Multi-targeted dihydrazones as potent biotherapeutics

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Design

Background:

• Hydrazone compounds are recognized for their utility in drug design.
• Developing novel compounds with therapeutic potential is an ongoing area of research.

Purpose of the Study:

• To synthesize new dihydrazone compounds.
• To evaluate the in vitro H+/K+-ATPase inhibitory and anti-inflammatory activities of synthesized compounds.
• To investigate the structure-activity relationships (SAR) and binding interactions of active compounds.

Main Methods:

• Synthesis of novel dihydrazone derivatives.
• In vitro screening for H+/K+-ATPase inhibition using standard drug Omerazole as a reference.
• In vitro screening for anti-inflammatory activity using indomethacin as a reference.
• Structure-activity relationship analysis.
• Molecular docking studies against H+/K+-ATPase enzyme.

Main Results:

• Compounds 25 and 26 demonstrated excellent H+/K+-ATPase inhibitory activity with IC50 values of 6 ± 0.68 µg/mL and 8 ± 0.43 µg/mL, respectively, outperforming Omerazole.
• Compounds 21, 22, 23, and 24 exhibited significant anti-inflammatory activity with IC50 values ranging from 8 ± 0.47 µg/mL to 14 ± 0.84 µg/mL, surpassing indomethacin.
• SAR analysis indicated that electron-donating groups favor H+/K+-ATPase and antioxidant activity, while electron-withdrawing groups enhance anti-inflammatory effects.
• Molecular docking revealed high binding affinity for compounds 25 (G-score = -9.063) and 26 (G-score = -8.977) with the H+/K+-ATPase active site.

Conclusions:

• The synthesized dihydrazone derivatives possess significant H+/K+-ATPase inhibitory and anti-inflammatory properties.
• Compounds 25 and 26 are promising candidates for developing novel gastric acid secretion inhibitors.
• The study provides valuable insights into the SAR of dihydrazones for potential therapeutic applications.