Submit Manuscript  

Article Details


Coumarinyl Aryl/Alkyl Sulfonates with Dual Potential: Alkaline Phosphatase and ROS Inhibitory Activities: In-Silico Molecular Modeling and ADME Evaluation

[ Vol. 16 , Issue. 3 ]

Author(s):

Uzma Salar, Khalid Mohammed Khan*, Syeda Abida Ejaz, Abdul Hameed, Mariya al-Rashida, Shahnaz Perveen, Muhammad Nawaz Tahir, Jamshed Iqbal* and Muhammad Taha   Pages 256 - 272 ( 17 )

Abstract:


Background: Alkaline Phosphatase (AP) is a physiologically important metalloenzyme that belongs to a large family of ectonucleotidase enzymes. Over-expression of tissue non-specific alkaline phosphatase has been linked with ectopic calcification including vascular and aortic calcification. In Vascular Smooth Muscles Cells (VSMCs), the high level of Reactive Oxygen Species (ROS) resulted in the up-regulation of TNAP. Accordingly, there is a need to identify highly potent and selective inhibitors of APs for treatment of disorders related to hyper activity of APs.

Methods: Herein, a series of coumarinyl alkyl/aryl sulfonates (1-40) with known Reactive Oxygen Species (ROS) inhibition activity, was evaluated for alkaline phosphatase inhibition against human Tissue Non-specific Alkaline Phosphatase (hTNAP) and Intestinal Alkaline Phosphatase (hIAP).

Results: With the exception of only two compounds, all other compounds in the series exhibited excellent AP inhibition. For hIAP and hTNAP inhibition, IC50 values were observed in the range 0.62-23.5 µM, and 0.51-21.5 µM, respectively. Levamisole (IC50 = 20.21 ± 1.9 µM) and Lphenylalanine (IC50 = 100.1 ± 3.15 µM) were used as standards for hIAP and hTNAP inhibitory activities, respectively. 4-Substituted coumarinyl sulfonate derivative 23 (IC50 = 0.62 ± 0.02 µM) was found to be the most potent hIAP inhibitor. Another 4-substituted coumarinyl sulfonate derivative 16 (IC50 = 0.51 ± 0.03 µM) was found to be the most active hTNAP inhibitor. Some of the compounds were also found to be highly selective inhibitors of APs. Detailed Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) analysis were carried out to identify structural elements necessary for efficient and selective AP inhibition. Molecular modeling and docking studies were carried out to rationalize the most probable binding site interactions of the inhibitors with the AP enzymes. In order to evaluate drug-likeness of compounds, in silico ADMETox evaluation was carried out, most of the compounds were found to have favorable ADME profiles with good predicted oral bioavailability. X-ray crystal structures of compounds 38 and 39 were also determined.

Conclusion: Compounds from this series may serve as lead candidates for future research in order to design even more potent, and selective inhibitors of APs.

Keywords:

Coumarinyl sulfonates, alkaline phosphatase inhibition, structure-activity relationship, structure-selectivity relationship, in silico ADME, molecular docking, crystal structure.

Affiliation:

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore-54600, PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi- 75280, Department of Physics, University of Sargodha, Sargodha, Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam- 31441

Graphical Abstract:



Read Full-Text article