QUANTITATIVE STRUCTURE-HEPATOTOXICITY ASSESSMENT OF SERIES ARYLPIPERAZINE-N1-SUBSTITUTED THEOBROMINE DERIVATIVES
MAGDALENA KONDEVA-BURDINA 1, IVA VALKOVA 2, LILY ANDONOVA 3, MAYA GEORGIEVA 3*, VIRGINIA TZANKOVA 1, ALEXANDER ZLATKOV 3
1Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University-Sofia, 2 “Dunav” str., 1000, Sofia, Bulgaria
2Department of Chemistry, Faculty of Pharmacy, Medical University-Sofia, 2 “Dunav” str., 1000, Sofia, Bulgaria
3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University-Sofia, 2 “Dunav” str., 1000, Sofia, Bulgaria
*corresponding author: maya.bg77@gmail.com

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Abstract:
In this work series new theobromine derivatives containing an arylpiperazine moiety at N1 with established antioxidant and antiproliferative activities were evaluated for their hepatotoxic effects on cellular and sub-cellular level. On isolated rat hepatocytes, 3c and 4c expressed lowest toxicity, while 3f and 4f showed highest toxicity. The same compounds 3f and 4f showed the most evident pro-oxidant effect in a lipid peroxidation model on rat liver microsomes, followed by 3b and 4b, while the other compounds didn’t reveal statistically significant pro-oxidant effects. The performed quantitative structure-toxicity relationship (QSTR) analysis show that increased lipophilicity of the tested compounds positively correlates to their hepatotoxicity. Opposite, the presence in the structure of highly positive H-atoms and strongly negative oxygen, possibly originating from hydrogen bond donor groups, are associated with reduced hepatotoxicity.

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