Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase

Aamer Saeed; Saba Ashraf; Mubashir Aziz; Pervaiz Ali Channar; Syeda Abida Ejaz; Ammara Fayyaz; Qamar Abbas; Fatmah Ali Alasmary; Abdulnasser Mahmoud Karami; Arfa Tehzeeb; Amara Mumtaz; Hesham R El-Seedi

doi:10.1007/s00044-023-03051-9

Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase

Med Chem Res. 2023;32(6):1077-1086. doi: 10.1007/s00044-023-03051-9. Epub 2023 Apr 10.

Authors

Affiliations

¹ Department of Chemistry, Quaid-I-Azam University, Islamabad, 45320 Pakistan.
² Department of Chemistry, Rawalpindi Women University 6th Road, Satellite Town, Rawalpindi, Pakistan.
³ Department of Pharmaceutical Chemistry, Faculty of pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100 Pakistan.
⁴ Department of Basic sciences and Humanities, Faculty of Information Sciences and Humanities, Dawood University of Engineering and Technology, Karachi, 74800 Pakistan.
⁵ Department of Biology, College of Science, University of Bahrain, Sakhir, Kingdom of Bahrain.
⁶ College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju, 32588 Republic of Korea.
⁷ Department of Chemistry, College of Science, King Saud University, Riyadh, 11451 Saudi Arabia.
⁸ Department of Pharmacy, Quaid-I-Azam University, 45320 Islamabad, Pakistan.
⁹ Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060 Pakistan.
¹⁰ International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, 212013 China.
¹¹ Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom, 32512 Egypt.
¹² Division of Pharmacognosy, Department of Pharmaceutical Biosciences, Biomedical Centre, Uppsala University, P.O. Box 574, 751 23 Uppsala, Sweden.

Abstract

Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (5a-5j) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals. All of the investigated compounds displayed a more powerful inhibitory profile than the reference agent, KH₂PO₄ particularly compound 5h and 5a exhibited strong inhibitory potential against ALP with IC₅₀ value of 0.365 ± 0.011 and 0.436 ± 0.057 µM respectively. In addition, Lineweaver-Burk plots revealed the non-competitive inhibition mode of the most powerful derivative i.e., 5h (ki value 0.5 µM). To investigate the putative binding mode of selective inhibitor interactions, molecular docking was performed. It is recommended that future research will focus on developing selective alkaline phosphatase inhibitors by modifying the structure of the 5h derivative.

Keywords: Alkaline phosphatase; Molecular docking; Naphthoyl thioureas; Structure-activity relationship.

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