Abstract
Aiming to obtain preliminary information on the toxicity, stability and pharmacokinetic behavior of a group of 12 methylxanthines, containing an arylpiperazine moiety at N1, we applied three virtual methods for prediction. The online hazard-screening tool-PBT profiler was used for toxicity evaluation. The pharmacokinetic behavior and drug like properties of the tested compounds were predicted by two online platforms: Molinspiration Cheminformatics and OSIRIS web-based server. The PBT-profiler tool determined, that the investigated compounds are soil persistent, do not bioaccumulate in the food chain and with the exception of the structures containing bulky bi-phenyl substituents all other molecules are of moderate toxicity. All tested compounds meet Lipinski’s Rule of Five border conditions and have high values for drug likeness and drug score, which makes them suitable for future optimizations.
Highlights
Among the purine derivatives, a great number of studies researches are aimed at modifying the structure of methylxanthines because of their diverse biological activity and their well known clinical application as psychostimulants, bronchodilators, diuretics, vasodilators, antiviral and antineoplastic drugs (Boike, 1990; Husain, 1998; Smith, 1995; Zlatkov, 2010)
It is important to note that this screening approach can be applied with two different aims: 1) to all existing chemicals, even without experimental data, to rank them and highlight the most potentially hazardous while focusing only on those which would need costly experimental tests, 2) to not yet synthesized molecules, for planning, a theoretical deduction in the chemical design, producing potentially environmentally safer and more sustainable alternatives to those molecules that are identified as potentially hazardous (Cassani, 2015)
In the presented research we evaluate the potential risk of a group of 12 methylxanthines, containing an arylpiperazine moiety at N1 (Scheme 1, series 1, compounds 1a-e and series 2, compounds 2a-e) using the online hazard-screening tool-PBT Profiler
Summary
A great number of studies researches are aimed at modifying the structure of methylxanthines because of their diverse biological activity and their well known clinical application as psychostimulants, bronchodilators, diuretics, vasodilators, antiviral and antineoplastic drugs (Boike, 1990; Husain, 1998; Smith, 1995; Zlatkov, 2010). The piperazine nucleus is one of the most important heterocycles exhibiting remarkable pharmacological activities. We are interested in the structural combination of these two fragments as a possibility to obtain new derivatives with biological activity. Of great importance for the use and introduction of newly synthesized molecules as potential drugs is any preliminary information on the toxicity, stability and influence of some structural parameters on the molecule’s pharmacokinetic behavior. Following the necessities and requirements of minimal usage of live animals, any possibility of preliminary identification of toxicity and hazardous properties of new compounds is advisable. The possibility of applying efficient screening systems in order to highlight the compounds predicted as the most hazardous, in particular for the environment is important when using fast and cheap computational tools as good preliminary screening methods to evaluate chemicals for their potential hazards (Sangion, 2016)
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