Coumarinyl Aryl/Alkyl Sulfonates with Dual Potential: Alkaline Phosphatase and ROS Inhibitory Activities: In-Silico Molecular Modeling and ADME Evaluation
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Published:2019-01-15
Issue:3
Volume:16
Page:256-272
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ISSN:1570-1808
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Container-title:Letters in Drug Design & Discovery
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language:en
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Short-container-title:LDDD
Author:
Salar Uzma1, Mohammed Khan Khalid1, Ejaz Syeda Abida2, Hameed Abdul1, al-Rashida Mariya3, Perveen Shahnaz4, Tahir Muhammad Nawaz5, Iqbal Jamshed2, Taha Muhammad6
Affiliation:
1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan 2. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan 3. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore-54600, Pakistan 4. PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi- 75280, Pakistan 5. Department of Physics, University of Sargodha, Sargodha, Pakistan 6. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam- 31441, Saudi Arabia
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.
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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).
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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.
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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.
Funder
Higher Education Commission
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
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