Title
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
Creator
Kolarević, Ana N. 1989-
Copyright date
2019
Object Links
Select license
Autorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
License description
Dozvoljavate samo preuzimanje i distribuciju dela, ako/dok se pravilno naznačava ime autora, bez ikakvih promena dela i bez prava komercijalnog korišćenja dela. Ova licenca je najstroža CC licenca. Osnovni opis Licence: http://creativecommons.org/licenses/by-nc-nd/3.0/rs/deed.sr_LATN. Sadržaj ugovora u celini: http://creativecommons.org/licenses/by-nc-nd/3.0/rs/legalcode.sr-Latn
Language
Serbian
Cobiss-ID
Theses Type
Doktorska disertacija
description
Datum odbrane: 01.07.2019.
Other responsibilities
mentor
Šmelcerović, Andrija 1973-
predsednik komisije
Kocić, Gordana
član komisije
Agbaba, Danica
član komisije
Milić, Nataša
član komisije
Tasić-Kostov, Marija
Academic Expertise
Medicinske nauke
University
Univerzitet u Nišu
Faculty
Medicinski fakultet
Group
Katedra za farmaciju
Alternative title
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
Publisher
[A. N. Kolarević]
Format
137 listova
description
Beleška o autoru: listovi 131-132;
Bibliografija: 118-130.
description
Pharmaceutical sciences;
Pharmaceutical chemistry and Biopharmacy.
Abstract (en)
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.
Authors Key words
Dezoksiribonukleaza I, Inhibicija, Tiazolidini, Benzimidazoli, 4H-Hromeni, 5,6,7,8-Tetrahidrobenzo[4,5]tieno[2,3-d]pirimidini, In silico studija
Authors Key words
Deoxyribonuclease I, Inhibition, Thiazolidines, Benzimidazoles, 4H-Chromenes, 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines, In silico study
Classification
577.152.1:547.1
Subject
B 740
Type
Tekst
Abstract (en)
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.
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