Novel glitazones as PPARγ agonists: molecular design, synthesis, glucose uptake activity and 3D QSAR studies

Abstract

BackgroundAn alarming requirement for finding newer antidiabetic glitazones as agonists to PPARγ are on its utmost need from past few years as the side effects associated with the available drug therapy is dreadful. In this context, herein, we have made an attempt to develop some novel glitazones as PPARγ agonists, by rational and computer aided drug design approach by implementing the principles of bioisosterism. The designed glitazones are scored for similarity with the developed 3D pharmacophore model and subjected for docking studies against PPARγ proteins. Synthesized by adopting appropriate synthetic methodology and evaluated for in vitro cytotoxicity and glucose uptake assay. Illustrations about the molecular design of glitazones, synthesis, analysis, glucose uptake activity and SAR via 3D QSAR studies are reported.ResultsThe computationally designed and synthesized ligands such as 2-(4-((substituted phenylimino)methyl)phenoxy)acetic acid derivatives were analysed by IR, 1H-NMR, 13C-NMR and MS-spectral techniques. The synthesized compounds were evaluated for their in vitro cytotoxicity and glucose uptake assay on 3T3-L1 and L6 cells. Further the activity data was used to develop 3D QSAR model to establish structure activity relationships for glucose uptake activity via CoMSIA studies.ConclusionThe results of pharmacophore, molecular docking study and in vitro evaluation of synthesized compounds were found to be in good correlation. Specifically, CPD03, 07, 08, 18, 19, 21 and 24 are the candidate glitazones exhibited significant glucose uptake activity. 3D-QSAR model revealed the scope for possible further modifications as part of optimisation to find potent anti-diabetic agents.

Competent synthesis of biaryl analogs via asymmetric Suzuki–Miyaura cross-coupling for the development of anti-inflammatory and analgesic agents

“…A molecular docking study fundamentally defines the binding modes of ligand interaction at the active site of the receptor [ 26 ]. In our study, the active compounds exhibiting notable activity were subjected to docking studies to assess their interaction with the inflammatory proteins COX-1 and COX-2, and the results are shown in Table 5 .…”

“…The synthesized compounds were virtually sketched for docking operation using the SERFLEXDOCK program present in the SYBYL-X 2.1.1 software package (Tripose, USA), and necessary calculations were performed as per Mandal et al [ 26 ]. The overall procedure of the DOCKING program includes ligand preparation, protein preparation, Protomol generation, and docking of ligands.…”

“…For performing temperature–pressure coupling, a coupling constant of 2 ps was applied using the extended ensemble Parrinello–Rahman algorithm. The equilibrated system was then subjected to 10 ns of production run [ 26 ] with a 2 fs time step integration. The trajectories were saved every 500 steps and analyzed using GROMACS analysis tools and the XMGRACE-5.1.22 program ( http://plasma-gate.weizmann.ac.il/Grace/ ).…”

Novel Imidazole Phenoxyacetic Acids as Inhibitors of USP30 for Neuroprotection Implication via the Ubiquitin-Rho-110 Fluorometric Assay: Design, Synthesis, and In Silico and Biochemical Assays

“…The equilibrated system was thus subjected to 50 ns of MD production run with a time step integration of 2 fs (0.002 ps). The trajectories were saved for every 500 steps and analyzed using default GROMACS analysis tools and plotted using the XMGRACE-5.1.22 program (). , …”

Isolation and characterization of ACE‐I inhibitory peptides from ribbonfish for a potential inhibitor of the main protease of SARS‐CoV‐2: An in silico analysis

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