Design, synthesis, biological evaluation and docking analysis of pyrrolidine-benzenesulfonamides as carbonic anhydrase or acetylcholinesterase inhibitors and antimicrobial agents

Recent insights about pyrrolidine core skeletons in pharmacology

“…Recently, our research group designed N- benzoylthiourea-pyrrolidine carboxylic acid derivative compounds carrying a series of imidazole rings as cholinesterase inhibitors, and their acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) inhibition properties were compared with those of the reference tacrine. The most active compounds were found to be phenyl- and methyl-substituted 15g (IC 50 : 0.029 µM), 15h (IC 50 : 0.041 µM), and 16g (IC 50 : 0.087 µM) with an indole ring in their structures ( Poyraz et al, 2023a ). Moreover, as part of our ongoing research work related to pyrroline-based potential bioactive molecules, we recently reported the design and synthesis of novel pyrrolidine-based benzenesulfonamide derivatives as carbonic anhydrase/acetylcholinesterase inhibitors, together with their antimicrobial properties.…”

“…Thus, compounds 19a and 19b bearing 2,4-dimethoxyphenyl and 4-methoxyphenyl substituents were the most promising AChE inhibitor candidates with the K i values of 22.34 ± 4.53 nM and 27.21 ± 3.96 nM, respectively, compared to tacrine inhibition. Compound 18 without a sulfonamide moiety showed significant inhibition of the hCAI enzyme, with a K i value of 17.61 ± 3.58 nM, approximately 10 times greater than that of the reference AZA (164.22 ± 14.13 nM), and for the hCAII enzyme, with a K i value of 5.14 ± 0.61 nM, approximately 26 times greater than that of the reference AZA (132.53 ± 7.44 nM) ( Poyraz et al, 2023a ).…”

“…Compounds bearing pyrrolidine scaffolds continue to be utilized as intermediates in drug research and development (R&D) studies for the development of molecules that could be new drug candidates ( Jeelan Basha et al, 2022 ; Bhat et al, 2023a ). Some pyrrolidine derivatives are known to be employed as pharmacophore groups, with some having antibacterial ( Huang et al, 2015 ), antifungal ( Lukowska-Chojnacka et al, 2019 ), antiviral ( Moni et al, 2015 ), antimalarial ( Meyers et al, 2019 ), antitumoral ( Li et al, 2020 ), anti-inflammatory ( Jan et al, 2020 ), anticonvulsant ( Góra et al, 2020 ), and antioxidant ( Hussain et al, 2019 ) activities, while others have diverse enzyme inhibitory effects ( Zhou et al, 2019 ; Salve and Jadhav, 2021 ; Toumi et al, 2021 ; Poyraz et al, 2023a ). In addition, several compounds with essential bioactive characteristics have been reported in the literature that comprise fused or spiropyrrolidine rings ( Łowicki and Przybylski, 2022 ).…”

Using deep learning and molecular dynamics simulations to unravel the regulation mechanism of peptides as noncompetitive inhibitor of xanthine oxidase

“…Molecular dynamics simulation is a strong method to investigate conformational changes of proteins, protein folding, protein–ligand binding, etc. 29 , 30 In this study, we conducted 200 ns classical molecular dynamics simulation after global molecular docking, we also utilized deep learning method NRI-MD 28 to reveal allosteric pathways, and explored the specific mechanism of non-competitive inhibition of XO by two different peptide inhibitors, including differences in peptide structure and different effects on protein conformations. This study may provide clues for the rational design of peptide inhibitors for XO.…”