Inhibicija dezoksiribonukleaze I derivatima tiazolidina, benzimidazola, 4H- hromena i 5,6,7,8-tetrahidrobenzo[4,5] tieno[2,3-d]pirimidina u in vitro uslovima

Abstract

In this doctoral dissertation the inhibition of deoxyribonuclease I by the derivatives of thiazolidine, benzimidazole, 4H-chromene and 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine was evaluated in vitro. As a result, 23 compounds, out of 91 tested, inhibited DNase I with IC50 values below 200 μM, including ten thiazolidine, four benzimidazole, one 4H-chromene, and eight 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. These compounds were more effective DNase I inhibitors than crystal violet (IC50 > 300 μM), used as a positive control. According to the Lineweaver-Burk plots, some of the most effective DNase I inhibitors show non-competitive type of inhibition. The intermolecular interactions of the tested compounds with DNase I were predicted by molecular docking studies. To provide a more complete picture of possible therapeutic applications of the investigated thiazolidines, benzimidazoles, 4H-chromenes and 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines that inhibited DNase I with IC50 values below 200 μM, in silico study of their physico-chemical, biopharmaceutical, pharmacokinetic, and toxicological properties was performed. Most DNase I inhibitors fulfilled Lipinski’s and Veber’s rules predicting good oral bioavailability in in vitro/in vivo conditions. All compounds were predicted as able to be absorbed by intestine, as well as permeable across blood-brain barrier. Most of the tested derivatives could be preliminary classified as biopharmaceutical class I and/or II. The investigated DNase I inhibitors are generally predicted as slightly toxic and non-carcinogenic compounds, without risk of mutagenic, tumorigenic and/or irritant effects. The general conclusion of this doctoral dissertation is that the most effective DNase I inhibitors from the groups of the investigated thiazolidines, benzimidazoles, 4H-chromenes and 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines represent a good basis for the development of novel and more efficient DNase I inhibitors with potential therapeutic applications, considering the importance of DNase I in the pathophysiology of numerous disease conditions. Since there is no DNase I inhibitor defined as a "gold standard", the tested compounds could represent a new ones in future research.