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Synthesis, in vitro and in silico studies on novel 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of mPGES-1

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dc.contributor.authorKULABAŞ, NECLA
dc.contributor.authorTATAR, ESRA
dc.contributor.authorKÜÇÜKGÜZEL, İLKAY
dc.contributor.authorBİNGÖL ÖZAKPINAR, ÖZLEM
dc.contributor.authorsErensoy G., Ding K., Zhan C., Çiftçi G., Yelekçi K., Duracık M., Bingöl Özakpınar Ö., Aydemir E., Yılmaz Z. N. , Şahin F., et al.
dc.date.accessioned2022-10-03T06:59:19Z
dc.date.available2022-10-03T06:59:19Z
dc.date.issued2023-01-01
dc.description.abstractHuman microsomal prostaglandin E synthase (mPGES)-1 is a glutathione-dependent membrane-bound enzyme which is involved in the terminal stage of prostaglandin E2 (PGE2) synthesis. It has been well reported as a key target for the discovery of new anti-inflammatory and anti-cancer drugs. Specific inhibitors of mPGES-1 are anticipated to selectively restrain the generation of PGE2 induced by the inflammatory stimuli, without obstructing of the regular biosynthesis of other homeostatic prostanoids. Therefore, the design of mPGES-1 inhibitors can represent a better choice to take control of PGE2 associated diseases, compared with conventional non-steroidal anti-inflammatory drugs and cyclooxygenase (COX) inhibitors, which are known for their serious side effects. Although there is an intensive effort for the identification of mPGES-1 inhibitors, none of the unveiled molecules so far have reached the clinical market. Therefore, the development of novel mPGES-1 inhibitors with proper drug-like properties is still an unmet medical need. As a continuation of our research for the identification of new chemotypes which might inhibit this enzyme, we now report the design and synthesis of 3-aryloxymethyl-5-[(2-oxo2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as inhibitors of human mPGES-1. All synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR (for compounds 12, 14, 15, 26, 27), HMBC (for compounds 6, 7, 8, 16, 19, 23, 28), and MS data. Twenty-four target compounds 7–30 were screened for their mPGES-1/COX-2 inhibitory activities as well as their cytotoxicity. Of these compounds, 20 and 24 showed potent mPGES-1 inhibition by IC50 values of 0.224±0.070 μM and 1.08±0.35 μM, respectively. These two compounds have also been observed to inhibit angiogenesis in matrigel tube formation assay with no toxicity toward HUVEC cells. In silico studies were also held to understand inhibition mechanisms of the most active compounds using molecular docking, molecular dynamics calculations and ADMET predictions.
dc.identifier.citationErensoy G., Ding K., Zhan C., Çiftçi G., Yelekçi K., Duracık M., Bingöl Özakpınar Ö., Aydemir E., Yılmaz Z. N. , Şahin F., et al., "Synthesis, in vitro and in silico studies on novel 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of mPGES-1", JOURNAL OF MOLECULAR STRUCTURE, cilt.1272, ss.1-19, 2023
dc.identifier.doi10.1016/j.molstruc.2022.134154
dc.identifier.endpage19
dc.identifier.issn0022-2860
dc.identifier.startpage1
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S0022286022018051?via%3Dihub
dc.identifier.urihttps://hdl.handle.net/11424/282031
dc.identifier.volume1272
dc.language.isoeng
dc.relation.ispartofJOURNAL OF MOLECULAR STRUCTURE
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectEczacılık
dc.subjectMeslek Bilimleri
dc.subjectFarmasötik Kimya
dc.subjectSağlık Bilimleri
dc.subjectPharmacology and Therapeutics
dc.subjectProfessional Sciences
dc.subjectPharmaceutical Chemistry
dc.subjectHealth Sciences
dc.subjectKlinik Tıp (MED)
dc.subjectYaşam Bilimleri (LIFE)
dc.subjectFarmakoloji ve Toksikoloji
dc.subjectFARMAKOLOJİ VE ECZACILIK
dc.subjectClinical Medicine (MED)
dc.subjectLife Sciences (LIFE)
dc.subjectPHARMACOLOGY & TOXICOLOGY
dc.subjectPHARMACOLOGY & PHARMACY
dc.subjectFarmakoloji
dc.subjectFarmakoloji, Toksikoloji ve Eczacılık (çeşitli)
dc.subjectGenel Farmakoloji, Toksikoloji ve Eczacılık
dc.subjectFarmakoloji (tıbbi)
dc.subjectİlaç Rehberleri
dc.subjectYaşam Bilimleri
dc.subjectPharmacy
dc.subjectPharmacology
dc.subjectPharmacology, Toxicology and Pharmaceutics (miscellaneous)
dc.subjectGeneral Pharmacology, Toxicology and Pharmaceutics
dc.subjectPharmacology (medical)
dc.subjectDrug Guides
dc.subjectLife Sciences
dc.subjectmPGES-1
dc.subjectInflammation
dc.subjectCancer
dc.subjectAngiogenesis
dc.subject1
dc.subject2
dc.subject4-triazoles
dc.subjectMolecular docking
dc.titleSynthesis, in vitro and in silico studies on novel 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of mPGES-1
dc.typearticle
dspace.entity.typePublication
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relation.isAuthorOfPublication.latestForDiscovery0ec36ba9-248d-4929-8d15-5f417ba3f523

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