Lead modification via computational studies: Synthesis of pyrazole‐containing β‐amino carbonyls for the treatment of type 2 diabetes

Abstract

This article describes studies on the design, synthesis, and biological evaluation of pyrazole‐containing β‐amino carbonyl compounds (5a–5q) as DPP‐4 inhibitors and anti‐diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3)3) catalyst in the presence of ethanol and produced pyrazole‐containing β‐amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP‐4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme‐based in vitro DPP‐4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP‐4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5 nM, respectively. The most potent compound, 5j, was further selected for in vivo anti‐diabetic activity using an STZ‐induced diabetic mice model, and 5j showed a significant diabetic control effect.

Thermal, spectroscopic, ADMET and toxicological studies of synthesized β-Amino carbonyl compounds

“…All the synthesized compounds showed striking similarity with expected 1 H and 13 C spectra. In 13C spectra, all of the compounds showed a carbonyl range between 197-202 ppm, confirming keto-bond.…”

“…Elemental analysis for carbon, hydrogen, and nitrogen (C, H, N) was performed using the Elementar Analysensysteme Germany (Vario Micro Cube). The 1 H-NMR and 13 C-NMR spectra were recorded using the Jeol JNM-ECZ 400S instrument operating at 400 MHz and 100 MHz, respectively. The molecular weight was determined via Mass Spectrometry using the Xevo G2-XS QTof Mass Spectrophotometer, while FTIR (ATR) analysis was conducted using the Nicolet iS50 FTIR Tri-detector.…”

“…These compounds have been found to exhibit inhibitory effects on specific metabolic enzymes [10] and play a crucial role in diverse heterocyclic synthesis and pharmaceutical development [11] . The oral bioavailability [12] and toxicity [13] assessments have indicated their promising potential as potent drugs. However, limited attention has been given to the investigation of the thermal properties of these compounds.…”