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Synthesis and docking studies of N ‐(5‐(alkylthio)‐1,3,4‐oxadiazol‐2‐yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors
Author(s) -
Iqbal Zafar,
Iqbal Ambreen,
Ashraf Zaman,
Latif Muhammad,
Hassan Mubashir,
Nadeem Humaira
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21542
Subject(s) - hippuric acid , chemistry , hydrazide , benzamide , oxadiazole , alkaline phosphatase , aryl , docking (animal) , lead compound , stereochemistry , enzyme , medicinal chemistry , alkyl , organic chemistry , biochemistry , in vitro , medicine , urine , nursing
A series of N ‐(5‐(alkylthio)‐1,3,4‐oxadiazol‐2‐yl)methyl)benzamides 6a–i were synthesized as alkaline phosphatase inhibitors. The intermediate 5‐substituted 1,3,4‐oxadiazole‐2‐thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3 . The hippuric acid hydrazide was then cyclized into 5‐substituted 1,3,4‐oxadiazole‐2‐thione 4 . The intermediate 4 was then reacted with alkyl or aryl halides 5a–5i to afford the title compounds N ‐(5‐(methylthio)‐1,3,4‐oxadiazol‐2‐yl)methyl)benzamides 6a–i . The bioassay results showed that compounds 6a–i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC 50 value 0.420 μM, whereas IC 50 value of standard (KH 2 PO 4 ) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a–i against target protein. The docking results showed that three compounds 6c , 6e , and 6i have maximum binding interactions with binding energy values of −8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.