Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors

Askin, Sercan; Tahtacı, Hakan; Türkeş, Cüneyt; Demir, Yeliz; Ece, Abdulilah; Çiftçi, Gülşen Akalın; Beydemır, Şükrü

doi:10.1016/j.bioorg.2021.105009

Cited by 93 publications

(57 citation statements)

References 112 publications

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“…The 4JIR was minimized using the Protein Preparation Wizard tool (Sastry et al, 2013; Türkeş, Beydemir, & Küfrevioğlu, 2019) applying force field OPLS4 with default parameters at pH 7.0 ± 0.0 (Cetin et al, 2021; Işık, Beydemir, et al, 2020) and the active site of its was predicted using the SiteMap module (Beydemir et al, 2019; Halgren, 2009). The docking grid box was generated used the Receptor Grid Generation tool (Askin et al, 2021; Kilic et al, 2020). Finally, docking runs were carried out using the extra precision (XP) method (Friesner et al, 2006; Türkeş, 2019a; Türkeş & Beydemir, 2020).…”

Section: Methodsmentioning

confidence: 99%

“…with default parameters at pH 7.0 ± 0.0 (Cetin et al, 2021; and the active site of its was predicted using the SiteMap module (Beydemir et al, 2019;Halgren, 2009). The docking grid box was generated used the Receptor Grid Generation tool (Askin et al, 2021;Kilic et al, 2020). Finally, docking runs were carried out using the extra precision (XP) method (Friesner et al, 2006;Türkes ¸, 2019a;.…”

Section: In Silico Studiesmentioning

confidence: 99%

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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%

Section: In Silico Studiesmentioning

confidence: 99%

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

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“…[31] Previously, dual hCAs/AChE inhibitors were reported to exert anticholinergic effects and play a vital role in several pathophysiological continuums mentioned above. [32][33][34][35][36][37][38][39][40][41] In a previous work conducted by our research team, [39] 1-(4-phenylthiazol- were identified as promising dual hCA/AChE inhibitors exerting their action at nanomolar levels (Figure 2). In the next process of our ongoing research on dual hCA/AChE inhibitors designed based on the molecular hybridization of thiazole and pyrazoline scaffolds, [15,39,42] herein, new thiazolyl-pyrazolines (4a-k) were synthesized according to a facile and versatile synthetic route.…”

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

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et al. 2021

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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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“…In vitro effects on AChE activity of the newly synthesized N -substituted sulfonyl amides ( 6a–j ) incorporating 1,3,4-oxadiazol structural motif and reference compound, THA, were evaluated by the method of Ellman et al [ 42 , 43 ]. Analysis results were obtained spectrophotometrically at 412 nm using acetylthiocholine iodide (PubChem CID: 74629, Sigma 01480) as a substrate as in our previous assays [ 44 , 45 ]. Also, h CAs ( h CA I and II) were purified from human erythrocytes by Sepharose‐4B‐ l ‐tyrosine‐sulfanilamide affinity chromatography.…”

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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Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors

Cited by 93 publications

References 112 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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