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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pryidazinylpyrazolone 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
Pages (from-to)339-346
Number of pages8
JournalBioorganic Chemistry
Volume84
DOIs
Publication statusPublished - Mar 2019

Keywords

  • Pyridazine
  • Human IAPP
  • Molecular docking
  • Amyloids
  • Diabetes

Cite this

Bin Farrukh, Syed Usama ; Javed, Ibrahim ; Ather, Abdul Qayyum ; Emwas, Abdul-Hamid ; Alazmi, Meshari ; Gao, Xin ; Chotana, Ghayoor Abbas ; Davis, Thomas P ; Ke , Pu Chun ; Saleem, Rahman Shah Zaib. / Synthesis and identification of novel pryidazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation. In: Bioorganic Chemistry. 2019 ; Vol. 84. pp. 339-346.
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abstract = "We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pryidazinylpyrazolone 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.",
keywords = "Pyridazine, Human IAPP, Molecular docking, Amyloids, Diabetes",
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Synthesis and identification of novel pryidazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation. / Bin Farrukh, Syed Usama; Javed, Ibrahim; Ather, Abdul Qayyum; Emwas, Abdul-Hamid; Alazmi, Meshari; Gao, Xin; Chotana, Ghayoor Abbas; Davis, Thomas P; Ke , Pu Chun ; Saleem, Rahman Shah Zaib.

In: Bioorganic Chemistry, Vol. 84, 03.2019, p. 339-346.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bin Farrukh, Syed Usama

AU - Javed, Ibrahim

AU - Ather, Abdul Qayyum

AU - Emwas, Abdul-Hamid

AU - Alazmi, Meshari

AU - Gao, Xin

AU - Chotana, Ghayoor Abbas

AU - Davis, Thomas P

AU - Ke , Pu Chun

AU - Saleem, Rahman Shah Zaib

PY - 2019/3

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N2 - We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pryidazinylpyrazolone 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.

AB - We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pryidazinylpyrazolone 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.

KW - Pyridazine

KW - Human IAPP

KW - Molecular docking

KW - Amyloids

KW - Diabetes

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DO - 10.1016/j.bioorg.2018.11.039

M3 - Article

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SP - 339

EP - 346

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

ER -