Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors

Türkeş, Cüneyt; Akocak, Süleyman; Işık, Mesut; Lolak, Nabih; Taslimi, Parham; Durgun, Mustafa; Gülçın, İlhami; Budak, Yakup; Beydemır, Şükrü

doi:10.1080/07391102.2021.1916599

Cited by 75 publications

(51 citation statements)

References 94 publications

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“…Finally, docking runs were carried out using the extra precision (XP) method (Friesner et al, 2006; Türkeş, 2019a; Türkeş & Beydemir, 2020). MM‐GBSA binding energies (Barreiro et al, 2007; Sever, Türkeş, et al, 2020), which predict relative binding affinities for these quinazolinone derivatives ( 1–21 ), were also computed in the VSGB energy model (Türkeş, Akocak, et al, 2021; Yaşar et al, 2021) and OPLS4 force field.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

et al. 2021

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A series of novel sulfonates containing quinazolin-4(3H)-one ring derivatives was designed to inhibit aldose reductase (ALR2, EC 1.1.1.21). Novel quinazolinone derivatives (1-21) were synthesized from the reaction of sulfonated aldehydes with 3-amino-2-alkylquinazolin-4(3H)-ones in glacial acetic acid with good yields (85%-94%). The structures of the novel molecules were characterized using IR, 1 H-NMR, 13 C-NMR, and HRMS. All the novel quinazolinones (1-21) demonstrated nanomolar levels of inhibitory activity against ALR2 (K I s are in the range of 101.50-2066.00 nM). Besides, 4-[(2-isopropyl-4-oxoquinazolin-3[4H]-ylimino)methyl]phenyl benzenesulfonate (15) showed higher inhibitor activity inhibited ALR2 up to 7.7-fold compared to epalrestat, a standard inhibitor. Binding interactions between ALR2 and quinazolinones have been investigated using Schrödinger Small-Molecule Drug Discovery Suite 2021-1, reported possible inhibitor-ALR2 interactions. Both in vitro and in silico study results suggest that these quinazolin-4(3H)-one ring derivatives (1-21) require further molecular modification to improve their drug nominee potency as an ALR2 inhibitor.

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Section: Methodsmentioning

confidence: 99%

Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

et al. 2021

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“…To begin with, the X-ray crystal structures of the hCA I (PDB code: 4WUQ, species Homo sapiens), [71] hCA II (PDB code: 4FU5, species H. sapiens), and AChE (PDB code: 4EY7, species H. sapiens), [72] which have resolutions of 1.55, 0.98, and 2.35 Å, respectively, were retrieved from the RCSB Protein Data Bank. [73] These were prepared by adding hydrogen atoms, bond orders, and missing side chains by proper ionization at pH 7.0 ± 2.0 [74] using the Protein Preparation Wizard panel [75,76] integrated into the Schrödinger Small-Molecule Drug Discovery Suite [77] 2021-2 for Mac (Schrödinger, LLC). Thereupon, the 2D structures of the new hybrid thiazolyl-pyrazoline derivatives (4a-k) were drawn utilizing the ChemDraw version 19.1 for Mac (PerkinElmer, Inc.) [78] and suitably optimized for docking by the LigPrep tool [79] using the OPLS4 force field [80] at a pH range of 7.0 ± 2.0 using Epik.…”

Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

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Türkeş

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et al. 2021

Archiv der Pharmazie

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New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined.All new thiazolyl-pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with K I values in the range of 13.35-63.79, 7.01-115.80, and 17.89-48.05 were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a-k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand-receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.

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“…The prepared small molecules were docked into the binding sites of the target enzymes by the Ligand Docking module with Glide extra precision (XP) mode [ 90 – 92 ]. MM-GBSA relative binding free energy computations [ 93 – 95 ] of target proteins (4EY7, 6I0L, and 5NY3) with the agents were carried out using the Prime tool in the VSGB energy model and OPLS4 force field [ 96 , 97 ].…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

et al. 2022

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The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and h CAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and h CAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N -substituted sulfonyl amide derivatives ( 6a–j ) were determined to be highly potent inhibitors for AChE and h CAs ( K I s are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE, h CA I, and h CA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a , 6d , and 6h , which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and h CAIs. The docking studies revealed precise binding modes between 6a , 6d , and 6h and h CA II, h CA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and h CAIs. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10422-8.

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Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors

Cited by 75 publications

References 94 publications

Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

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