Abstract
New series of caffeine-8-(2-thio)-propanoic hydrazid-hydrazone derivatives were designed and synthesized. The targed compounds were obtained in yields of 51 to 96% and their structures were elucidated by FTIR,1H NMR,13C NMR, MS and microanalyses. All of the compounds were found to be “drug-like” as they fulfill the criteria of drug-likeness, which includes the MDDR-like rule. The tested compounds were subjected toin silicoprediction of substrate/metabolite specificity and Drug Induced Liver Injury (DILI). The prediction for indicated that the evaluated compounds would most probably act as CYP1A2 substrates. The performedin vitrostudies didn’t reveal statistically significant hepatotoxicity of the tested compounds, probably due to the pro-oxidant effects expressed on sub-cellular (isolated rat liver microsomes) level. The obtained experimental results confirmed the predicted low hepatotoxicity for the tested structures. Based on these results the compounds may be considered as promising structures for design of future molecules with low hepatotoxicity.
Highlights
Caffeine (1,3,7-trimethylxanthine) is a naturally occurring compound and one of the methylxanthines classified as a member of the alkaloid class of natural compounds
Based on some literary data, in addition, we set as purpose to evaluate the effects of the newly synthesized compounds on isolated rat liver microsomes as a model of hepatotoxicity on subcellular level, applying the level of generated malondialdehyde (MDA) in the rat liver microsomes as a measure of the hepatotoxicity
The starting 8-bromocaffeine (1) was obtained using oxidative bromination of caffeine according to protocol, described by Mitkov et al (Mitkov et al 2012)
Summary
Caffeine (1,3,7-trimethylxanthine) is a naturally occurring compound and one of the methylxanthines classified as a member of the alkaloid class of natural compounds. Caffeine and its derivatives in human liver are metabolized by the cytochrome P450 oxidase enzyme system (in particular by the CYP1A2 isoenzyme (Bloomer et al 1995)). The role of caffeine in lipid peroxidation is varied and possibly depends on the dose of caffeine ingested Acylhydrazone derivatives are another molecular scaffold, on the basis of which new biologically active compounds can be generated. Correlation analysis is applied to study metabolic pathways in the context of enzymatic topology (Barcelos et al 2014), where malondialdehyde (MDA) is known to be the most frequently used biomarker of lipid peroxidation and oxidative stress evaluation. Based on some literary data, in addition, we set as purpose to evaluate the effects of the newly synthesized compounds on isolated rat liver microsomes as a model of hepatotoxicity on subcellular level, applying the level of generated malondialdehyde (MDA) in the rat liver microsomes as a measure of the hepatotoxicity
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