Pyrazole Incorporated New Thiosemicarbazones: Design, Synthesis and Investigation of DPP-4 Inhibitory Effects

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SEVER B., Soybir H., Gorgulu S., CANTÜRK Z., ALTINTOP M. D.

MOLECULES, vol.25, no.21, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 21
  • Publication Date: 2020
  • Doi Number: 10.3390/molecules25215003
  • Journal Name: MOLECULES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, Agricultural & Environmental Science Database, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, EMBASE, MEDLINE, Metadex, Veterinary Science Database, Directory of Open Access Journals, Civil Engineering Abstracts
  • Keywords: dipeptidyl peptidase-4, thiosemicarbazone, pyrazole, molecular docking, DIPEPTIDYL PEPTIDASE-4, MEDICINAL CHEMISTRY, DERIVATIVES, ANALOGS, POTENT
  • Anadolu University Affiliated: Yes


Dipeptidyl peptidase-4 (DPP-4) inhibition has been recognized as a promising approach to develop safe and potent antidiabetic agents for the management of type 2 diabetes. In this context, new thiosemicarbazones (2a-o) were prepared efficiently by the reaction of aromatic aldehydes with 4-[4-(1H-pyrazol-1-yl)phenyl]thiosemicarbazide (1), which was obtained via the reaction of 4-(1H-pyrazol-1-yl)phenyl isothiocyanate with hydrazine hydrate. Compounds 2a-o were evaluated for their DPP-4 inhibitory effects based on a convenient fluorescence-based assay. 4-[4-(1H-pyrazol-1-yl)phenyl]-1-(4-bromobenzylidene)thiosemicarbazide (2f) was identified as the most effective DPP-4 inhibitor in this series with an IC50 value of 1.266 +/- 0.264 nM when compared with sitagliptin (IC50 = 4.380 +/- 0.319 nM). MTT test was carried out to assess the cytotoxic effects of compounds 2a-o on NIH/3T3 mouse embryonic fibroblast (normal) cell line. According to cytotoxicity assay, compound 2f showed cytotoxicity towards NIH/3T3 cell line with an IC50 value higher than 500 mu M pointing out its favourable safety profile. Molecular docking studies indicated that compound 2f presented pi-pi interactions with Arg358 and Tyr666 via pyrazole scaffold and 4-bromophenyl substituent, respectively. Overall, in vitro and in silico studies put emphasis on that compound 2f attracts a great notice as a drug-like DPP-4 inhibitor for further antidiabetic research.