Design, synthesis,<i>in silico</i>molecular modelling studies and biological evaluation of novel indole-thiazolidinedione hybrid analogues as potential pancreatic lipase inhibitors

George, Ginson; Auti, Prashant S.; Paul, Atish T.

doi:10.1039/d0nj05649a

Cited by 23 publications

(16 citation statements)

References 36 publications

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“…The key starting materials, TZD ( 3 ) was synthesized by the condensation reaction of thiourea ( 1 ) with chloroacetic acid ( 2 ) under ice‐cold condition followed by acidification and refluxing. N ‐arylated analogues of TZD ( 4 ) and indole‐3‐carboxaldehyde ( 5a–5f ) were obtained by the treatment of the corresponding starting materials ( 3 or 5 ) with NaH in anhydrous THF, followed by the addition of various alkyl/aryl halides (George et al., 2020). The final hybrid analogues ( 6a to 6ab ) were prepared by Knoevenagel condensation, wherein 4 and 5a–f derivatives in ethanol were refluxed in the presence of piperidine and glacial acetic acid.…”

Section: Resultsmentioning

confidence: 99%

“…The in vitro PL inhibitory activity of the synthesized analogues were evaluated by a standardized assay protocol (George et al., 2020; Sridhar, Bhurta, et al., 2017). As summarized in Table 1, synthesized analogues displayed potential to moderate PL inhibition (IC 50 ‐6.19 to 45.00 µM).…”

Section: Resultsmentioning

confidence: 99%

“…To find out the putative mode of structural interactions responsible for the PL inhibition, molecular docking simulation of the analogues were performed with the crystal structure of the PL‐Colipase complex (PDB ID: 1LPB, 2.46 Å resolution n ) via Molegro Virtual Docker 6.0 (Thomsen & Christensen, 2006) with validated grid parameters (George et al., 2020; Sridhar, Bhurta, et al., 2017). The obtained MolDock scores and the various interactions exhibited by the hybrid analogues are represented in Figure 7 and Supplementary Data.…”

Section: Resultsmentioning

confidence: 99%

“…The experimental procedures for synthesis and biological evaluation for analogues ( 6a to 6ab ) have been discussed elsewhere [(George et al., 2020; Sridhar, Ginson, et al., 2017) Supplementary Data].…”

Section: Methodsmentioning

confidence: 99%

“…Some of the five‐membered heterocycles possessed these active warheads for the PL inhibition. For instance, thiazolidinedione and rhodanine analogues with a nitrogen centred diamide linkage exerted a potential PL inhibitory activity (Chauhan et al., 2019; George et al., 2020; Sridhar, Bhurta, et al., 2017). The structural diversity at two positions of thiazolidinedione and rhodanine offers an additional advantage for the further incorporation of essential pharmacophoric features coverts these as attractive structural scaffolds in the area of PL inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and biological evaluation of N‐substituted indole‐thiazolidinedione analogues as potential pancreatic lipase inhibitors

2021

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Pancreatic Lipase (PL) is a key enzyme responsible for the digestion of 50%–70% of dietary triglycerides, hence its inhibition is considered as a viable approach for the management of obesity. A series of indole‐TZD hybrid analogues were synthesized, characterized and evaluated for their PL inhibitory activity. Knoevenagel condensation of various substituted indole‐3‐carboxaldehyde with substituted thiazolidinediones resulted in the formation of titled analogues. Analogues 6d and 6e exerted potent PL inhibitory activity (IC50‐6.19 and 8.96 µM, respectively). Further, these analogues exerted a competitive mode of PL inhibition. Moreover, molecular modelling studies were in agreement with the in vitro results (Pearson's r = .8682, p < .05). The fluorescence spectroscopic analysis further supported the strong binding affinity of these analogues with PL. A molecular dynamics study (20 ns) indicated that these analogues were stable in a dynamic environment. Thus, the present study highlighted the potential role of indole‐thiazolidinedione hybrid analogues as potential PL inhibitors and further optimization might result in the development of new PL inhibitory lead candidates.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and biological evaluation of N‐substituted indole‐thiazolidinedione analogues as potential pancreatic lipase inhibitors

2021

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Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

Jagetiya,

Auti,

Paul

2023

Chemistry & Biodiversity

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Inhibition of Pancreatic lipase (PL) is considered to be a promising target for management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide‐hydrazone analogues (5aa‐cm) were designed, synthesized and evaluated for their PL inhibitory potential. The designed analogues were synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the analogues showed PL inhibitory activity in the range of 4.13 – 48.35 µM, as compared with orlistat (0.86 ± 0.09 µM). The most potent analogue 5bi (IC50 = 4.13 ± 0.95 µM) was found to show a competitive type of inhibition with Ki value of 0.725 µM. Additionally, the molecular docking study proved the binding of analogue 5bi at the active site of PL (PDB ID: 1LPB) with MolDock score of ‐141.279 kcal/mol. Furthermore, the protein‐ligand complex of analogue 5bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Å for the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide‐hydrazone analogues in PL inhibition and further optimization could result in the generation of new leads as anti‐obesity agents.

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5‐Indolylidene‐2‐iminothiazolidin‐4‐ones – Convenient Starting Compounds for Stereoselective Synthesis of Novel Dispirooxindole Derivatives

et al. 2022

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A convenient method for the synthesis of novel dispirooxindoles containing 2‐iminothiazolidin‐4‐one moiety has been proposed. The method relies on a 1,3‐dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N‐alkyl amino acids including chiral ones to 5‐indolylidene‐2‐iminothiazolidin‐4‐ones. The method is suitable for preparing enantiomerically pure derivatives.

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Design, synthesis,in silicomolecular modelling studies and biological evaluation of novel indole-thiazolidinedione hybrid analogues as potential pancreatic lipase inhibitors

Abstract: A series of thiazolidinedione-indole hybrids are designed and synthesized as a potential inhibitor for pancreatic lipase (PL).

Cited by 23 publications

References 36 publications

Design, synthesis and biological evaluation of N‐substituted indole‐thiazolidinedione analogues as potential pancreatic lipase inhibitors

Design, synthesis and biological evaluation of N‐substituted indole‐thiazolidinedione analogues as potential pancreatic lipase inhibitors

Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

5‐Indolylidene‐2‐iminothiazolidin‐4‐ones – Convenient Starting Compounds for Stereoselective Synthesis of Novel Dispirooxindole Derivatives

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