Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds
No Thumbnail Available
Date
2020
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery. © 2020 Deutsche Pharmazeutische Gesellschaft
Description
Keywords
Animals , Antiprotozoal Agents , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors , Leishmania major , Macrophages , Mice , Models, Molecular , Molecular Structure , Oxidoreductases , Parasitic Sensitivity Tests , Pyrimidines , RAW 264.7 Cells , Structure-Activity Relationship , Thiazoles , 2 bromo n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide , 2 chloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide , 2,4 dichloro n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)benzamide , 4 chloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide , amphotericin B , antileishmanial agent , enzyme inhibitor , meglumine antimonate , methotrexate , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 2 trifluoromethylbenzamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 3 phenylpropionamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 fluorobenzamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 methoxybenzamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 methylbenzamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 nitrobenzamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)cinnamamide , n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)furan 2 carboxamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl) 2 iodobenzamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 fluorobenzamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 methoxybenzamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 methylbenzamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)acetamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)butyramide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)isobutyramide , n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)propionamide , n (5 chlorothiazolo[5,4 d]]pyrimidin 2 yl)cyclohexane carboxamide , oxidoreductase , pteridine reductase 1 , pyrimidine derivative , unclassified drug , antiprotozoal agent , enzyme inhibitor , oxidoreductase , pteridine reductase , pyrimidine derivative , thiazole derivative , amastigote , animal cell , antileishmanial activity , Article , controlled study , drug cytotoxicity , drug design , drug synthesis , enzyme inhibition , IC50 , in vitro study , Leishmania major , Leishmania tropica , molecular docking , molecular dynamics , nonhuman , priority journal , promastigote , protein expression , RAW 264.7 cell line , animal , chemical structure , chemistry , dose response , drug effect , drug sensitivity , enzymology , macrophage , metabolism , molecular model , mouse , structure activity relation , synthesis