Imine Derivatives of Hydrochlorothiazide Bear Potential Diuretic Activity in in vivo Experimental Model by Targeting Renal Outer Medullary Potassium Channel

Introduction: This study involves several recently synthesized Schiff base derivatives of hydrochlorothiazide (3a-3e), characterized by advanced spectroscopic techniques including Fourier transform infrared (FTIR), 1H-, 13C-NMR (Nuclear magnetic resonance), and High-resolution electrospray ionization mass spectrometry (HR-ESI-MS). Methods: Hydrochlorothiazide (HCTZ, 2 mM) was mixed with 2 mM aldehydes in ethanol (20 mL) in the presence of glacial acetic acid, and the product was stirred with the help of a magnetic stirrer under the specified conditions. Keeping in mind the importance of imine derivatives against DPPH radical, the synthesized compounds were evaluated for antioxidant activity (in-vitro) using DPPH assay and diuretic activity (in-vivo) by Lipschitz method. All derivatives demonstrated notable antioxidant activity, exhibiting 52-86% inhibition. Results: The compounds 3a-3e also displayed remarkable diuretic effects in an in-vivo model at a dose of 50 mg/kg. The computational studies of all the newly synthesized compounds were interpreted for the diuretic activity at the molecular level against human renal outer medullary potassium channel (ROMK1, PDB: ID) protein present on the nephron involved in diuresis indicating all compounds showed significant interactions at all receptors. Conclusion: As the derivatives were more active than drugs in some regards; therefore, these derivatives will be beneficial and open new windows for research and additional pharmacological screening could be planned as part of the project's extension.