Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors.

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.
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