Diethylalkylsulfonamido(4-methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives act as acid phosphatase inhibitors: synthesis accompanied by experimental and molecular modeling assessments

• Published in: Journal of enzyme inhibition and medicinal chemistry 2017-01, Vol.32 (1), p.20-28
• Main Authors: Alimoradi, Nahid, Ashrafi-Kooshk, Mohammad Reza, Shahlaei, Mohsen, Maghsoudi, Shabnam, Adibi, Hadi, McGeary, Ross P., Khodarahmi, Reza
• Format: Article
• Language: English
• Subjects: Acid phosphatase; Acid Phosphatase - antagonists & inhibitors; Acid Phosphatase - metabolism; Acids; Bone resorption; Dose-Response Relationship, Drug; enzyme inhibition; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme kinetics; Fungi; Glycoproteins - antagonists & inhibitors; Glycoproteins - metabolism; Humans; Metabolic disorders; Models, Molecular; Molecular modelling; Molecular Structure; Osteoporosis; Phaseolus - enzymology; Phosphonates; phosphonic acid; Phosphorous Acids - chemical synthesis; Phosphorous Acids - chemistry; Phosphorous Acids - pharmacology; Purple acid phosphatase; Structure-Activity Relationship; synthesis
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2016.1230109

Purple acid phosphatases (PAPs) are binuclear metallo-hydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals, PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. The aim of the present study was to investigate inhibitory effect of synthesized diethylalkylsulfonamido(4-methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives as potential red kidney bean PAP (rkbPAP) inhibitors accompanied by experimental and molecular modeling assessments. Enzyme kinetic data showed that they are good rkbPAP inhibitors whose potencies improve with increasing alkyl chain length. Hexadecyl derivatives, as most potent compounds (K i  = 1.1 µM), inhibit rkbPAP in the mixed manner, while dodecyl derivatives act as efficient noncompetitive inhibitor. Also, analysis by molecular modeling of the structure of the rkbPAP-inhibitor complexes reveals factors, which may be important for the determination of inhibition specificity.