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

Author(s): Uzma Salar, Khalid Mohammed Khan*, Syeda Abida Ejaz, Abdul Hameed, Mariya al-Rashida, Shahnaz Perveen, Muhammad Nawaz Tahir, Jamshed Iqbal*, Muhammad Taha.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 3 , 2019

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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.

[1]
Coleman, J.E. Structure and mechanism of alkaline phosphatase. Annu. Rev. Biophys. Biomol. Struct., 1992, 21, 441.
[2]
Duarte, F.; Amrein, B.A.; Kamerlin, S.C.L. Modeling catalytic promiscuity in the alkaline phosphatase superfamily. Phys. Chem. Chem. Phys., 2013, 15, 11160.
[3]
Pabis, A.; Kamerlin, S.C.L. Promiscuity and electrostatic flexibility in the alkaline phosphatase superfamily. Curr. Opin. Struct. Biol., 2016, 37, 14.
[4]
Al-Rashida, M.; Iqbal, J. Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5′-nucleotidase, and alkaline phosphatase inhibitors. Med. Res. Rev., 2014, 34, 703.
[5]
Zimmermann, H.; Zebisch, M.; Sträter, N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal., 2012, 8, 437.
[6]
Bonan, C.D. Ectonucleotidases and nucleotide/nucleoside transporters as pharmacological targets for neurological disorders. CNS Neurol. Disord. Drug Targets, 2012, 11, 739.
[7]
Holtz, K.M.; Kantrowitz, E.R. The mechanism of the alkaline phosphatase reaction: Insights from NMR, crystallography and site‐specific mutagenesis. FEBS Lett., 1999, 462, 7.
[8]
Millán, J.L. Alkaline phosphatases. Purinergic Signal., 2006, 2, 335.
[9]
Hotton, D.; Mauro, N.; Lézot, F.; Forest, N.; Berdal, A. Differential expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) in rat odontogenic cells in vivo. J. Histochem. Cytochem., 1999, 47, 1541.
[10]
Orimo, H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J. Nippon Med. Sch., 2010, 77, 4.
[11]
Buchet, R.; Millán, J.L.; Magne, D. Multisystemic functions of alkaline phosphatases. Phosphatase Modulators. Methods Mol. Biol., 2013, 27.
[12]
Bobryshev, Y.V.; Orekhov, A.N.; Sobenin, I.; Chistiakov, D.A. Role of bone-type tissue-nonspecific alkaline phosphatase and PHOSPO1 in vascular calcification. Curr. Pharm. Des., 2014, 20, 5821.
[13]
Millán, J.L. The role of phosphatases in the initiation of skeletal mineralization. Calcif. Tissue Int., 2013, 93, 299.
[14]
Yang, J-H.; Oh, K-J.; Pandher, D.S. Hydroxyapatite crystal deposition causing rapidly destructive arthropathy of the hip joint. Indian J. Orthop., 2011, 45, 569.
[15]
Lomashvili, K.; Garg, P.; Narisawa, S.; Millan, J.; O’neill, W. Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification. Kidney Int., 2008, 73, 1024.
[16]
Narisawa, S.; Harmey, D.; Yadav, M.C.; O’Neill, W.C.; Hoylaerts, M.F.; Millán, J.L. Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J. Bone Miner. Res., 2007, 22, 1700.
[17]
Shioi, A.; Katagi, M.; Okuno, Y.; Mori, K.; Jono, S.; Koyama, H.; Nishizawa, Y. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells. Circ. Res., 2002, 91, 9.
[18]
Denu, R.A.; Hematti, P. Effects of oxidative stress on mesenchymal stem cell biology. Oxid. Med. Cell. Longev., 2016, Article ID 2989076.
[19]
Zhou, X.; Cui, Y.; Zhou, X.; Han, J. Phosphate/pyrophosphate and MV-related proteins in mineralisation: Discoveries from mouse models. Int. J. Biol. Sci., 2012, 8, 778.
[20]
Al-Rashida, M.; Iqbal, J. Inhibition of alkaline phosphatase: An emerging new drug target. Mini Rev. Med. Chem., 2015, 15, 41.
[21]
Al-Rashida, M.; Raza, R.; Abbas, G.; Shah, M.S. Kostakis, George E.; Lecka, J.; Sévigny, J.; Muddassar, M.; Papatriantafyllopoulou, C.; Iqbal, J. Identification of novel chromone based sulfonamides as highly potent and selective inhibitors of alkaline phosphatases. Eur. J. Med. Chem., 2013, 66, 438.
[22]
Salar, U.; Khan, K.M.; Iqbal, J.; Ejaz, S.A.; Hameed, A.; al-Rashida, M.; Perveen, S.; Tahir, M.N. Coumarin sulfonates: New alkaline phosphatase inhibitors; in vitro and in silico studies. Eur. J. Med. Chem., 2017, 131, 29.
[23]
Salar, U.; Khan, K.M.; Jabeen, A.; Faheem, A.; Fakhri, M.I.; Saad, S.M.; Perveen, S.; Taha, M.; Hameed, A. Coumarin sulfonates: As potential leads for ROS inhibition. Bioorg. Chem., 2016, 69, 37.
[24]
Saeed, Aamer. Ejaz, S.A.; Khurshid, A.; Hassan, S.; al-Rashida, M.; Latif, M.; Lecka, J.; Sévigny, J.; Iqbal, J. Synthesis, characterization and biological evaluation of N-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-4-yl)benzamides. RSC Adv, 2015, 5, 86428.
[25]
Davis, I.W.; Murray, L.W.; Richardson, J.S.; Richardson, D.C. PMCID: PMC441536 Mol Probity: Structure validation and all-atom contact analysis for nucleic acids and their complexes. Nucleic Acids Res., 2004, 32, W615.
[26]
Lüthy, R.; Bowie, J.U.; Eisenberg, D. VERIFY3D: Assessment of protein models with three-dimensional profiles. Methods Enzymol., 1997, 277, 396.
[27]
Delaney, J.S. ESOL: Estimating aqueous solubility directly from molecular structure. J. Chem. Inf. Comput. Sci., 2004, 44, 1000.
[28]
Hughes, J.D.; Blagg, J.; Price, D.A.; Bailey, S.; DeCrescenzo, G.A.; Devraj, R.V.; Ellsworth, E.; Fobian, Y.M.; Gibbs, M.E.; Gilles, R.W. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg. Med. Chem. Lett., 2008, 18, 4872.
[29]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45, 2615.
[30]
HyperChem 8.0, Hypecube Inc., Gainesville, FL, USA http://www.hyper.com/
[31]
Visually Informed LeadOpt. A BioSolveIT White Paper, http:// www.biosolveit.de/LeadIT/
[32]
Accelrys Software Inc. Discovery Studio Modeling Environment, Release 4.0; Accelrys Software Inc.: San Diego, 2013.
[33]
Bravo, Y.; Teriete, P.; Dhanya, R-P.; Dahl, R.; San Lee, P.; Kiffer-Moreira, T.; Ganji, S.R.; Sergienko, E.; Smith, L.H.; Farquharson, C. Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1. Bioorg. Med. Chem. Lett., 2014, 24, 4308.


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Article Details

VOLUME: 16
ISSUE: 3
Year: 2019
Page: [256 - 272]
Pages: 17
DOI: 10.2174/1570180815666180327125738
Price: $58

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