Synthesis, characterization, alkaline phosphatase inhibition assay and molecular modeling studies of 1-benzylidene-2-(4-tert- butylthiazol-2-yl) hydrazines
Creators: name: Aziz, Hamid
name: Mahmood, Abid
name: Zaib, Sumera
name: Saeed, Aamer
name: El-Seedi, Hesham R.
name: Pelletier, Julie
name: Sévigny, Jean
name: Iqbal, Jamshed
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Molecular Biology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences

description: Alkaline phosphatases are homodimeric protein enzymes which removes phosphates from several types of molecules. These catalyze the hydrolysis of monoesters in phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are a privileged class of heterocyclic compounds which may potentially serve as effective phosphatase inhibitors. In this regard, the present research paper reports the facile synthesis and characterization of substituted 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines with excellent yields. The synthesized compounds were tested for inhibitory potential against alkaline phosphatases. The compound 1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (<b>5e)</b> was found to be the most potent inhibitor of human tissue non-alkaline phosphatase in this group of molecules with an IC<sub>50</sub> value of 1.09 ± 0.18 µM. The compound 1-(3,4-dimethoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine <b>(5d)</b> exhibited selectivity and potency for human intestinal alkaline phosphatase with an IC<sub>50</sub> value of 0.71 ± 0.02 µM. In addition, structure activity relationship and molecular docking studies were performed to evaluate their binding modes with the target site of alkaline phosphatase. The docking analysis revealed that the most active inhibitors showed the important interactions within the binding pockets of human intestinal alkaline phosphatase and human tissue non-alkaline phosphatase and may be responsible for the inhibitory activity of the compound towards the enzymes. Therefore, the screened thiazole derivatives provided an outstanding platform for further development of alkaline phosphatase inhibitors. Alkaline phosphatase assay revealed compound <b>5e</b> (1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine) as the most active inhibitor of <b><i>h</i>-TNAP</b> with an IC<sub>50</sub> value of 1.09 ± 0.18 µM. Computational evaluation clearly depicts several interactions within the binding pockets of <b><i>h</i>-IAP</b> and <b><i>h</i>-TNAP</b> and maybe responsible for the inhibitory potential of the compound towards the enzymes.HighlightsThe synthesis of 1-(benzylidene) thiosemicarbazides <b>3(a-i)</b> was performed by reacting thiosemicarbazide with substituted aromatic aldehydes <b>1(a-i)</b>.The synthesized 1-(benzylidene) thiosemicarbazides was cyclized with 1-chloropinacolone to obtain the respective 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b>.The synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b> were successfully characterized using elemental analysis, FT-IR and multi nuclear NMR.Alkaline phosphatase assay and computational study was performed in favor of the synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b>. The synthesis of 1-(benzylidene) thiosemicarbazides <b>3(a-i)</b> was performed by reacting thiosemicarbazide with substituted aromatic aldehydes <b>1(a-i)</b>. The synthesized 1-(benzylidene) thiosemicarbazides was cyclized with 1-chloropinacolone to obtain the respective 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b>. The synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b> were successfully characterized using elemental analysis, FT-IR and multi nuclear NMR. Alkaline phosphatase assay and computational study was performed in favor of the synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines <b>5(a-i)</b>. Communicated by Ramaswamy H. Sarma