Synthesis, biological evaluation, and molecular docking studies of benzyl, alkyl and glycosyl [2-(arylamino)-4,4-dimethyl-6-oxo-cyclohex-1-ene] carbodithioates, as potential immunomodulatory and immunosuppressive agents

El Sayed H El Ashry, Mohammad R. Amer, Omer M. Abdalla, Aly A. Aly, Samreen Soomro, Almas Jabeen, Sobia Ahsan Halim, Osman Mesaik Mohammed Ahmed Hassan, Zaheer Ul-Haq

Research output: Contribution to journalArticle

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Abstract

The immunomodulating properties of functionalized [2-(arylamino)-4,4- dimethyl-6-oxo-cyclohex-1-ene] carbodithioates and 6,6-dimethyl-4-(2-(propan-2- ylidene)hydrazinyl)-6,7-dihydro-2H-indazole-3(5H)-thione compounds have been investigated. Four of them, 13, 18, 19 and 20 inhibited PBMC proliferation induced by phytohemagglutinin (PHA) in a dose dependent manner with an IC 50 of ≤20 μM. The Th-1 cytokine, interleukin-2 (IL-2) in PHA/PMA-stimulated peripheral blood mononuclear cells (PBMCs) is significantly inhibited by 13, 19 and 20 with an IC 50 of 8.4 ± 0.4, 5.34 ± 0.15 and 4.9 ± 0.7 μM, respectively. They also inhibited the PMA/lipopolysaccharide-induced proinflammatory cytokines, IL-1β and TNF-α production in human monocytic leukemia cells (THP-1), by 86%, 46% and 59.2% for IL-1β and by 83.8%, 48.2% and 58.7% for TNF-α, respectively. Only 20 showed significant suppressive activity against the phagocyte oxidative burst in a dose dependent manner, with an IC 50 of 23.8 μM. LPS-induced nitrites in mouse macrophages were found to be inhibited by compounds 6, 8, 13-15 and 19 with an IC 50, which range between 7.7 and 63 μM. The cytotoxicity for the active compounds was also studied on Rat Wistar Hepatocyte cell line, CC1 and the Mouse Fibroblast cell line 3T3 NIH in the presence of compounds using a standard MTT assay. Furthermore, structural-activity relationship using automated docking software revealed that active compounds 7, 13 and 19, adapted the same binding mode, however the most active compound 20 is found deeply inserted within the ligand binding site of IL-2, as multiple hydrophobic and hydrophilic key interactions stabilize the compound inside the binding site, thus contributing higher activity.

Original languageEnglish
Pages (from-to)3000-3008
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number9
DOIs
Publication statusPublished - 1 May 2012
Externally publishedYes

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Phytohemagglutinins
Immunosuppressive Agents
Interleukin-1
Interleukin-2
Blood Cells
Blood
Binding Sites
Indazoles
Cells
Cytokines
Thiones
Cell Line
Respiratory Burst
Macrophages
Cell proliferation
Fibroblasts
Cytotoxicity
Phagocytes
Nitrites
Hydrophobic and Hydrophilic Interactions

Keywords

  • Carbodithioate
  • Dimedone
  • Docking
  • Enamine
  • Glycosyl
  • Immunomodulatory
  • Immunosuppressive
  • Indazolethione

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Synthesis, biological evaluation, and molecular docking studies of benzyl, alkyl and glycosyl [2-(arylamino)-4,4-dimethyl-6-oxo-cyclohex-1-ene] carbodithioates, as potential immunomodulatory and immunosuppressive agents. / El Ashry, El Sayed H; Amer, Mohammad R.; Abdalla, Omer M.; Aly, Aly A.; Soomro, Samreen; Jabeen, Almas; Halim, Sobia Ahsan; Mohammed Ahmed Hassan, Osman Mesaik; Ul-Haq, Zaheer.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 9, 01.05.2012, p. 3000-3008.

Research output: Contribution to journalArticle

El Ashry, El Sayed H ; Amer, Mohammad R. ; Abdalla, Omer M. ; Aly, Aly A. ; Soomro, Samreen ; Jabeen, Almas ; Halim, Sobia Ahsan ; Mohammed Ahmed Hassan, Osman Mesaik ; Ul-Haq, Zaheer. / Synthesis, biological evaluation, and molecular docking studies of benzyl, alkyl and glycosyl [2-(arylamino)-4,4-dimethyl-6-oxo-cyclohex-1-ene] carbodithioates, as potential immunomodulatory and immunosuppressive agents. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 9. pp. 3000-3008.
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abstract = "The immunomodulating properties of functionalized [2-(arylamino)-4,4- dimethyl-6-oxo-cyclohex-1-ene] carbodithioates and 6,6-dimethyl-4-(2-(propan-2- ylidene)hydrazinyl)-6,7-dihydro-2H-indazole-3(5H)-thione compounds have been investigated. Four of them, 13, 18, 19 and 20 inhibited PBMC proliferation induced by phytohemagglutinin (PHA) in a dose dependent manner with an IC 50 of ≤20 μM. The Th-1 cytokine, interleukin-2 (IL-2) in PHA/PMA-stimulated peripheral blood mononuclear cells (PBMCs) is significantly inhibited by 13, 19 and 20 with an IC 50 of 8.4 ± 0.4, 5.34 ± 0.15 and 4.9 ± 0.7 μM, respectively. They also inhibited the PMA/lipopolysaccharide-induced proinflammatory cytokines, IL-1β and TNF-α production in human monocytic leukemia cells (THP-1), by 86{\%}, 46{\%} and 59.2{\%} for IL-1β and by 83.8{\%}, 48.2{\%} and 58.7{\%} for TNF-α, respectively. Only 20 showed significant suppressive activity against the phagocyte oxidative burst in a dose dependent manner, with an IC 50 of 23.8 μM. LPS-induced nitrites in mouse macrophages were found to be inhibited by compounds 6, 8, 13-15 and 19 with an IC 50, which range between 7.7 and 63 μM. The cytotoxicity for the active compounds was also studied on Rat Wistar Hepatocyte cell line, CC1 and the Mouse Fibroblast cell line 3T3 NIH in the presence of compounds using a standard MTT assay. Furthermore, structural-activity relationship using automated docking software revealed that active compounds 7, 13 and 19, adapted the same binding mode, however the most active compound 20 is found deeply inserted within the ligand binding site of IL-2, as multiple hydrophobic and hydrophilic key interactions stabilize the compound inside the binding site, thus contributing higher activity.",
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AU - El Ashry, El Sayed H

AU - Amer, Mohammad R.

AU - Abdalla, Omer M.

AU - Aly, Aly A.

AU - Soomro, Samreen

AU - Jabeen, Almas

AU - Halim, Sobia Ahsan

AU - Mohammed Ahmed Hassan, Osman Mesaik

AU - Ul-Haq, Zaheer

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N2 - The immunomodulating properties of functionalized [2-(arylamino)-4,4- dimethyl-6-oxo-cyclohex-1-ene] carbodithioates and 6,6-dimethyl-4-(2-(propan-2- ylidene)hydrazinyl)-6,7-dihydro-2H-indazole-3(5H)-thione compounds have been investigated. Four of them, 13, 18, 19 and 20 inhibited PBMC proliferation induced by phytohemagglutinin (PHA) in a dose dependent manner with an IC 50 of ≤20 μM. The Th-1 cytokine, interleukin-2 (IL-2) in PHA/PMA-stimulated peripheral blood mononuclear cells (PBMCs) is significantly inhibited by 13, 19 and 20 with an IC 50 of 8.4 ± 0.4, 5.34 ± 0.15 and 4.9 ± 0.7 μM, respectively. They also inhibited the PMA/lipopolysaccharide-induced proinflammatory cytokines, IL-1β and TNF-α production in human monocytic leukemia cells (THP-1), by 86%, 46% and 59.2% for IL-1β and by 83.8%, 48.2% and 58.7% for TNF-α, respectively. Only 20 showed significant suppressive activity against the phagocyte oxidative burst in a dose dependent manner, with an IC 50 of 23.8 μM. LPS-induced nitrites in mouse macrophages were found to be inhibited by compounds 6, 8, 13-15 and 19 with an IC 50, which range between 7.7 and 63 μM. The cytotoxicity for the active compounds was also studied on Rat Wistar Hepatocyte cell line, CC1 and the Mouse Fibroblast cell line 3T3 NIH in the presence of compounds using a standard MTT assay. Furthermore, structural-activity relationship using automated docking software revealed that active compounds 7, 13 and 19, adapted the same binding mode, however the most active compound 20 is found deeply inserted within the ligand binding site of IL-2, as multiple hydrophobic and hydrophilic key interactions stabilize the compound inside the binding site, thus contributing higher activity.

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