Design, synthesis, in vitro – In vivo biological evaluation of novel thiazolopyrimidine compounds as antileishmanial agent with PTR1 inhibition

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dc.contributor.authorIstanbullu H.
dc.contributor.authorBayraktar G.
dc.contributor.authorKarakaya G.
dc.contributor.authorAkbaba H.
dc.contributor.authorPerk N.E.
dc.contributor.authorCavus I.
dc.contributor.authorPodlipnik C.
dc.contributor.authorYereli K.
dc.contributor.authorOzbilgin A.
dc.contributor.authorDebelec Butuner B.
dc.contributor.authorAlptuzun V.
dc.date.accessioned2024-07-22T08:03:06Z
dc.date.available2024-07-22T08:03:06Z
dc.date.issued2023
dc.description.abstractThe leishmaniasis are a group of vector-borne diseases caused by a protozoan parasite from the genus Leishmania. In this study, a series of thiazolopyrimidine derivatives were designed and synthesized as novel antileishmanial agents with LmPTR1 inhibitory activity. The final compounds were evaluated for their in vitro antipromastigote activity, LmPTR1 and hDHFR enzyme inhibitory activities, and cytotoxicity on RAW264.7 and L929 cell lines. Based on the bioactivity results, three compounds, namely L24f, L24h and L25c, were selected for evaluation of their in vivo efficacy on CL and VL models in BALB/c mice. Among them, two promising compounds, L24h and L25c, showed in vitro antipromastigote activity against L. tropica with the IC50 values of 0.04 μg/ml and 6.68 μg/ml; against L. infantum with the IC50 values of 0.042 μg/ml and 6.77 μg/ml, respectively. Moreover, the title compounds were found to have low in vitro cytotoxicity on L929 and RAW264.7 cell lines with the IC50 14.08 μg/ml and 21.03 μg/ml, and IC50 15.02 μg/ml and 8.75 μg/ml, respectively. LmPTR1 enzyme inhibitory activity of these compounds was determined as 257.40 μg/ml and 59.12 μg/ml and their selectivity index (SI) over hDHFR was reported as 42.62 and 7.02, respectively. In vivo studies presented that L24h and L25c have a significant antileishmanial activity against footpad lesion development of CL and at weight measurement of VL group in comparison to the reference compound, Glucantime®. Also, docking studies were carried out with selected compounds and other potential Leishmania targets to detect the putative targets of the title compounds. Taken together, all these findings provide an important novel lead structure for the antileishmanial drug development. © 2022 Elsevier Masson SAS
dc.identifier.DOI-ID10.1016/j.ejmech.2022.115049
dc.identifier.issn02235234
dc.identifier.urihttp://akademikarsiv.cbu.edu.tr:4000/handle/123456789/12131
dc.language.isoEnglish
dc.publisherElsevier Masson s.r.l.
dc.subjectAnimals
dc.subjectAntiprotozoal Agents
dc.subjectLeishmania
dc.subjectLeishmaniasis
dc.subjectMice
dc.subjectMice, Inbred BALB C
dc.subject2,4 dichloro n (5 morpholinothiazolo[5,4 d]pyrimidin 2 yl)benzamide
dc.subject2,4 dichloro n [5 (diethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject2,4 dichloro n [5 (dimethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject2,4 dichloro n [5 (piperidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject2,4 dichloro n [5 (pyrrolidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject3,4 dichloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl)benzamide
dc.subject3,4 dichloro n (5 morpholinothiazolo[5,4 d]pyrimidin 2 yl)benzamide
dc.subject3,4 dichloro n [5 (4 methylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject3,4 dichloro n [5 (dimethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject3,4 dichloro n [5 (piperidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject3,4 dichloro n [5 (pyrrolidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro 3 nitro n [5 (4 methylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro 3 nitro n [5 (diethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro 3 nitro n [5 (dimethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro 3 nitro n [5 (piperidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro 3 nitro n [5 (pyrrolidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro n (5 chlorothiazolo[5,4 d]pyrimidin 2 yl) 3 nitrobenzamide
dc.subject4 chloro n (5 morpholinothiazolo[5,4 d]pyrimidin 2 yl)benzamide
dc.subject4 chloro n [5 (4 methylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro n [5 (diethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro n [5 (dimethylamino)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro n [5 (piperidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subject4 chloro n [5 (pyrrolidin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl]benzamide
dc.subjectantileishmanial agent
dc.subjectethyl 4 [2 (2,4 chlorobenzamido)thiazolo[5,4 d]pyrimidin 5 yl]piperazine1 carboxylate
dc.subjectethyl 4 [2 (3,4 chlorobenzamido)thiazolo[5,4 d]pyrimidin 5 yl]piperazine1 carboxylate
dc.subjectethyl 4 [2 (3,4 dichlorobenzamido)thiazolo[5,4 d]pyrimidin 5 yl]piperazine 1 carboxylate
dc.subjectethyl 4 [2 (4 chlorobenzamido)thiazolo[5,4 d]pyrimidin 5 yl]piperazine1 carboxylate
dc.subjectmeglumine antimonate
dc.subjectmethotrexate
dc.subjectn [5 (4 acetylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl] 2,4 chlorobenzamide
dc.subjectn [5 (4 acetylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl] 3,4 chlorobenzamide
dc.subjectn [5 (4 acetylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl] 4 chloro 3 nitrobenzamide
dc.subjectn [5 (4 acetylpiperazin 1 yl)thiazolo[5,4 d]pyrimidin 2 yl] 4 chlorobenzamide
dc.subjectoxidoreductase
dc.subjectoxidoreductase inhibitor
dc.subjectpteridine reductase 1
dc.subjectpyrimethamine
dc.subjectpyrimidine derivative
dc.subjectthiazole derivative
dc.subjectthiazolopyrimidine derivative
dc.subjectunclassified drug
dc.subjectantiprotozoal agent
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectantileishmanial activity
dc.subjectArticle
dc.subjectBagg albino mouse
dc.subjectbiological activity
dc.subjectcomparative effectiveness
dc.subjectcontrolled study
dc.subjectcrystal structure
dc.subjectcutaneous leishmaniasis
dc.subjectcytotoxic concentration
dc.subjectcytotoxicity
dc.subjectdrug design
dc.subjectdrug efficacy
dc.subjectdrug mechanism
dc.subjectdrug potency
dc.subjectdrug synthesis
dc.subjectdrug targeting
dc.subjectenzyme activity
dc.subjectenzyme inhibition
dc.subjectfoot pad
dc.subjecthuman
dc.subjectIC50
dc.subjectin vitro study
dc.subjectin vivo study
dc.subjectLeishmania infantum
dc.subjectLeishmania major
dc.subjectLeishmania tropica
dc.subjectmale
dc.subjectmolecular docking
dc.subjectmolecular model
dc.subjectmolecular weight
dc.subjectmouse
dc.subjectNCTC clone 929 cell line
dc.subjectnonhuman
dc.subjectpromastigote
dc.subjectRAW 264.7 cell line
dc.subjectselectivity index
dc.subjectvisceral leishmaniasis
dc.subjectXTT assay
dc.subjectanimal
dc.subjectLeishmania
dc.subjectleishmaniasis
dc.titleDesign, synthesis, in vitro – In vivo biological evaluation of novel thiazolopyrimidine compounds as antileishmanial agent with PTR1 inhibition
dc.typeArticle

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