Synthesis and identification of novel pyridazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation

Syed Usama Bin Farrukh, Ibrahim Javed, Abdul Qayyum Ather, Abdul-Hamid M. Emwas, Meshari Alazmi, Xin Gao, Ghayoor Abbas Chotana, Thomas P. Davis, Pu Chun Ke, Rahman Shah Zaib Saleem

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pyridazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic β-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.
Original languageEnglish (US)
Pages (from-to)339-346
Number of pages8
JournalBioorganic Chemistry
StatePublished - Nov 28 2018

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We thank Lahore University of Management Sciences and Higher Education Commission of Pakistan for financial support in the form of FIF and NRPU research grants. We also thank King Abdullah University of Science and Technology and Lahore University of Management Sciences for NMR and HRMS studies. IJ thanks Monash International Postgraduate Research Scholarship and Australian Government Research Training Program Scholarship.


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