Synthesis, in vitro thymidine phosphorylase inhibitory activity and molecular docking study of novel pyridine-derived bis-oxadiazole bearing bis-schiff base derivatives

The current study has afforded twelve analogs (4a-l) of pyridine-derived bis-oxadiazole containing bis-schiff base and subsequently evaluated for their potential to inhibit thymidine phosphorylase(in vitro). All the synthesized analogs were structurally elucidated using various spec-troscopic tools including NMR and HREIMS. All synthesized scaffolds showed varied range of inhibitory potential with IC50values ranging from 5.19 +/- 1.10 to 36.18 +/- 4.60 lM in comparison to 7-deazaxanthine (IC50 = 30.28 +/- 2.10 lM) as a standard drug. All analogs (except analog 4 l which displayed less potency than standard drug) showed improved potency having IC50 values of 19.73 +/- 2.30, 16.14 +/- 1.20, 18.93 +/- 1.60, 22.78 +/- 1.80, 30.47 +/- 3.70, 5.19 +/- 1.10, 23.13 +/- 1.90, 21.56 +/- 2.50, 4.88 +/- 1.10, 26.63 +/- 2.90 and 6.67 +/- 1.10 respectively.Results obatined were compared to standard 7-deazxanthine drug with IC50 values of 30.28 +/- 2.10 lM. Structure-activity relationship (SAR) studies revealed that analogs bearing -NO2,-CF3, -OH and -Cl moieties at var-ious position of aryl part showed many folds more potency than standard 7-deazaxathine standard drug. In order to determine the potential mode of interactions with thymidine phosphorylase active sites, the most active analogs 4f (bearing 3-CF3& 5-NO2), 4i (bearing 3-OH & 5-NO2), and 4 k (bearing 2-OH &5-NO2) were further subjected to molecular docking study. The results confirmed that these active analogs adopted numerous important interactions including hyrognen bonding, pi -donor hydrogen bond, pi-pi T shaped, pi-pi stacking, pi-alkyl, pi-anion, pi-sigma, halogen (flourine) and numerous Vander Waals interactions with the amino acid of enzyme being targeted.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The present study synthesized twelve analogs of pyridine-derived bis-oxadiazole with bis-schiff base and evaluated their inhibitory potential against thymidine phosphorylase in vitro. The synthesized compounds were characterized using various spectroscopic techniques. The results showed that all analogs exhibited varying degrees of inhibitory potential, with IC50 values ranging from 5.19 +/- 1.10 to 36.18 +/- 4.60 μM. Most of the analogs showed improved potency compared to the standard drug, and structure-activity relationship studies revealed the importance of certain substituents in enhancing potency. Molecular docking studies further confirmed the interactions between the active analogs and the target enzyme. Rating: 7/10.