Discovery of a benzimidazole series of ADAMTS-5 (aggrecanase-2) inhibitors by scaffold hopping

Sogame, Shinya; Suenaga, Yoshihito; Atobe, Masakazu; Kawanishi, Masashi; Tanaka, Eiichi; Miyoshi, Shiro

doi:10.1016/j.ejmech.2013.10.075

Cited by 15 publications

(6 citation statements)

References 21 publications

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“…One pot condensation reaction of heterocyclic amine with aryl/heteroaryl carbonyl compounds gave desired SBs. Benzimidazole was chosen as a heterocyclic amine due to its wide availability as a bioactive scaffold [2, 18] and diversified pharmaceutical applications [19, 20, 21, 22, 23, 24, 25, 26, 27, 28] with DNA minor groove binding capability [29].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole

Singhal

Khanna

2019

Heliyon

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Novel Schiff bases (SBs) were synthesized by condensation of 2-(1-Amino benzyl) benzimidazole with heterocyclic and aromatic carbonyl compounds. The structural characterization was done using 1H, 13C NMR, FTIR and ES-MS spectroscopic techniques. The in silico pharmacokinetics showed that nearly all compounds obeyed Lipinski rule of 5 with low toxicity and metabolic stability. The global reactivity descriptors were calculated using DFT approach. The molecular docking result of SBs with ct-DNA suggested interaction via groove binding mode. The antibacterial activity was tested against S. aureus and E. coli, indicated significant inhibition than reference drug. The compound 4d gave best results at 50 μg ml−1 concentrations. UV/Vis and Fluorescence spectroscopy tools were used to evaluate ct-DNA binding ability of compounds 4a–e through hypochromic shift. The steady state fluorescence predicted a moderate binding constant of 1.12 × 104 for 4d, indicative of non-intercalative mode.

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Section: Introductionmentioning

confidence: 99%

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole

Singhal

Khanna

2019

Heliyon

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“…87 However, given the magnification To address this issue, the structure of compound 31 was modified by removing the carboxylic acid alkyl chain, which was considered responsible for the low membrane permeability, while maintaining the thiazolidinone as ZBG. 89 The 2-pyridyl thiazole central core was then replaced by various heterocyclic systems (monocycle, bicycle, or tricycle) to investigate the effect on ADAMTS5 inhibition. The benzimidazole derivative 32 (Figure 12) showed improved membrane permeability compared to 31, but this was achieved at a cost of a loss in selectivity over MMPs and ADAM17.…”

Section: Inhibitors With Sulfur-basedmentioning

confidence: 99%

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

et al. 2022

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Osteoarthritis (OA) is the most common degenerative joint disease. In 1999, two members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family of metalloproteinases, ADAMTS4 and ADAMTS5, or aggrecanases, were identified as the enzymes responsible for aggrecan degradation in cartilage. The first aggrecanase inhibitors targeted the active site by chelation of the catalytic zinc ion. Due to the generally disappointing performance of zinc-chelating inhibitors in preclinical and clinical studies, inhibition strategies tried to move away from the active-site zinc in order to improve selectivity. Exosite inhibitors bind to proteoglycan-binding residues present on the aggrecanase ancillary domains (called exosites). While exosite inhibitors are generally more selective than zinc-chelating inhibitors, they are still far from fulfilling their potential, partly due to a lack of structural and functional data on aggrecanase exosites. Filling this gap will inform the design of novel potent, selective aggrecanase inhibitors.

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“…Some protocols describe utilization of 3-bromodihydrofuran-2(3H)-one (α-bromoγ-butyrolactone) as [C2] 2+ syntons for synthesis of substituted 4-thiazolidinone derivatives in [2+3]cyclocondensation reactions with row of S,N-binucleophiles. The thioamides [13], mono-and disubstituted thioureas [14], thiosemicarbazides and thiocarbohydrazides [15] react with α-bromo-γbutyrolactone by Hantzsch type reaction under mild conditions provides to appropriate 5hydroxoethyl-4-thiazolidinone derivatives.…”

Section: Introductionmentioning

confidence: 99%

Study of 1,2,4-triazole-3(5)-thiol Behavior in Reactions with 1-phenyl-1H-pyrrole-2,5-dione Derivatives and 3-bromodihydrofuran-2(3H)-one and Antimicrobial Activity of Products

Holota

Derkach

Antoniv

et al. 2020

The 24th International Electronic Conference on Synthetic Organic Chemistry

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In present work we report our studies of the interaction of 1-phenyl-1H-pyrrole-2,5-dione derivatives (N-arylmaleimides) and 3-bromodihydrofuran-2(3H)-one (α-bromo-γ-butyrolactone) as possible [C2] 2+ synthons with 1,2,4-triazole-3(5)-thiole targeting on synthesis of novel 5substituted thiazolo[3,2-b][1,2,4]triazole-6-ones. According to obtained results was establish that in above-mentioned interactions (conditions: convenient heating, range of solvents/reaction time) the thiol-ene click (for N-arylmaleimides) and SN (for α-bromo-γ-butyrolactone) processes take place, but not [2+3]-cyclocondensation reaction. The structure of compounds was studied using 1 H, 13 C NMR spectroscopy, LC-MS spectrometry and X-ray analysis. The prescreening of antimicrobial activity for synthesized compounds was performed against Gram-positive and Gram-negative bacteria, as well as yeasts.

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Discovery of a benzimidazole series of ADAMTS-5 (aggrecanase-2) inhibitors by scaffold hopping

Cited by 15 publications

References 21 publications

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

Study of 1,2,4-triazole-3(5)-thiol Behavior in Reactions with 1-phenyl-1H-pyrrole-2,5-dione Derivatives and 3-bromodihydrofuran-2(3H)-one and Antimicrobial Activity of Products

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