Istanbullu H.Bayraktar G.Akbaba H.Cavus I.Coban G.Debelec Butuner B.Kilimcioglu A.A.Ozbilgin A.Alptuzun V.Erciyas E.2024-07-222024-07-22202003656233http://akademikarsiv.cbu.edu.tr:4000/handle/123456789/13922A 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 GesellschaftEnglishAnimalsAntiprotozoal AgentsDose-Response Relationship, DrugDrug DesignEnzyme InhibitorsLeishmania majorMacrophagesMiceModels, MolecularMolecular StructureOxidoreductasesParasitic Sensitivity TestsPyrimidinesRAW 264.7 CellsStructure-Activity RelationshipThiazoles2 bromo n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide2 chloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide2,4 dichloro n (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)benzamide4 chloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamideamphotericin Bantileishmanial agentenzyme inhibitormeglumine antimonatemethotrexaten (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 2 trifluoromethylbenzamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 3 phenylpropionamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 fluorobenzamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 methoxybenzamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 methylbenzamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl) 4 nitrobenzamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)cinnamamiden (5 chlorothiazolo[5 4 d]pyrimidin 2 yl)furan 2 carboxamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl) 2 iodobenzamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 fluorobenzamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 methoxybenzamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)2 methylbenzamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)acetamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)butyramiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)isobutyramiden (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)propionamiden (5 chlorothiazolo[5,4 d]]pyrimidin 2 yl)cyclohexane carboxamideoxidoreductasepteridine reductase 1pyrimidine derivativeunclassified drugantiprotozoal agentenzyme inhibitoroxidoreductasepteridine reductasepyrimidine derivativethiazole derivativeamastigoteanimal cellantileishmanial activityArticlecontrolled studydrug cytotoxicitydrug designdrug synthesisenzyme inhibitionIC50in vitro studyLeishmania majorLeishmania tropicamolecular dockingmolecular dynamicsnonhumanpriority journalpromastigoteprotein expressionRAW 264.7 cell lineanimalchemical structurechemistrydose responsedrug effectdrug sensitivityenzymologymacrophagemetabolismmolecular modelmousestructure activity relationsynthesisArticle10.1002/ardp.201900325