New sulfonamide derivatives based on 1,2,3-triazoles: synthesis, in vitro biological activities and in silico studies.

Eight new hybrid constructs containing a series of sulfonamide and 1,2,3-triazole units were designed and synthesized. Anticancer, antioxidant and cholinesterase activities of these hybrid structures were investigated. In our design, the Cu(I)-catalyzed click reaction between N,4-dimethyl-N-(prop-2-yn-1-yl)benzenesulfonamide (6) and aryl azides 8a-h was used. Antioxidant activity values of 9f (IC50: 229.46 ± 0.001 µg/mL) and 9h (IC50: 254.32 ± 0.002 µg/mL) hybrid structures were higher than BHT (IC50: 286.04 ± 0.003 µg/mL) and lower than Ascorbic acid (IC50: 63.53 ± 0.001 µg/mL) and α-Tocopherol (IC50: 203.21 ± 0.002 µg/mL). We determined that the cytotoxic effects of hybrid constructs 9d (IC50: 3.81 ± 0.1084 µM) and 9g (IC50: 4.317 ± 0.0367 µM) against A549 and healthy cell line (HDF) are much better than standard cisplatin (IC50: 6.202 ± 0.0705 µM). It was determined that the AChE inhibitory activities of all synthesized compounds were much better than Galantamine used as a standard. In particular, 9c (IC50: 13.81 ± 0.0026 mM) had ten times better activity than the standard Galantamine (IC50: 136 ± 0.008 mM). The ADMET properties of the molecules have been thoroughly examined and met the criteria for drug-like substances. They also have a high oral absorption rate, as they can effectively cross the blood-brain barrier and are easily absorbed in the gastrointestinal tract. In vitro experiments were confirmed by in silico molecular docking studies.Communicated by Ramaswamy H. Sarma.

A Novel Donepezil-Caffeic Acid Hybrid: Synthesis, Biological Evaluation, and Molecular Docking Studies.

A novel donepezil-caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect were investigated by the IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry. DP-CA was highly active against acetylcholine esterase and inhibited it at the micromolar concentrations. Fluorescence and UV-Vis spectroscopy studies showed strong binding of DP-CA to DNA. Moreover, DP-CA exhibited protective effects against H2O2-induced toxicity in U-118 MG glioblastoma cells. Finally, molecular docking showed a high affinity of DP-CA in all concentrations, and the active 4EY7 site exhibited essential residues with polar and apolar contacts. Taken together, these findings indicate that DP-CA could be a prospective multifunctional agent for the treatment of neurodegenerative diseases.

Discovery of new 1,4-disubstituted 1,2,3-triazoles: in silico ADME profiling, molecular docking and biological evaluation studies.

In this work, eight new 1,2,3-triazoles (6a-h) were synthesized from acetylenes' "click" reaction with p-substituted azide derivatives. The structures of the compounds were characterized using standard analytical and spectroscopic methods (elemental analysis, FT-IR, 1H(13C)NMR). The anticancer, antioxidant, α-amylase, ADME, molecular docking studies of synthesized triazoles were investigated. According to α -amylase enzyme inhibition results, all compounds except 6c (IC50: 2299 µg/mL) were found to have a higher IC50 value than the standard drug acarbose (IC50: 891 µg/mL). Compound 6g (IC50: 68 µg/mL) exhibited 13 times higher activity than standard acarbose. All compounds, except 6e, have been shown to have greater DPPH radical scavenging capabilities than BHT and ß-carotene standards. According to ABTS radical scavenging studies, all compounds showed higher scavenging activity than ascorbic acid and Trolox. To determine the anticancer activity of the synthesized compounds, they were screened against the Hela cell line, and the results were compared with standard cisplatin (IC50: 16.30 µg/mL). Compound 6a (IC50: 49.03 µg/mL) was determined to have moderate activity relative to cisplatin. The compounds were examined comprehensively for ADME characteristics and did not violate any drug-likeness rule. ADME data showed that all physicochemical and pharmacological parameters of the compounds remained within defined limits as specified in Lipinski's rules (RO5) and put forth a high bioavailability profile. The molecular docking findings show that all molecules have a high affinity by exhibiting polar and apolar contact with essential residues in the binding pocket of α-amylase.Communicated by Ramaswamy H. Sarma.

Triazole based novel molecules as potential therapeutic agents: Synthesis, characterization, biological evaluation, in-silico ADME profiling and molecular docking studies.

In this study, eight new compounds (7a-h) based on triazole compounds containing ester groups were synthesized with high yields. The structures of the synthesized compounds (7a-h) were elucidated by various spectroscopic methods (element analysis, FT-IR, 1H-(13C) NMR). Antioxidant, anticancer, and α-amylase enzyme inhibition activities of synthesized new triazole derivatives were carried out, and the effects of different groups on the activity were investigated. When the determined antioxidant properties of the compounds were examined, all synthesized compounds showed a moderate radical scavenging effect against radicals depending on the concentration (6.25-200 g/mL). All compounds except the three derivatives were found to have higher IC50 values than the standard drug acarbose (IC50: 891 µg/mL) according to the α-amylase enzyme inhibition results. Compound 7g (IC50: 50 g/mL) was discovered to have nearly eighteen (18) times the activity of the conventional medication acarbose (IC50: 891 µg/mL). Compounds synthesized for anticancer activity studies were screened against the Hela cell line, and the results were compared with standard cis-platinum (IC50: 16.30 µg/mL). Compound 7g (IC50: 19.78 µg/mL) was found to have almost the same activity as cis-platinum. Using Qikprop, the compounds were thoroughly tested for ADME qualities, and none violated any drug similarity standards. According to ADME data, whole physicochemical drug-likeness parameters of molecules remained within defined ranges as stipulated in the Lipinski rules (RO5) and revealed a high bioavailability profile. The molecular docking results with 2QV4 and 4GQR alpha-amylase enzymes demonstrated that all molecules have a high affinity, indicating polar and apolar interaction with critical amino acids in the α-amylase binding pocket.

Rational design of 1,2,3-triazole hybrid structures as novel anticancer agents: synthesis, biological evaluation and molecular docking studies.

New hybrid compounds belonging to the class of 1,4-disubstituted 1,2,3-triazoles were synthesized. The structural characterization of the synthesized compounds was performed using IR, 1H-NMR, 13C NMR and elemental analysis techniques. Diarylketones 1a and 1b were used as starting compounds for the synthesis of triazoles. The corresponding diarylmethanol derivatives (2a,b) were obtained from reduction of ketone units with NaBH4. Oxyalkynes (3a,b) were obtained by treating the hydroxyl group with NaH in anhydrous THF and then with propargylbromide. The target hybrid structures 6a-n were obtained from the metal-catalyzed "click reaction" of the arylazide and alkyne units. The newly synthesized compounds were structurally analysed using 1H-NMR, 13C-NMR, elemental analysis, LC-MS and FT-IR. The antioxidant and anticancer activities of all compounds were investigated. It has been determined that the new hybrid structures have very good antioxidant and anticancer activities according to the standards. In particular, compounds 6b, 6h, 6i and 6j (IC50: 1.87, 12.5, 7.22, 8.04 µM) showed excellent activity compared to standard 5-Fu (IC50: 40.89 µM). According to the results of molecular docking of compounds 6b and 6i with the highest cancer activity, MetAP-2 was found to have a high affinity through exposed polar and apolar contacts with fundemental residues in the binding pocket.Communicated by Ramaswamy H. Sarma.

Synthesis, biological and computational studies of flavonoid acetamide derivatives.

This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin. Flavonoids display numerous biological properties but are limited by aqueous insolubility, enzymatic degradation, instability, and low bioavailability. FAs were synthesized, with 80-82% yields, through the sequential modification of the flavonoid hydroxyl groups into the acetamide moieties. Bioavailability, antioxidant, and ADMET are structure-activity-dependent properties that vary across different classes of flavonoids and dictate the prevalent biological applications of the flavonoids. Thus, the FAs were evaluated for their bioavailability, antioxidant, and ADMET toxicity properties versus the unmodified flavonoids (UFs). In vitro bioavailability analysis shows that the UFs have bio-availabilities in the range of 10.78-19.29% against that of the FAs in the range of 20.70-34.87%. The antioxidant capacity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) assay with recorded IC50 values of 2.19-13.03 µM for the UFs. Conversely, the FAs had high DPPH IC50 values ranging from 33.83 to 67.10 µM and corresponding to lower antioxidant activity. The FAs showed favorable ADMET properties. The modification of flavonoids into FAs significantly improves the bioavailability and the ADMET toxicity properties, albeit with decreased antioxidant activity. This work highlights the effect of the global modification of the flavonoids with the acetamide groups on the bioavailability, antioxidant, and ADMET toxicity properties which are critical determinants in the biological applications of the flavonoids.

New imino-methoxy derivatives: design, synthesis, characterization, antimicrobial activity, DNA interaction and molecular docking studies.

Four new diarylmethylamine imine compounds (5a-5d) were prepared in order to examine their DNA binding properties, antimicrobial activity and molecular docking. The compounds were characterized by the common spectroscopic and analytic methods. Furthermore, solid-state structure of compounds 5a and 5c were determined by single-crystal X-ray diffraction studies. The compounds were then investigated for their DNA binding properties employing UV absorption, fluorescence spectroscopy under the physiological pH condition Tris-HCl buffer at pH 7.4. The compounds 5a-5d showed moderate binding constants with Kb values of 3.56 ± 0.3 × 104, 2.18 ± 0.2 × 105, 1.44 ± 0.3 × 105 and 2.56 ± 0.3 × 104 M-1, respectively. The molecular dockings were performed to investigate the ligand-DNA interactions. The in-silico DNA-compound interaction studies showed that the compounds interact with DNA in groove binding mode. Antimicrobial activity studies of imine compounds were tested against E. coli as bacteria, S. typhimurium, S. aureus, B. cereus, B. subtilis, and C. albicans as fungi. While all compounds show moderate activity against bacteria, no activity against fungi has been investigated.Communicated by Ramaswamy H. Sarma.

Novel quercetin and apigenin-acetamide derivatives: design, synthesis, characterization, biological evaluation and molecular docking studies.

Flavonoids exhibit essential but limited biological properties which can be enhanced through chemical modifications. In this study, we designed, synthesized, and characterized two novel flavonoid derivatives, quercetin penta-acetamide (1S3) and apigenin tri-acetamide (2S3). These compounds were confirmed using (1H, 13C) NMR, UV-Vis, and FT-IR characterizations. Their interaction with fish sperm DNA (FS-DNA) at physiological pH was investigated by UV-Vis and fluorescence spectrophotometry. The binding constant (K b) for the UV-Vis experiment was found to be 1.43 ± 0.3 × 104 M-1 for 1S3 and 2.08 ± 0.2 × 104 M-1 for 2S3. The binding constants (K SV) for the fluorescence quenching experiment were 1.83 × 104 M-1 and 1.96 × 104 M-1 for 1S3 and 2S3, respectively. Based on molecular modeling and docking studies, the binding affinities were found to be -7.9 and -9.1 kcal mol-1, for 1S3 and 2S3, respectively. The compound-DNA docked model correlated with our experimental results, and they are groove binders. Furthermore, mutagenicity potential was examined. 1S3 and its metabolites showed no mutagenic activity for both TA98 and TA100 strains. 2S3 did not show any mutagenic activity for the strain TA 98, while its metabolites were only active at high doses. Both 2S3 and its metabolites showed mutagenic activity in the TA100 strain.

Photochemical Synthesis and Catalytic Applications of Gold Nanoplates Fabricated Using Quercetin Diphosphate Macromolecules.

The demand for safer design and synthesis of gold nanoparticles (AuNPs) is on the increase with the ultimate goal of producing clean nanomaterials for biological applications. We hereby present a rapid, greener, and photochemical synthesis of gold nanoplates with sizes ranging from 10 to 200 nm using water-soluble quercetin diphosphate (QDP) macromolecules. The synthesis was achieved in water without the use of surfactants, reducing agents, or polymers. The edge length of the triangular nanoplates ranged from 50 to 1200 nm. Furthermore, the reduction of methylene blue was used to investigate the catalytic activity of AuNPs. The catalytic activity of triangular AuNPs was three times higher than that of the spherical AuNPs based on kinetic rate constants (k). The rate constants were 3.44 × 10-2 and 1.11 × 10-2 s-1 for triangular and spherical AuNPs, respectively. The X-ray diffraction data of gold nanoplates synthesized by this method exhibited that the nanocrystals were mainly dominated by (111) facets which are in agreement to the nanoplates synthesized by using thermal and chemical approaches. The calculated relative diffraction peak intensity of (200), (220), and (311) in comparison with (111) was found to be 0.35, 0.17, and 0.15, respectively, which were lower than the corresponding standard values (JCPDS 04-0784). For example, (200)/(111) = 0.35 compared to 0.52 obtained from the standard (JCPDS 04-0784), indicating that the gold nanoplates are dominated by (111) facets. The calculated lattice from selected area electron diffraction data of the as-synthesized and after 1 year nanoplates was 4.060 and 4.088 Å, respectively. Our calculations were found to be in agreement with 4.078 Å for face-centered cubic gold (JCPDS 04-0784) and literature values of 4.07 Å. The computed QDP-Au complex demonstrated that the reduction process took place in the B ring of QDP. This approach contributes immensely to promoting the ideals of sustainable nanotechnology by eradicating the use of hazardous and toxic organic solvents.

New metal based drugs: spectral, electrochemical, DNA-binding, surface morphology and anticancer activity properties.

The NSAID piroxicam (PRX) drug was used for complex formation reactions with Cu(II), Zn(II) and Pt(II) metal salts have been synthesized. Then, these complexes have been characterized by spectroscopic and analytical techniques. Thermal behavior of the complexes were also investigated. The electrochemical properties of all complexes have been investigated by cyclic voltammetry (CV) using glassy carbon electrode. The biological activity of the complexes has been evaluated by examining their ability to bind to fish sperm double strand DNA (FSFSdsDNA) with UV spectroscopy. UV studies of the interaction of the PRX and its complexes with FSdsDNA have shown that these compounds can bind to FSdsDNA. The binding constants of the compounds with FSdsDNA have also been calculated. The morphology of the FSdsDNA, PRX, metal ions and metal complexes has been investigated by scanning electron microscopy (SEM). To get the SEM images, the interaction of compounds with FSdsDNA has been studied by means of differential pulse voltammetry (DPV) at FSdsDNA modified pencil graphite electrode (PGE). The decrease in intensity of the guanine oxidation signals has been used as an indicator for the interaction mechanism. The effect of proliferation PRX and complexes were examined on the HeLA and C6 cells using real-time cell analyzer with four different concentrations.

Synthesis of trimethoprim metal complexes: Spectral, electrochemical, thermal, DNA-binding and surface morphology studies.

Complexes of trimethoprim (TMP), with Cu(II), Zn(II), Pt(II), Ru(III) and Fe(III) have been synthesized. Then, these complexes have been characterized by spectroscopic techniques involving UV-vis, IR, mass and (1)H NMR. CHN elemental analysis, electrochemical and thermal behavior of complexes have also been investigated. The electrochemical properties of all complexes have been investigated by cyclic voltammetry (CV) using glassy carbon electrode. The biological activity of the complexes has been evaluated by examining their ability to bind to calf-thymus DNA (CT DNA) with UV spectroscopy and cyclic voltammetry. UV studies of the interaction of the complexes with DNA have shown that these compounds can bind to CT DNA. The binding constants of the complexes with CT DNA have also been calculated. The cyclic voltammograms of the complexes in the presence of CT DNA have shown that the complexes can bind to CT DNA by both the intercalative and the electrostatic binding mode. The antimicrobial activity of these complexes has been evaluated against three Gram-positive and four Gram-negative bacteria. Antifungal activity against two different fungi has been evaluated and compared with the reference drug TMP. Almost all types of complexes show excellent activity against all type of bacteria and fungi. The morphology of the CT DNA, TMP, metal ions and metal complexes has been investigated by scanning electron microscopy (SEM). To get the SEM images, the interaction of compounds with CT DNA has been studied by means of differential pulse voltammetry (DPV) at CT DNA modified pencil graphite electrode (PGE). The decrease in intensity of the guanine oxidation signals has been used as an indicator for the interaction mechanism.