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. 2023 Dec;38(1):2163394.
doi: 10.1080/14756366.2022.2163394.

Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors

Muhammad Naeem Mustafa  1 , Pervaiz Ali Channar  2 , Muhammad Sarfraz  3 , Aamer Saeed  1 , Syeda Abida Ejaz  4 , Mubashir Aziz  4 , Fatmah Ali Alasmary  5 , Hanadi Yaqob Alsoqair  5 , Hussain Raza  6 , Song Ja Kim  6 , Asad Hamad  7
Affiliations

Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors

Muhammad Naeem Mustafa et al. J Enzyme Inhib Med Chem. 2023 Dec.

Abstract

Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N-benzamide quinolinyl iminothiazoline (6g), N-dichlorobenzamide quinolinyl iminothiazoline (6i) and N-nitrobenzamide quinolinyl iminothiazoline (6j) were found as the most reactive compounds. Then during the in-vitro testing, the compound N-benzamide quinolinyl iminothiazoline (6g) exhibited the maximum alkaline phosphatase inhibitory effect (IC50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH2PO4 (IC50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N-benzamide quinolinyl iminothiazoline (6g) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.

Keywords: Alkaline phosphatase; DFT; kinetic analysis; molecular docking; synthesis.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Structures of biologically active quinoline and thiazolines.
Scheme 1.
Scheme 1.
Synthetic route for synthesis of quinolinyl iminothiazoline 6(a–j).
Figure 2.
Figure 2.
Optimised structures of potent compounds (6d, 6e, 6g and 6i).
Figure 3.
Figure 3.
HOMO-LUMO structures of potent compounds (6d, 6e, 6g and 6i).
Figure 4.
Figure 4.
Alkaline phosphatase inhibition by compounds 6g as shown by Lineweaver-Burk plots (a). The plot of the slope vs inhibitor concentrations to get the inhibition constant is shown in the insets (b). Using the linear least squares fit, the lines were drawn.
Figure 5.
Figure 5.
Illustrating the 3D and 2D binding interactions of potent compounds (6d, 6e, 6g, 6i and 6j).
Figure 6.
Figure 6.
RMSD trajectory analysis for protein (brown coloured trajectory), protein ligand complex (blue coloured trajectory).
Figure 7.
Figure 7.
Evolution of RMSF for amino acid residues of targeted protein.
Figure 8.
Figure 8.
Contact profile for protein-ligand complex. Green coloured peaks are representing hydrogen bonding while purple peaks are representing hydrophobic interactions. Blue coloured histograms are water bridges.
Figure 9.
Figure 9.
Ligand properties analysed using various analytical metrics.
Figure 10.
Figure 10.
Radius of gyration.
See this image and copyright information in PMC

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