Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-β type-I receptor kinase (ALK5)

Patel, Harun; Sing, Baljeet; Bhardwaj, Varun; Palkar, Mahesh B.; Shaikh, Mahamadhanif S.; Rane, Rajesh A.; Alwan, Wesam S.; Gadad, Andanappa K.; Noolvi, Malleshappa N.; Karpoormath, Rajshekhar

doi:10.1016/j.ejmech.2014.09.002

Cited by 50 publications

(29 citation statements)

References 19 publications

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“…In TGF‐β signalling, Smad2 or Smad3 binds to its specific TGF‐β receptor I, named ALK5, and is phosphorylated by the catalytic region of ALK5 . Based on our data described above, we then hypothesized that baicalein bound directly to the catalytic region of ALK5 to inhibit phosphorylation of Smad2 and Smad3.…”

Section: Resultsmentioning

confidence: 91%

“…Researchers have shown an affinity between a variety of small molecules and the ATP-binding site of ALK5, and such an interaction has been found to be associated with downregulated TGF-b signalling. 24,35,43 In light of this, we performed a molecular docking study and kinase binding assay in search of an interaction between baicalein and ALK5. Intriguingly, it was validated in our study that baicalein bound to the ATPbinding pocket of ALK5 through two hydrogen bonds in different directions.…”

Section: Discussionmentioning

confidence: 99%

“…In TGF-b signalling, Smad2 or Smad3 binds to its specific TGF-b receptor I, named ALK5, and is phosphorylated by the catalytic region of ALK5. 35 Based on our data described above, we then hypothesized that baicalein bound directly to the catalytic region of ALK5 to inhibit phosphorylation of Smad2 and Smad3. Therefore we performed a computational protein-molecule docking study using human ALK5 kinase domain models to determine whether baicalein might bind directly to ALK5.…”

Section: Baicalein Downregulates Phosphorylation Of Smad2 and Smad3mentioning

confidence: 99%

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Baicalein attenuates hypertrophic scar formation via inhibition of the transforming growth factor‐β/Smad2/3 signalling pathway

et al. 2015

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Baicalein Downregulates Phosphorylation Of Smad2 and Smad3mentioning

confidence: 99%

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Baicalein attenuates hypertrophic scar formation via inhibition of the transforming growth factor‐β/Smad2/3 signalling pathway

et al. 2015

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“…Among the most commonly used heterocyclic compounds in pharmaceutics and clinical drugs are imidazole, 1,3,4‐thiadiazole, and their derivatives. In recent years, synthesis and characterization studies of bioactive compounds such as imidazole and 1,3,4‐thiadiazole have been steadily increasing . The synthesis of compounds containing these bioactive groups together with various biological activities has received much interest as well .…”

Section: Introductionmentioning

confidence: 99%

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Molecular Docking Study, and Investigation of Their In Vitro Antifungal Activities

Tahtacı

Karakurt

et al. 2019

Journal of Heterocyclic Chem

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In this study, a new series of substituted imidazo[2,1‐b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2‐amino‐1,3,4‐thiadiazole derivatives (compounds 2a and 2b), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1‐b][1,3,4]thiadiazole derivatives (4–16), the target compounds, were synthesized from reactions of 2‐amino‐1,3,4‐thiadiazole derivatives (2a and 2b) with 2‐bromoacetophenone derivatives (3a–3i) (in yields of 52% to 71%). All of the synthesized compounds were characterized by 1H NMR, 13C NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X‐ray diffraction analysis (compounds 4–12, 14, and 15) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds (5, 6, and 8) were optimized using the density functional theory B3LYP/6‐31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.

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“…If a compound fails in this test, it is likely that some oral bioavailability problem will be encountered. 29 According to the RO5, the compounds should present logP ≤ 5, molecular weight ≤ 500, number of hydrogen bond acceptors (n ON ) ≤ 10, number of hydrogen bond donors (n OHNH ) ≤ 5, and number of rotatable bonds (n rotb ) ≤ 10, wherein compounds should not violate more than one rule. In this sense, molecules A, B and C were constructed in the Molinspiration Online Property Calculation Software Toolkit 30 for the evaluation of the Lipinski's Rule.…”

mentioning

confidence: 99%

Design of Novel N-Myristoyltransferase Inhibitors of Leishmania donovani Using Four-Dimensional Quantitative Structure-Activity Relationship Analysis

Santos-Garcia¹,

Silva²,

Assis³

et al. 2018

J. Braz. Chem. Soc.

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N-Myristoylation protein is catalyzed by N-myristoyltransferase (NMT), an essential target in Leishmania donovani, the causative agent of kala-azar. Four-dimensional quantitative structureactivity relationship (4D-QSAR) analysis was applied to a series of 77 Leishmania donovani NMT inhibitors. Then, three new compounds were proposed using QSAR models. In addition, molecular docking was performed to predict the binding affinities and interaction modes among the proposed compounds and the NMT active site. In silico absorption, distribution, metabolism and excretion (ADME) evaluation was performed and potential inhibitors demonstrated satisfactory pharmacokinetic properties.

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Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-β type-I receptor kinase (ALK5)

Cited by 50 publications

References 19 publications

Baicalein attenuates hypertrophic scar formation via inhibition of the transforming growth factor‐β/Smad2/3 signalling pathway

Baicalein attenuates hypertrophic scar formation via inhibition of the transforming growth factor‐β/Smad2/3 signalling pathway

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Molecular Docking Study, and Investigation of Their In Vitro Antifungal Activities

Design of Novel N-Myristoyltransferase Inhibitors of Leishmania donovani Using Four-Dimensional Quantitative Structure-Activity Relationship Analysis

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