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

Abstract

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.

Methyl benzoate derivatives: in vitro Paraoxonase 1 inhibition and in silico studies

“…6). Additionally, the drug probability of methyl benzoates (1-17) was assessed using the QikProp module [25][26][27] of derivatives exhibited drug-like qualities, showing that the compounds follow Lipinski [28] and Jorgensen's [29] criteria (Table 2).…”

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

“…Therefore, the efficacy and safety of the designed molecules were determined by computing the ADMET properties of top hits, (identified by docking studies) using some freely available tools such as SwissADME. [ 47–51 ]…”

“…Therefore, the efficacy and safety of the designed molecules were determined by computing the ADMET properties of top hits, (identified by docking studies) using some freely available tools such as SwissADME. [47][48][49][50][51] 4.11 | Chemicals, synthesis, and characterization Chemicals and solvents used for the synthesis were of analytical grade and were purchased from Sigma Aldrich, S.D. Fine and Loba Chemicals.…”

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

“…The Maestro ver. 13.1, 41 Protein Preparation Wizard, 42 SiteMap, 43 Receptor Grid Generation, 44 LigPrep, 45 Glide Ligand Docking, 46 and Prime MM‐GBSA 47 tools from the Small‐Molecule Drug Discovery Suite 2022‐1 for Mac (Schrödinger, LLC, NY, USA) were used to perform molecular docking calculations. Fluorophenylthioureas were sketched in the 2D‐sdf format using ChemDraw ver.…”