Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles

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dc.authoridDonmez, Serhat/0000-0002-6301-7243
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.authoridSiyah, Pinar/0000-0003-1192-9416
dc.authoridYilmaz, Yakup Berkay/0000-0001-8989-8045
dc.authoridAtalay, Hazal Nazlican/0000-0001-8859-0268
dc.contributor.authorYilmaz, Yakup Berkay
dc.contributor.authorGungor, Tugba
dc.contributor.authorDonmez, Serhat
dc.contributor.authorAtalay, Hazal Nazlican
dc.contributor.authorSiyah, Pinar
dc.contributor.authorDurdagi, Serdar
dc.contributor.authorAy, Mehmet
dc.date.accessioned2025-01-27T20:38:42Z
dc.date.available2025-01-27T20:38:42Z
dc.date.issued2024
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractThe development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [117Z398]; Canakkale Onsekiz Mart University Scientific Research Projects [FIA-2021-3666]; Istanbul Development Agency (ISTKA) [TR10/21/YEP/0133]; Bahcesehir University, Scientific Research Projects Unit [BAP.2022-01.22, BAP.2022-02.59]
dc.description.sponsorshipThe study was funded by research grants from the Scientific and Technological Research Council of Turkey (TUBITAK) with Grant No. 117Z398 and Canakkale Onsekiz Mart University Scientific Research Projects with Grant No. FIA-2021-3666. The computational part of this study was supported by Istanbul Development Agency (ISTKA), Project No: TR10/21/YEP/0133. This study was also partially supported by Bahce & scedil;ehir University, Scientific Research Projects Unit, Project No: BAP.2022-01.22 and BAP.2022-02.59. Murine RAW macrophage (RAW264.7, ATCC (R) TIB-71 (TM)) cell lines were kind gifts of Dr. Ilya Raskin (Rutgers University, NJ, USA).
dc.identifier.doi10.1039/d4md00495g
dc.identifier.issn2632-8682
dc.identifier.pmid39507615
dc.identifier.scopus2-s2.0-85208711155
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1039/d4md00495g
dc.identifier.urihttps://hdl.handle.net/20.500.12428/23717
dc.identifier.wosWOS:001347608500001
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherRoyal Soc Chemistry
dc.relation.ispartofRsc Medicinal Chemistry
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20250125
dc.subjectHydrogen-Sulfide
dc.subjectPhenylethyl Isothiocyanate
dc.subjectNsaids
dc.subjectSulforaphane
dc.subjectProtein
dc.subjectAcid
dc.subjectCarcinogenesis
dc.subjectCelecoxib
dc.subjectToxicity
dc.subjectDocking
dc.titleSynthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles
dc.typeArticle

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