Synthesis, molecular docking, and biological investigations of new pyrazolone chalcones

Abstract

Heterocyclic compounds are essential to the drug development and discovery processes. Herein, we synthesized new pyrazolone chalcones (3a-g) through the reaction of azopyrazolone (2) with different aromatic aldehydes in a basic medium. Numerous techniques including elemental analysis, ¹H-NMR, ¹³C-NMR, and FT-IR spectroscopies, were used to characterize pyrazolone chalcone derivatives. Compound 3b exhibited the highest binding energy towards YAP/TEAD protein with a value of -8.45 kcal mol^-1 in in silico studies. This observation suggested that compound 3b inhibits the YAP/TEAD Hippo signaling pathway. In addition, compound 3b offered a prospective anticancer effect against various cancer cell lines, such as HepG-2, MCF-7, and HCT-116, among the other synthesized compounds, with IC₅₀ values equal to 5.03 ± 0.4, 3.92 ± 0.2, and 6.34 ± 0.5 μM, respectively. These results validated our findings regarding the in silico suppression of the YAP/TEAD protein. Its pharmacokinetic properties were theoretically observed using ADMET. Additionally, compound 3b demonstrated a potent antioxidant scavenging action (in vitro) against DPPH free radicals. Thus, based on our findings, compound 3b may act as a potential anticancer scaffold owing to its inhibitory impact towards the YAP/TEAD-mediated Hippo signaling pathway with a safe toxic profile on normal cells.

Fig. 1. Marketed pyrazolone- and chalcone-based drugs.

Scheme 1. Synthesis route for compound 2.

Scheme 2. Synthesis route for compounds 3a–g.

Scheme 3. Suggested mechanism for compounds 3a–g.

Fig. 2. Antioxidant scavenging activity of chalcone derivatives (3a–g). Results are reported as mean ± SE; where n = 3.

Fig. 3. Inhibitory concentrations (IC₅₀) of chalcones 3a–gvia DPPH. Results are reported as mean ± SE, where n = 3.

Fig. 4. Two- and three-dimensional molecular interaction networks for all chalcone derivatives (3a–g) with the target YAP/TEAD-mediated Hippo signaling pathway.

Fig. 5. Bioavailability radar plot for chalcones (3a–g).

Fig. 6. Antitumor and cytotoxic impacts of chalcones 3a–g. Results are reported as mean ± SE of three independent triplicates.

Fig. 7. SAR of the most active compound.