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

Abstract

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. K E Y W O R D S alkaline phosphatase, molecular docking studies, oxadiazoles

2-Benzylidenebenzofuran-3(2H)-ones as a new class of alkaline phosphatase inhibitors: synthesis, SAR analysis, enzyme inhibitory kinetics and computational studies

“…In recent years, several inhibitors of APs based on biaryl sulfonamide, chromone, triazole and coumarin sulfonate motifs have been reported. [25][26][27][28][29][30][31][32] APs have become important target enzymes owing to their considerable pharmacological importance in medicinal chemistry. 33,34a,b Some compounds were found to be effective inhibitors of AP, but most of them inhibited APs non-selectively.…”

Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies

“…The oxygen atom of 7g forms two hydrogen bonds with His_153 and His_317 having bond lengths 1.78 and 2.55 Å, respectively. The importance of these amino acid residues in binding with other ALP inhibitors has also been well documented [ 64 , 65 ]. The comparative binding energy and SAR analysis showed a significance of 7g and may be considered as a potent inhibitor of the enzyme.…”

Current status ofN-,O-,S-heterocycles as potential alkaline phosphatase inhibitors: a medicinal chemistry overview

“…The results suggest that the alkylthio substitution has a signicant effect on the inhibitory activity and binding affinity of the compounds towards AP. 157 Ashraf et al (2019) synthesized and evaluated substituted acetamides as AP inhibitors. The inhibitory potential of each of the title compounds was assessed against h-AP.…”

“…The results suggest that the alkylthio substitution has a significant effect on the inhibitory activity and binding affinity of the compounds towards AP. 157 …”