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

Abstract

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.

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

“…First, the 2D‐sdf formats of all molecules, including novel synthesized quinazolinone derivatives ( 1–21 ) and the reference compound, EPR, were sketched using ChemDraw version 19.1 for Mac (PerkinElmer, Inc., Waltham, MA, USA) and were subjected to ligand preparation using the LigPrep tool (Işık, Akocak, et al, 2020). These compounds were subjected to ADME‐Tox prediction using the QikProp module (Lolak et al, 2020; Sağlık et al, 2019; Sever, Türkeş, Altıntop, Demir, et al, 2021) and the pan‐assay interference compounds (PAINS) alerts (Baell & Holloway, 2010) were also evaluated using the SwissADME platform (Akocak et al, 2021). Moreover, the number of violations of Jorgensen's rule of three (Duffy & Jorgensen, 2000) and Lipinski's rule of five (Lipinski et al, 1997) for these molecules was investigated as described in previous studies (Durgun et al, 2020; Istrefi et al, 2020).…”

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

“…The ligand-binding sites were calculated using the Receptor Grid Generation tool [ 88 ]. LigPrep module was used for preparing all the synthesized N -substituted sulfonyl amides ( 6a–j ) where bond order and the bond angle were assigned as well as minimization was done using OPLS4 force field [ 89 ]. 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 ].…”

Screening of in vitro and in silico effect of Fluorophenylthiourea compounds on glucose 6‐phosphate dehydrogenase and 6‐phosphogluconate dehydrogenase enzymes

“…The X‐ray structures of the templates 6E08 55 (Resolution: 1.90 Å; Species: Homo sapiens) and 4GWK 56 (Resolution: 1.53 Å; Species: Homo sapiens) were obtained from the Protein Data Bank (http://www.rcsb.org/), 57‐59 and the Protein Preparation Wizard tool 60‐62 was used to construct them as in prior investigations. The Receptor Grid Generation panel was used to generate the docking grid box 63‐65 . The extra precision (XP) approach was used to perform molecular docking calculations 66‐68 .…”

“…The Receptor Grid Generation panel was used to generate the docking grid box. [63][64][65] The extra precision (XP) approach was used to perform molecular docking calculations. [66][67][68] The MM-GBSA binding energies [69][70][71][72] were computed using the VSGB energy model and the OPLS4 force field [72][73][74] to predict relative binding affinities for these fluorophenylthioureas.…”