge (DEREK) module of StarDrop software [20,21] These alerts could be used as a new strategy for reducing the side effects of the newly developed bioactive compounds without affecting their pharmacological activity by incorporating targeted modifications to improve their safety while retaining their efficacy. The in silico toxicity assessments of compounds 1–7 were performed using DEREK software
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