o:1605 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 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 in in vitro conditions : doctoral dissertation sr 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. Beleška o autoru: listovi 131-132;Bibliografija: 118-130. Datum odbrane: 01.07.2019. Pharmaceutical sciences;Pharmaceutical chemistry and Biopharmacy. 1026399725 91552101 7163 91552100 1026399725 2020-01-27T13:00:26.053Z 45 no 46 mentor Ana N. 1989- Kolarević 2019 63 mentor Andrija 1973- Šmelcerović 2019 63 predsednik komisije Gordana Kocić 2019 63 član komisije Danica Agbaba 2019 63 član komisije Nataša Milić 2019 63 član komisije Marija Tasić-Kostov 2019 137 listova 12683576 http://phaidrabg.bg.ac.rs/o:1605 no yes 4 2020-01-27T13:00:26.320Z 70 Dezoksiribonukleaza I, Inhibicija, Tiazolidini, Benzimidazoli, 4H-Hromeni, 5,6,7,8-Tetrahidrobenzo[4,5]tieno[2,3-d]pirimidini, In silico studija Deoxyribonuclease I, Inhibition, Thiazolidines, Benzimidazoles, 4H-Chromenes, 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines, In silico study 577.152.1:547.1 B 740 1738 18A05 18A0530 2019