Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors.

Eleven new thiosemicarbazone derivatives (1-11) were designed from nine different biologically and pharmacologically important isothiocyanate derivatives containing functional groups such as fluorine, chlorine, methoxy, methyl, and nitro at various positions of the phenyl ring, in addition to the benzyl unit in the molecular skeletal structure. First, their substituted-thiosemicarbazide derivatives were synthesized from the treatment of isothiocyanate with hydrazine to synthesize the designed compounds. Through a one-step easy synthesis and an eco-friendly process, the designed compounds were synthesized with yields of up to 95 % from the treatment of the thiosemicarbazides with aldehyde derivatives having methoxy and hydroxy groups. The structures of the synthesized molecules were elucidated with elemental analysis and FT-IR, 1 H-NMR, and 13 C-NMR spectroscopic methods. The electronic and spectroscopic properties of the compounds were determined by the DFT calculations performed at the B3LYP/6-311++G(2d,2p) level of theory, and the experimental findings were supported. The effects of some global reactivity parameters and nucleophilic-electrophilic attack abilities of the compounds on the enzyme inhibition properties were also investigated. They exhibited a highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 23.54±4.34 to 185.90±26.16 nM, 103.90±23.49 to 325.90±77.99 nM, and 86.15±18.58 to 287.70±43.09 nM for AChE, hCA I, and hCA II, respectively). Furthermore, molecular docking simulations were performed to explain each enzyme-ligand complex's interaction.

Synthesis, anticancer activity and molecular modeling study of novel substituted triazole linked tetrafluoronaphthalene hybrid derivatives.

To create some novel anticancer molecules, a library of novel series of various triazoles linked to the hydroxyl group of 5,6,7,8-tetrafluoronaphthalen-1-ol (3) was designed and synthesized via CuAAC reaction 'Click Chemistry' of tetrafluoronaphthalene based terminal alkyne with substituted organic azides. The structural characterizations of the targeted Click products 9-18 were confirmed by FTIR, 1H NMR, 19F NMR, 13C NMR and HRMS spectroscopy. Synthesized compounds were tested in two triple negative breast cancer (TNBC) cell lines to understand their anticancer potentials. According to our findings, compounds 14 and 13 showed high cytotoxicity in BT549 cells at 20 µM and 30 µM, respectively. Moreover, these compounds blocked the migration of BT549 cells. In the MDA-MB-231 cell line, compound 18 exhibited high cytotoxicity and can block cell migration for 24 h. Molecular docking study with synthesized novel compounds was performed by Glide/SP method against SphK1 drug target. Furthermore, molecular dynamics (MD) simulation was carried out for the compounds 12-14 and 18. The compounds 13 and 14 may be potential inhibitor candidates in place of a reference inhibitor. A pharmacophore model was generated with the most potent compound 14, and the approved drugs were screened using the modules of Discovery Studio to find similar drugs. Consequently, this comprehensive study encompassing design, synthesis, in vitro and in silico analyses were correlated with the structure-activity relationship between compounds. The findings have the potential to unveil promising drug candidates for future studies.Communicated by Ramaswamy H. Sarma.

Enzyme inhibition, molecular docking, and density functional theory studies of new thiosemicarbazones incorporating the 4-hydroxy-3,5-dimethoxy benzaldehyde motif.

New Schiff base-bearing thiosemicarbazones (1-13) were obtained from 4-hydroxy-3,5-dimethoxy benzaldehyde and various isocyanates. The structures of the synthesized molecules were elucidated in detail. Density functional theory calculations were also performed to determine the spectroscopic properties of the compounds. Moreover, the enzyme inhibition activities of these compounds were investigated. They showed highly potent inhibition effects on acetylcholinesterase (AChE) and human carbonic anhydrases (hCAs) (KI values are in the range of 51.11 ± 6.01 to 278.10 ± 40.55 nM, 60.32 ± 9.78 to 300.00 ± 77.41 nM, and 64.21 ± 9.99 to 307.70 ± 61.35 nM for AChE, hCA I, and hCA II, respectively). In addition, molecular docking studies were performed, confirmed by binding affinities studies of the most potent derivatives.

Substituted naphthoxy-phthalonitrile derivatives: Synthesis, substituent effects, DFT, TD-DFT Calculations, antimicrobial properties and DNA interaction studies.

Herein, substituted-naphthol derivatives 4a-e were synthesized in two steps, namely the Diels Alder cycloaddition and Cu-catalyzed aromatization reactions, respectively. Then, pththalonitrile derivatives 7-12 have been prepared by a nucleophilic displacement reaction of 3-nitrophthalonitrile with the naphthol derivatives 4a-e, 5 and, obtained in excellent yields. Structural characterization of the compounds was identified by different spectroscopic techniques. Antimicrobial properties of the synthesized compounds were determined by the microdilution procedure against Gram-positive, Gram-negative bacteria, and yeast. Furthermore, the DNA interaction of the compounds were determined by gel electrophoresis. One of the most prominent findings is that compounds 9 and 10 have more inhibitory effects on Gram-positive bacteria than Gram-negative bacteria. These compounds especially exhibited the highest antibacterial potency against S. aureus (625 µg/mL) among Gram-positive bacteria. According to the plasmid DNA interaction results, the synthesized compounds caused changes in the structure and mobility of the plasmid DNA. Then, geometry optimizations and frequency calculations were conducted at B3LYP/6-311 G(d,p) level of DFT, and optimized structures were used for further analyses. The NBO results revealed that the π→π * and n→π * interactions were greatly contributed to lowering the stabilization energy of all compounds (7-12). FMO energy analyses showed that compound 9 has the biggest electrodonating power.

Synthesis and biological evaluation of some 1-naphthol derivatives as antioxidants, acetylcholinesterase, and carbonic anhydrase inhibitors.

A series of some naphthol derivatives 4a-f, 5a,f, 6a, and 7a,b (six novel ones: 4c,d, 5a, 6a, 7a,b) bearing F, Cl, Br, OMe, and dioxole substituents at different positions of the aromatic rings was designed, synthesized, and characterized. The naphthol derivatives were synthesized in three steps, namely the addition reaction of furan via Diels-Alder cycloaddition reaction, copper(II) trifluoromethanesulfonate (Cu(OTf)2 )-catalyzed aromatization reaction, and the bromination reaction, respectively. The structures of the newly obtained compounds (4c,d, 5a, 6a, 7a,b) were characterized by spectroscopic techniques. In addition, some biological activity studies were investigated under in vitro conditions. Inhibition studies of these compounds were performed on human carbonic anhydrase (hCA) I and II isoenzymes purified from human erythrocytes as a biological evaluation. Moreover, their potential antioxidant and antiradical activities were studied by analytical methods like ABTS•+ and DPPH• scavenging, and it was determined that some molecules showed good activity. Also, inhibition of acetylcholinesterase (AChE), which is a marker of many degenerative neurological diseases, was tested and the results were discussed. Excellent enzyme inhibition results were recorded for most of the molecules. These 1-naphthol derivatives were found as effective inhibitors for hCA I, hCA II, and AChE with K i values ranging from 0.034 ± 0.54 to 0.724 ± 0.18 µM for hCA I, 0.172 ± 0.02 to 0.562 ± 0.21 µM for hCA II, and 0.096 ± 0.01 to 0.177 ± 0.02 µM for AChE.

Synthesis and docking calculations of tetrafluoronaphthalene derivatives and their inhibition profiles against some metabolic enzymes.

Syntheses of tetrahydroepoxy, O-allylic, O-prenylic, and O-propargylic tetrafluoronaphthalene derivatives, starting from 1-bromo-2,3,4,5,6-pentafluorobenzene, are reported here for the first time. The O-substituted tetrafluoronaphthalene derivatives were designed and also synthesized via a one-pot nucleophilic substitution reaction in excellent yields, whereas the tetrafluorotetrahydroepoxynaphthalene derivate was synthesized via a reduction reaction in excellent yield. The chemical structures of all the synthesized molecules were characterized by nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry techniques. In this study, a series of novel tetrafluoronaphthalene derivatives (2, 2a, 4-6) was tested toward several enzymes including α-glucosidase, acetylcholinesterase (AChE), and human carbonic anhydrase I and II (hCA I/II). The tetrafluoronaphthalene derivatives 2, 2a, and 4-6 showed IC50 and Ki values in the range of 0.83-1.27 and 0.71-1.09 nM against hCA I, 1.26-1.85 and 1.45-5.31 nM against hCA II, 39.02-56.01 and 20.53-56.76 nM against AChE, and 15.27-34.12 and 22.58-30.45 nM against α-glucosidase, respectively. Molecular docking calculations were made to determine the biological activity values of the tetrafluoronaphthalene derivatives against the enzymes. After the calculations, ADME/T analysis was performed to examine the effects on human metabolism. Finally, these compounds had antidiabetic and anticholinesterase potentials.

Design, synthesis, characterization, and anticancer activity of a novel series of O-substituted chalcone derivatives.

A new series of O-substituted chalcone derivatives bearing an/a allyl-, prenyl- or propargyl-substituent at different positions of rings A and B and their derivatives as drug leads, was designed, synthesized, and characterized. The chalcone derivatives were synthesized via base catalyzed Claisen-Schmidt condensation in MeOH or EtOH solutions of appropriately substituted aromatic ketones with O-allyl, and O-propargylvanillin, respectively. The intermediates O-substituted phenylketone derivatives were firstly synthesized by nucleophilic substitution reaction. All the newly synthesized compounds were characterized by IR, NMR spectral data and elemental analyses. A preliminary cytotoxicity was performed with the compounds (1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a-f, 6a-d, 7a-d) and the positive control, doxorubicin towards CCRF-CEM leukemia cells. Amongst them, compounds 1a, 2a, 5b-d, 6b, 7a, 7c and doxorubicin displayed IC50 values below 20 µM while other compounds were less or not active at up to 50 µM. Remarkably interesting cytotoxic effects, with IC50 values below 1 µM were recorded with 5c against HCT116 p53-/- colon adenocarcinoma cells, 5e against CCRF-CEM cells and MDA-MB-231-BCRP breast adenocarcinoma cells, and 6b against HCT116 p53+/+ cells and HCT116 p53-/- cells.