Synthesis, physical-chemical and biological properties of 1,8-disubstituted compounds of theobromine. III. 8-Amino-p-chlorobenzyltheobromines

Authors

  • D. G. Ivanchenko
  • M. I. Romanenko
  • A. M. Kamyshny
  • N. M. Polishchuk

DOI:

https://doi.org/10.14739/2409-2932.2014.2.26144

Keywords:

Theobromine, Synthesis, NMR Spectroscopy, Antimicrobial Agents, Antifungal Agents, Antioxidant Effect

Abstract

Introduction. This work is a follow-up to a series of research activities dedicated to the search of biologically active compounds among the xanthine derivatives.

Aim of the Work.Development of simple laboratory-based methods for 8-amino-1-p-chlorobenzyltheobromines synthesis and the study of antioxidant, antimicrobial and antifungal effect of the synthesized compounds.

Materials and Methods of Research.The  melting  point  has  been  determined  with  the  help  of  an  open  capillary method  with  TAP  device  (M).  Elemental  analysis  has  been  performed  with  the helpof the instrument ElementarVario L cube, NMR-spectra have been taken on a spectrometer Bruker SF-400 (operating frequency of 400 MHz, solvent DMSO-d6 or DMSO-d6 + CDCl3, internal standard – TMS). These data correspond to thecalculated elemental analysis.

The synthesis of 8-aminosubstituted 1-p-chlorobenzyltheobromine (2,3).Mixture 0.01 mole of8-bromo-1-p-chlorobenzyltheobromine (1), 0.03 mole of pyrrolidine (2) or piperidine (3), 40 ml of cellosolve is boiled during 4 hours, then it is allowed to steam out dry in a vacuum. Dry residue is processed with water, then residual matter which has been formed is filtered out, washed with water and recrystallized from the aqueous ethanol.

The synthesis of 8-amino-1-p-chlorobenzyltheobromines (4-7). Mixture 0.01 mole of initial compound (1), 0.03 mole of the respective amine and 40 ml of cellosolve is boiled during 4 hours, thenit is allowed to cool down and is diluted with water. After this, residual matter which has been formed is filtered out, washed with water and aqueous propanol-2 and recrystallized from the water ethanol.

Molecular descriptors have been calculated using the computer programs ALOGPS and DRAGON, whereas biological properties of the synthesized compounds have been calculated with the help of GUSAR and ACD / Percepta Platform. Antioxidant activity (AOA) has been studied in vitro applying the method of nonenzymic initiation of free-radicaloxidation. For the initial screening study of the newly-synthesized substances benchmark testing-cultures of both gram-positive and gram-negative bacteria have been used, which belong to clinically significant groups of infectious agents which are differing by their morpho-physiological properties,.

Results and their discussion. Through the reaction of 8-bromo-1-p-chlorobenzyltheobromine with secondary heterocyclic amines (pyrrolidine, morpholine, hexamethylenimine, piperidine and its derivatives) in cellosolve environment a range of 8-heteryle-substituted (2-7) has been obtained which was not described earlier.

All the obtained compounds satisfy to the Lipinski's ‘rule of five’, which proves the viability of further research activities. The application of ACD/Percepta Platform has allowed to calculate the absorption characteristics, permeability via blood-brain barrier, as well as establish probable transport forms of blood of the synthesized compounds. Assisted by computer programs GUSAR and ACD / Percepta Platform, further on there has been calculated the acute toxicity rate for rats and mice.

Among the synthesized substances, 8-(hexahydroazepin-1-yl)-1-p-chlorobenzyltheobromine (6) has appeared to be the most active antioxidant, being more active than tiotriazolini while ranking below the ascorbic acid as per this indicator. It has beenfound, that among the synthesized 8-aminosubstituted 1-p-chlorobenzyltheobromine there is no evidence of prospective compounds with antibacterial activity in reference to E. coli, S. aureus and P. aeruginosa.

Conclusion. There have been developed available laboratory-based methods for the synthesis of 8-aminosubstituted 1-p-chlorobenzyltheobromine, the structure of which has been proved by data obtained from elemental analysis and NMR- spectroscopy. Molecular (LogP, TPSA, A) and pharmaceutical (Pe, Ka, PPB, LogKaHSA, LogPS, LogPB, Log(PS*fu)) descriptors have been calculated for forecasting the properties of obtained substances. Acute toxicity indexhas been calculated too. Finally, antioxidant, antimicrobial and antifungal effect of the synthesized compounds has been studied and priorities for further search of biologically active compounds have been set out.

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How to Cite

1.
Ivanchenko DG, Romanenko MI, Kamyshny AM, Polishchuk NM. Synthesis, physical-chemical and biological properties of 1,8-disubstituted compounds of theobromine. III. 8-Amino-p-chlorobenzyltheobromines. Current issues in pharmacy and medicine: science and practice [Internet]. 2014Jul.8 [cited 2024Jun.21];(2). Available from: http://pharmed.zsmu.edu.ua/article/view/26144

Issue

Section

Pharmacognosy and chemistry of natural compounds