Pharmacokinetic evaluation, molecular docking and in vitro biological evaluation of 1, 3, 4-oxadiazole derivatives as potent antioxidants and STAT3 inhibitors

Abstract

1, 3, 4-Oxadiazole derivatives (4a–5f) were previously synthesized to investigate their anticancer properties. However, studies relating to their antioxidant potential and signal transducer and activator of transcription (STAT) inhibition have not been performed. We investigated previously synthesized 1, 3, 4-oxadiazole derivatives ( 4a–5f) for various radical scavenging properties using several in vitro antioxidant assays and also for direct inhibition of STAT3 through molecular docking. The data obtained from various antioxidant assays such as 2, 2,-diphenyl-1-picrylhydrazyl radical (DPPH), nitric oxide, hydrogen peroxide, and superoxide anion radical revealed that among all the derivatives, compound 5e displayed high antioxidant activities than the standard antioxidant L -ascorbic acid. Additionally, the total reduction assay and antioxidant capacity assay further confirmed the antioxidant potential of compound 5e . Furthermore, the molecular docking studies performed for all derivatives along with the standard inhibitor STX-0119 showed that binding energy released in direct binding with the SH2 domain of STAT3 was the highest for compound 5e (-9.91kcal/mol). Through virtual screening, compound 5e was found to exhibit optimum competency in inhibiting STAT3 activity. Compound 5e decreased the activation of STAT3 as observed with Western blot. In brief, compound 5e was identified as a potent antioxidant agent and STAT3 inhibitor and effective agent for cancer treatment.

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

“…The predictive studies using the PASS application indicated the inhibition of the STAT3 transcription factor as the most probable anticancer mechanism. Recent evidence shows that the 1,3,4-oxadiazole scaffold is frequently used in the structure of STAT3 inhibitors active against various cancer cells [ 39 , 40 , 41 ]. STAT3 is closely related to the occurrence of cancers and is an attractive therapeutic target for oncology and drug development.…”

Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

“…Fathi and coworkers reported the anticancer and STAT3-inhibitory activity of oxadiazole conjugated chalcones [ 48 ]. Khanam and team identified a 1,3,4-oxadiazole derivative that directly interacts with the SH2 domain of STAT3 in docking analysis and direct binding studies [ 49 ]. Collectively, these studies proposed that the conjugation of 1,3,4-oxadiazole moiety with other heterocycle yield new structures with STAT3 inhibitory activity.…”

Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation

“…Subsequently, the authors further expanded the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3 . Similarly, Khanam et al identified a 1,3,4-oxadiazole derivative 87 as a STAT3 inhibitor by screening their previously synthesized compounds . AlphaScree-based assays revealed 87 strongly interacted with the SH2 domain and exhibited significant activity against STAT3 (74.12% of inhibition at 60 μg/mL concentration).…”

“…As shown above, the oxadiazole ring in STX-0119 emerged as a key molecular feature for STAT3 inhibition. , Using structure-based computational database screening coupled to cell-based high-throughput screening, Kim et al also discovered oxadiazole-based ODZ10117 ( 86 , Figure ) as a specific STAT3 inhibitor . In comparison with the known STAT3 inhibitors S3I-201, STA-21, and nifuroxazide, ODZ10117 has a greater inhibition on STAT3 activation via directly blocking the SH2 domain of STAT3 and thereafter suppressing its homodimerization and transcriptional activity, which mediated its diverse anticancer effects against breast cancer cells including apoptosis induction as well as reduction of migration and invasion.…”

“…Similarly, Khanam et al identified a 1,3,4-oxadiazole derivative 87 as a STAT3 inhibitor by screening their previously synthesized compounds 151. …”