Optimization of an α-aminonaphthylmethylphosphonic acid inhibitor of purple acid phosphatase using rational structure-based design approaches

Daniel Feder; Siti Hajar Mohd-Pahmi; Hadi Adibi; Luke W Guddat; Gerhard Schenk; Ross P McGeary; Waleed M Hussein

doi:10.1016/j.ejmech.2023.115383

Optimization of an α-aminonaphthylmethylphosphonic acid inhibitor of purple acid phosphatase using rational structure-based design approaches

Eur J Med Chem. 2023 Jun 5:254:115383. doi: 10.1016/j.ejmech.2023.115383. Epub 2023 Apr 16.

Authors

Daniel Feder¹, Siti Hajar Mohd-Pahmi¹, Hadi Adibi², Luke W Guddat¹, Gerhard Schenk³, Ross P McGeary¹, Waleed M Hussein⁴

Affiliations

¹ The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD, 4072, Australia.
² The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD, 4072, Australia; Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
³ The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD, 4072, Australia; The University of Queensland, Sustainable Minerals Institute, Brisbane, QLD, 4072, Australia; The University of Queensland, Australian Institute of Bioengineering and Nanotechnology, Brisbane, QLD, 4072, Australia.
⁴ The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD, 4072, Australia; Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan, Egypt. Electronic address: w.hussein@uq.edu.au.

PMID: 37087894
DOI: 10.1016/j.ejmech.2023.115383

Abstract

Purple acid phosphatases (PAPs) are ubiquitous binuclear metallohydrolases that have been isolated from various animals, plants and some types of fungi. In humans and mice, elevated PAP activity in osteoclasts is associated with osteoporosis, making human PAP an attractive target for the development of anti-osteoporotic drugs. Based on previous studies focusing on phosphonate scaffolds, as well as a new crystal structure of a PAP in complex with a derivative of a previously synthesized α-aminonaphthylmethylphosphonic acid, phosphonates 24-40 were designed as new PAP inhibitor candidates. Subsequent docking studies predicted that all of these compounds are likely to interact strongly with the active site of human PAP and most are likely to interact strongly with the active site of pig PAP. The seventeen candidates were synthesized with good yields and nine of them (26-28, 30, 33-36 and 38) inhibit in the sub-micromolar to nanomolar range against pig PAP, with 28 and 35 being the most potent mammalian PAP inhibitors reported with K_i values of 168 nM and 186 nM, respectively. This study thus paves the way for the next stage of drug development for phosphonate inhibitors of PAPs as anti-osteoporotic agents.

Keywords: Chemotherapeutics; Drug Development; Metallohydrolases; Osteoporosis; Purple acid phosphatase; Tartrate-resistant acid phosphatase.

MeSH terms

Acid Phosphatase
Animals
Glycoproteins / chemistry
Humans
Mammals
Mice
Organophosphonates* / pharmacology
Osteoporosis*
Plants
Swine

Substances

purple acid phosphatase
Glycoproteins
Acid Phosphatase
Organophosphonates