Compound 3b Research Articles

Synthesis, spectral characterization and biological activities of o,o'-dihydroxyazo compounds containing gallic acid: Molecular docking and dynamics simulation and MM-PBSA studies

In the investigation, diazonium derivatives of 2-aminophenol, 2-amino-4-methylphenol, 2-amino-4-chlorophenol, and 2-amino-5-nitrophenol reacted with gallic acid to produce four distinct o,o'-dihydroxyazo compounds. Description of the o,o'-dihydroxyazo compounds that were produced identified the substituent spectrum data using UV–Vis, FT-IR, NMR spectroscopy and MS spectrometry methods. The UV–Vis behaviors of compounds in ethanol and DMSO were noted at various pH values. The antioxidant, antimicrobial, and urease inhibitory activities of the compounds were determined spectrophotometrically and compared to standard compounds. The DPPH˙ scavenging and metal chelating activities of compound 4b were 2.17 ± 0.04 and 11.62 ± 0.64 μg/mL, respectively. Compounds exhibited an effective antibacterial activity against B. cereus. The urease inhibition capacity of compound 4c (IC50: 4.79 ± 0.01 μg/mL) was more effective than thiourea (IC50: 20.04 ± 0.16 μg/mL). Moreover, molecular docking calculations were used to assess the urease inhibition potentials, inhibition kinetics, and interactions of the synthesized compounds with antimicrobial enzymes and urease. The compounds had substantial impacts on density functional theory (DFT), molecular electrostatic potential (MEP), inhibition kinetics, enzyme inhibition, and PASS prediction tests. For this reason, molecular dynamics simulation and MM-PBSA energy calculation were performed to assess the compounds' stability during urease binding.As a result, the effective pharmacological properties of the newly synthesized o,o'-dihydroxyazo compounds were revealed by different in vitro bioactivity tests and in silico calculations.

Synthesis of Multivalent Glycoside-Immobilized Carboxymethyl Cellulose Nanohydrogel Particles with Superadsorption Ability for Lectins.

Carboxymethyl cellulose (CMC) is a water-soluble cellulose derivative that is nontoxic, biocompatible, biodegradable, and nonallergenic. As developing an adsorbent material for carbohydrate-binding proteins is challenging, we aimed to synthesize CMC nanohydrogel particles (CMCGPs) with an extremely high lectin adsorption tendency in this study. CMCGPs were used as the backbone of an adsorption carrier that was synthesized by cross-linking CMC with ethylene glycol diglycidyl ether. A series of glycoside-immobilized CMCGPs were synthesized by binding two types of glycans (LacNAc and lactose) to the polyvalent carboxymethyl groups that are present on the CMCGP surface and act as reaction sites. These immobilized glycosides function as molecular recognition sites. Glycan moieties were incorporated into the CMCGP backbone at degrees of immobilization (DI) ranging from 8.7 to 21.0% by altering the reaction composition. LacNAc-CMCGP (3b) showed a 19.9% DI of LacNAc glycoside to the CMCGP carboxymethyl group; on average, its particle size swelled to 418 nm in phosphate-buffered saline, which is approximately 1.4 times its dry-state size. Analyzing the adsorbent properties of glyco-CMCGPs using a lectin-binding assay showed the high structural specificity of glyco-CMCGPs to lectins. The equilibrium isotherm data was explained by the Langmuir adsorption model. Notably, compound 3b adsorbed 1.95 ± 0.05 μg of wheat germ agglutinin (WGA) lectin per 1.0 μg-dry of 3b particles at an adsorption equilibrium time of a few minutes. Furthermore, solid-state 13C nuclear magnetic resonance analysis showed that WGA lectin retained its natural structure without denaturation after binding to LacNAc-CMCGP. These results were also supported by affinity purification experiments of WGA from raw wheat germ extract using LacNAc-CMCGP, demonstrating that glyco-CMCGP is capable of adsorbing and desorbing lectin while maintaining its biological activity. Thus, multivalent glycoside-immobilized CMCGPs that use woody biomass derivatives as the backbone are expected to be applied as biorefinery materials, which specifically and abundantly adsorb not just plant lectins but also pathogenic viruses and toxin proteins.

Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats

In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro &invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.

Synthesis of new piperazine‐oxadiazole derivatives and investigation of their anticancer activities

Since cancer is one of the leading causes of human death, recent research has largely focused on developing multi-target drug designs. In this study, we designed and synthesized a series of piperazine-oxadiazole derivatives as aromatase inhibitors for the treatment of cancer. Their structures were confirmed by 1H NMR, 13C NMR, HRMS and FTIR spectroscopic methods. Cytotoxicity (MTT) was performed to determine the anticancer activity of the compounds as aromatase inhibitors against breast (MCF7), fibroblast (NIH3T3) and lung (A549) cell lines. Letrazol was used as the reference agent, compound 4b exhibited a significant effect among other derivatives with a value of IC50=2.103±0.088 μM against the MCF7 cell line. Docking study showed that 4b was one of the compounds with the best pose on the aromatase. The docking study showed that 4e was one of the compounds that gave the best pose on EGFR and topoisomerase. When the aromatase, EGFR and topoisomerase docking results were compared, it was concluded that our synthesized compounds may be more effective on the Aromatase macromolecule. From the obtained evaluations of the designed batches, compound 4b appeared to be a promising agent as an aromatase inhibitor for further research and evaluation studies in the future.

Discovery of novel nematicidal active ingredient 2,4,7-trichloroquinazoline as a potential succinic dehydrogenase inhibitor

Plant-parasitic nematodes seriously affect the growth and yield of crops, causing huge economic losses to world agriculture. One of the effective ways to manage nematode diseases is the use of nematicides. Compound B1 was found to have good nematicidal activity in the biological test. Therefore, some compounds with similar structures to B1 were tested for better nematicidal activities. Among them, the LC50 of compound C3 against pine wood nematode (Bursaphelenchus xylophilus), rice stem nematode (Aphelenchoides besseyi), and sweet potato stem nematode (Ditylenchus destructor) were 4.6, 22.4, and 16.9 mg/L, respectively, which are markedly better than tioxazafen (103.9, 56.2, and 61.0 mg/L). Compound C3 was capable of not only significantly promoting oxidative stress in Bursaphelenchus xylophilus (B. xylophilus), but also curtailing population growth by influencing the frequency of head swing frequency, feeding behaviors, reproductive capabilities, and egg hatching rates. Furthermore, Compound C3 has demonstrated a favorable binding affinity to the succinic dehydrogenase (SDH) protein and has significantly dampened the activity of the SDH in B. xylophilus. Therefore, compound C3 can be used as a potential lead compound to discover new nematicides.

Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA

PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a–14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.

2-Ferrocene-4-amine-1H-benzo[d]imidazole and their derivatives: Synthesis, biological and docking study

An organometallic series based on 2-ferrocene-4-amine-1H-benzo[d]imidazole derivative has been synthesized and characterized through FTIR, H/CNMR, and LCMS. Their antimicrobial activity was assessed by testing them against B. subtills, Staphylococcus aureus, E. faecalis, S. marcescens, E. coli, K. pneumoniae, C. albicans, A. niger, Mucor sp. where they showed good zone of inhibition (ZOI) as compared to standards. The cytotoxicity of synthesized compounds was tested against Hela (cervical) and MCF-7 (breast) cancer cell lines where compound 5a and 5b displayed equivalent potency to the standard while 5e demonstrated highest cytotoxicity against both cell lines. Their comparative docking analysis with DNA suggested that docking score of 5e was −7.4 kcal/mol versus −6 kcal/mol of ethidium bromide, indicating that our designed compound acts via DNA intercalation.

Novel benzothiophene‒tethered 1,3,4‒oxadiazoles as potent antimicrobial targets: Design, synthesis, biological evaluation, DFT exploration and in silico docking study

Based on previous developments of oxadiazole research programs in trying to find novel compounds with multiple biological targets, such as antibacterial and antitubercular medications. In the context, a new series of 1,3,4-oxadiazole derivatives based on benzo[b]thiophene moiety 6a‒d, 7a‒d, and 8a‒d was synthesized from 5-(3-methylbenzo[b]thiophen-2-yl)-1,3,4-oxadiazole-2-thiol. The structures of 1,3,4‒oxadiazole derivatives were elucidated via NMR (1H and 13C), IR, and HRMS spectrum data as well as physical data. Subsequently, the derivatives were evaluated for their inhibitory activity against different bacterial microorganisms, and the MICs were determined in vitro tubercular activity against the sensitive M. tuberculosis H37Rv strain. Remarkably, hybrids 6c and 7a exhibited excellent antibacterial activity against S. aureus with ZI values of 31 ± 0.99, and 30 ± 0.32 mm, and it has been noticed that 8b demonstrated the most prominent antibacterial efficiency with MICs = 3.1, 3.6, 5.6, and 5.1 μg/mL against S. pneumoniae, S. pyrogenes, E. coli, and K. pneumoniae. Among them, compound 8b, featuring a benzo[b]thiophene moiety linked to oxadiazole, exhibited a significant tubercular inhibitory effect with an MIC value of 2.2.5 μM. Additionally, the docked compound 7a showed the strongest key active key amino acids Arg44(A), Arg45(A), Ala126(A), Gly18(A), Ser49(A), Asp48(A) in the antitubercular active site of 1DG5 protein. The study of computer aided ADMET was also carried out, using SwissADME and ADMETlab2.0 to investigate the pharmacokinetic properties of the tested triazole compounds. To support the experimental data, molecular docking and density functional theory (DFT) studies help in understanding the interactions better.

Design, synthesis, and computational analysis (molecular docking, DFT, MEP, RDG, ELF) of diazepine and oxazepine sulfonamides: biological evaluation for in vitro and in vivo anti-inflammatory, antimicrobial, and cytotoxicity predictions.

We report the synthesis and extensive characterization of Diazepane and Oxazepane derivatives, followed by their biological evaluation. These compounds were assessed for in vitro and in vivo antimicrobial, anti-inflammatory, and anticancer activities. Among the synthesized molecules, compound 5b demonstrated remarkable antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis with MIC values of 20 and 40 μg/mL, respectively. Additionally, 5b exhibited potent anti-inflammatory effects both in vitro and in vivo. Advanced computational studies, including DFT, MEP, RDG, and ELF analyses, were performed to understand the electronic distribution and molecular interactions. The bioactivity and physicochemical properties of these derivatives were further predicted using PASS and pkCSM platforms, emphasizing their potential as promising lead molecules in drug development.

Synergistic effect of hydrogen bonding and C–H…π interactions to modulate the supramolecular assemblies of isobenzofuranones: X-ray crystallography, DFT analysis and antihyperglycemic potential

This manuscript reports the synthesis, X-ray characterization and antihyperglycemic potential of two isobenzofuranone derivatives. The Suzuki-Miyaura cross-coupling of 5-bromoisobenzofuran-1(3H)-one with phenylboronic acid and p-tolylboronic acid under the action of palladium catalysis afforded the desired compounds in good yields. The structures were fully established using FTIR and NMR spectroscopy and X-ray crystallography. The study further delves into the synergistic effects of hydrogen bonding and C–H…π interactions on the supramolecular assemblies of isobenzofuranones, leveraging a holistic approach that combines X-ray crystallography, Density Functional Theory (DFT) analysis, and evaluation of antihyperglycemic activity. Focusing on two isobenzofuranone derivatives, we meticulously elucidate their structural features and how noncovalent interactions shape their crystal packing. Our exploration extends to assessing the antihyperglycemic potential of these compounds, underpinned by α-glucosidase inhibitory assays and augmented by molecular docking analysis. Compound 3b showed the best potency with an IC50 value of 13 ± 0.01 µM which is 67-folds strong inhibition than acarbose (IC50 = 870.2 ± 1.54 µM). Furthermore, the admetSAR and ProTox-II demonstrated that compound 3b follows the druggable criteria with a safe toxicity profile. Overall, these findings highlight the pivotal role of noncovalent interactions in modulating the supramolecular architectures of isobenzofuranones, thereby offering insights into their therapeutic potential against diabetes mellitus.

Curcuminoid Chalcones: Synthesis and Biological Activity against the Human Colon Carcinoma (Caco-2) Cell Line.

There are many current scientific reports on the synthesis of various derivatives modelled on the structure of known small-molecular and natural bioactive compounds. Curcuminoid chalcones are an innovative class of compounds with significant therapeutic potential against various diseases and they perfectly fit into the current trends in the search for new biologically active substances. The aim of this study was to design and synthesise a series of curcuminoid chalcones. The objective of this scientific paper was to synthesise twelve curcuminoid chalcones and confirm their structures using spectral methods. Additionally, the biological activity of three of the synthesised compounds was evaluated using various assays, and their anticancer properties and toxicity were studied. The proposed derivatives were obtained via the Claisen-Schmidt reaction of selected acetophenones and aldehydes in various conditions using both classical methods: the solutions and solvent-free microwave (MW) or ultrasound (US) variants. The most optimal synthetic method for the selected curcuminoid chalcones was the classical Claisen-Schmidt condensation in an alkaline (NaOH) medium. Spectral methods were used to confirm the structures of the compounds. The resazurin reduction assay, caspase-3 activity assay, and RT-qPCR method were performed, followed by measurements of the intracellular reactive oxygen species (ROS) level and the lactate dehydrogenase (LDH) release level. Twelve designed curcuminoid chalcones were successfully synthesized and structurally confirmed by NMR, MS, and IR spectroscopy. Examination of the anticancer activity was carried out for the three most interesting chalcone products. The results suggested that compound 3a increased the metabolism and/or proliferation of the human colon carcinoma (Caco-2) cell line, while compounds 3b and 3f showed significant toxicity against the Caco-2 cell line. Overall, the preliminary results suggested that compound 3b exhibited the most favourable anticancer activity.

Synthesis of new phenothiazine derivatives: Molecular docking, assessment of cytotoxic activity and oxidant-antioxidant properties on PCS-201-012, HT-29, and SH-SY5Y cell lines.

Phenothiazine (PTZ) derivatives have been acknowledged as versatile compounds with significant implications across various areas of medicine, particularly, in cancer research. The cytotoxic effects of synthesized compounds on both normal and cancerous cells, along with their oxidant-antioxidant properties, are pivotal factors in cancer treatment strategies. In the current study, eight new PTZ derivatives were synthesized and the compounds' cytotoxic activities were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay while the oxidant-antioxidant properties were evaluated by oxidative stress index (OSI) calculation in SH-SY5Y (a human neuroblastoma cell line), HT-29 (a human colorectal adenocarcinoma cell line), and PCS-201-012 (a human primary dermal fibroblast cell line) cells. Consequently, the half-maximal inhibitory concentration (IC50) values of compound 3a were determined to be 218.72, 202.85, and 227.86 μM while the IC50 values of compound 3b were defined to be 227.42, 199.27, and 250.11 μM in PCS-201-012, HT-29, and SH-SY5Y cells, respectively. Additionally, it was determined that the synthesized compounds demonstrated the lowest OSI in PCS-201-012 cells as compared to the other cell lines.

Synthesis of new 1,4-benzodioxin derivatives containing thiazolidin-4-one skeleton, molecular modelling and docking as antibacterial agents

In this study, we synthesized a variety of 1,4-benzodioxin derivatives containing the thiazolidin-4-one skeleton and evaluated their antimicrobial properties. Several of the newly synthesized compounds exhibited potent inhibitory effects against the Gram-negative bacteria Escherichia coli. By conducting molecular docking simulations and molecular dynamics with the fatty acid synthesis enzyme FabH, we unveiled the potential antimicrobial activity of these compounds, suggesting they interfered with fatty acid biosynthesis pathways. Additionally, we optimized compound 3b and assessed its ability to disrupt biofilms using live/dead cell staining techniques. The results highlighted significant biofilm disruption, enhancing the compounds' antimicrobial efficacy. These findings provided valuable insights for the development of novel antimicrobial agents and presented a promising avenue for addressing antimicrobial resistance through innovative therapeutic approaches.

Design, Synthesis, and Evaluation of Triazoline Schiff Bases as Potential Antibacterial Agents Against Methicillin-Resistant Staphylococcus aureus (MRSA): A Comprehensive Computational and Experimental Study

In this study, a series of novel triazoline Schiff bases are designed and synthesized on a triazole-based AADHR_1 hypothesis pharmacophore model tailored to meet structural requirements for antibacterial activity. FT-IR, 1H-NMR, and 13C-NMR spectroscopy techniques confirmed molecular structures. Assessment of ADMET properties utilizing the pkCSM online tool unveiled encouraging pharmacokinetic profiles. Detailed Density Functional Theory (DFT) calculations showed significant electronic properties, delineating certain compounds as potent electron donors or acceptors. Docking studies unveil that, the compound 1-((1-(p-tolyl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (2b) binded into the active site of the Penicillin-binding protein (PBP2a) of Methicillin-resistant Staphylococcus aureus (MRSA) with the docking score of -8.0 kcal/mol. Molecular dynamics simulations further corroborated the stability of the protein-ligand complex, emphasizing the compound 2b is enduring interaction at the MRSA protein's active site. Antibacterial assays against MRSA showed selective compounds exhibiting minimum inhibitory concentrations (MICs) of 20µg/mL and Zone of inhibition up to 14mm, highlighting their potential as effective antimicrobial agents against antibiotic-resistant bacteria. These findings collectively suggest the promising therapeutic prospects of the synthesized triazoline Schiff bases in combatting MRSA infections.

A multi-computational and crystallographic investigation for the antibiotic mechanism of two 2,4-bis(4-methoxyphenamino)pyrimidines

2,4-bis(4-methoxyphenamino)pyrimidines are effective anti-bacterial against various bacteria. The compounds 1a and 1b displayed IC50 values of 3µM and 6.1µM, respectively, against Salmonella Typhimurium. The research aims to comprehensively understand the mechanisms of action of these compounds against bacteria using a diverse array of experimental and computational techniques. The findings from the single-crystal X-ray crystallographic investigation reveal several key insights. First, compounds 1a and 1b adopt distinct conformations of the same structure. Second, the amine-pyrimidine resonance is favored over the amine-methoxy aryl resonance. Third, H⸱⸱⸱H, O⸱⸱⸱H, and N⸱⸱⸱H interactions are the primary driver of molecular assembly. Lastly, Van der Waals and hydrophobic interactions significantly influence the crystal architecture and are conformation-dependent. Computational results suggest that, depending upon the molecular volume, both compounds can inhibit SseF with a marginal difference by stable binding with the same conformer observed in the solid state of 1a through hydrophobic interactions due to the presence of electron-rich phenyl rings. The compound 1b exhibited greater structural variability in the binding site compared to 1a, leading to lower stability. Moreover, the higher molecular volume of 1b, attributed to the methyl group, results in its comparatively lesser fitting in the SseF pore compared to 1a.

Synthesis, Anticholinesterase and Antioxidant Activity of Thiosemicarbazone Derivatives

In this research, we report the synthesis and evaluation of novel thiosemicarbazones as anti-Alzheimer’s agents. The structural clarification of the newly synthesized compounds was carried out by 1H NMR, 13C NMR, and MS analyses. According to the in vitro cholinesterase inhibition assay, compounds showed more inhibitory potential against AChE than BuChE. The in vitro antioxidant activity of the synthesized compounds was measured via two different methods. According to ferrous ion-chelating assay compound 2b demonstrated 5.26% activity when compared to BHT (2.57%). DPPH radical scavenging activity assay revealed that compound 2b showed the most potent antioxidant activity with an IC50 value of 43.91 ± 0.021μM. Among the synthesized compounds, compound 2b was found as the most potent antioxidant agent.

Design, Synthesis, Molecular Docking Studies and Antimicrobial Profiling of 7-Nitroquinazoline Derivatives against Staphylococcus aureus (MRSA)

The alarming increase in antibiotic resistance contributes to the growing risk posed by Staphylococcus aureus (MRSA) in the worldwide healthcare sector. To address the challenge, this study designed, synthesized and evaluated novel quinazoline derivatives, specifically 7-nitroquinazolines, for their antimicrobial efficacy against Staphylococcus aureus (MRSA). Molecular docking studies revealed that compounds 8a and 8b exhibited superior binding affinity to the protein 1T2W, with binding energies of -9.6 kcal/mol and -8.8 kcal/mol, surpassing ciprofloxacin. The derivatives demonstrated favourable pharmacokinetic properties, including moderate lipophilicity, optimal polarity and good water solubility. Compound 8b shows a potent minimum inhibitory concentration (MIC) of 31.1 µg/mL against S. aureus (MRSA ATCC6538), outperforming ciprofloxacin. These findings indicate that compound 8b and related derivatives hold promise as novel therapeutic agents against MRSA, warranting further research to combat the growing issue of antibiotic resistance.

Crystal structures of seven mixed-valence gold compounds of the form [(R 1 R 2 R 3PE)2AuI]+[AuIII X 4]- (R = tert-butyl or isopropyl, E = S or Se, and X = Cl or Br).

During our studies of the oxidation of gold(I) complexes of tri-alkyl-phosphane chalcogenides, general formula R 1 R 2 R 3PEAuX, (R = tert-butyl or isopropyl, E = S or Se, X = Cl or Br) with PhICl2 or elemental bromine, we have isolated a set of seven mixed-valence by-products, the bis-(tri-alkyl-phosphane chalcogenido)gold(I) tetra-halogenidoaurates(III) [(R 1 R 2 R 3PE)2Au]+[AuX 4]-. These corres-pond to the addition of one halogen atom per gold atom of the AuI precursor. Com-pound 1, bis-(triiso-propyl-phosphane sulfide)-gold(I) tetra-chlorido-aur-ate(III), [Au(C9H21PS)2][AuCl4] or [( i Pr3PS)2Au][AuCl4], crystallizes in space group P21/n with Z = 4; the gold(I) atoms of the two cations lie on twofold rotation axes, and the gold(III) atoms of the two anions lie on inversion centres. Compound 2, bis-(tert-butyl-diiso-propyl-phosphane sulfide)-gold(I) tetra-chlorido-aurate(III), [Au(C10H23PS)2][AuCl4] or [( t Bu i Pr2PS)2Au][AuCl4], crystallizes in space group P1 with Z = 4; the asymmetric unit contains two cations and two anions with no imposed symmetry. A least-squares fit of the two cations gave an r.m.s. deviation of 0.19 Å. Compound 3, bis-(tri-tert-butyl-phosphane sulfide)-gold(I) tetra-chlorido-aurate(III), [Au(C12H27PS)2][AuCl4] or [( t Bu3PS)2Au][AuCl4], crystallizes in space group P1 with Z = 1; both gold atoms lie on inversion centres. Compound 4a, bis-(tert-butyl-diiso-propyl-phosphane sulfide)-gold(I) tetra-bromi-doaurate(III), [Au(C10H23PS)2][AuBr4] or [( t Bu i Pr2PS)2Au][AuBr4], crystallizes in space group P21/c with Z = 4; the cation lies on a general position, whereas the gold(III) atoms of the two anions lie on inversion centres. Compound 4b, bis-(tert-butyl-diiso-propyl-phosphane selenide)gold(I) tetra-bromido-aurate(III), [Au(C10H23PSe)2][AuBr4] or [( t Bu i Pr2PSe)2Au][AuBr4], is isotypic with 4a. Compound 5a, bis-(tri-tert-butyl-phosphane sulfide)-gold(I) tetra-bromido-aurate(III), [Au(C12H27PS)2][AuBr4] or [( t Bu3PS)2Au][AuBr4], is isotypic with compound 4a. Compound 5a, bis-(tri-tert-butyl-phosphane sulfide)-gold(I) tetra-bromido-aurate(III), [Au(C12H27PS)2][AuBr4] or [( t Bu3PS)2Au][AuBr4], crystallizes in space group P1 with Z = 1; both gold atoms lie on inversion centres. Compound 5b, bis-(tri-tert-butyl-phosphane selenide)gold(I) tetra-bromido-aurate(III), [Au(C12H27PSe)2][AuBr4] or [( t Bu3PSe)2Au][AuBr4], is isotypic with 5a. All AuI atoms are linearly coordinated and all AuIII atoms exhibit a square-planar coordination environment. The ligands at the AuI atoms are anti-periplanar to each other across the S⋯S vectors. There are several short intra-molecular H⋯Au and H⋯E contacts. Average bond lengths (Å) are: P-S = 2.0322, P-Se = 2.1933, S-Au = 2.2915, and Se-Au = 2.4037. The complex three-dimensional packing of 1 involves two short C-Hmethine⋯Cl contacts (and some slightly longer contacts). For 2, four C-Hmethine⋯Cl inter-actions combine to produce zigzag chains of residues parallel to the c axis. Additionally, an S⋯Cl contact is observed that might qualify as a 'chalcogen bond'. The packing of 3 is three-dimensional, but can be broken down into two layer structures, each involving an S⋯Cl and an H⋯Cl contact. For the bromido derivatives 4a/b and 5a/b, loose associations of the anions form part of the packing patterns. For all four compounds, these combine with an E⋯Br contact to form layers parallel to the ab plane.

One-Pot Synthesis of New Bipyridine and Yerpyridine Derivatives: Anti-proliferative Evaluation, DNA Flow Cytometry Analysis, and Molecular Docking Study

Some new bipyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile 1a. While terpyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carbonitrile 1b as starting material. Alkylation of compounds 1a, b gave the alkyl derivatives 2a, b which converted into aceto hydrazides 3a,b. Treating the aceto hydrazides with ethyl cyanoacetate afforded 2'-(2-(3,5-dioxopyrazolidin-1-yl)-2-oxoethoxy)-6'-(thiophen-2-yl)-3,4'-bipyridine-3'-carbonitrile 4a and 6'-[2-(3,5-dioxopyrazolidin-1-yl)-2-oxoethoxy]-(3,4':2',4''-terpyridine)-5'-carbonitrile 4b. While treatment of 3a, b with ethyl benzoylacetate afforded the carboniltrile derivatives 2'-(2-oxo-2-(5-oxo-3-phenyl-4,5-dihydropyrazol-1-yl)ethoxy)-6'-(thiophen-2-yl)-3,4'-bipyridine-3'-carbonitrile 5a and 6'-[2-oxo-2-(5-oxo-3-phenyl-4,5-dihydropyrazol-1-yl)ethoxy]-(3,4':2',4''-terpyridine)-5' carbonitrile 5b. Treating compounds 3a, and b with two aromatic aldehydes (3,4-dihydroxy benzaldehyde, 4-chlorobenzaldehyde) afforded Schiff bases 6a-d. Finally, treatment of 3a, b with p-toluenesulfonyl chloride (Tosyl chloride) afforded the corresponding benzene sulfonohydrazide 7a, b. IR, 1HNMR, 13CNMR, MS, and elemental analysis confirmed the synthesized compounds. The anti-cancer activity of the compounds was investigated against the breast cancer (MCF-7) cell line. Compound 6b demonstrated the strongest cytotoxic activity among the tested compounds and it is more active than the reference drug 5-fluorouracil (5-FU), so that, it is subjected to further investigations, where its effect on the cell cycle distribution in the MCF-7 cell line, its ability to inhibit Topoisomerase II, the level of Caspase‐3/7 green flow cytometry assay was investigated. Also, Molecular operating environmental docking (MOE) has been studied and found that the inhibition efficiency could be organized as follows (S, Kcal/mol) values: 5b ˃ 6d ˃ 3a ˃ 3b ˃ 6b, while compound 5a did not show any interaction data belonging to the shaped complex with 1cca. Hence, most synthesized compounds can be used as anti-cancer and anti-oxidant agents.

Discovery of novel 1,4-dicarbonylthiosemicarbazides as DNA gyrase inhibitors for the treatment of MRSA infection

Antibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compound B5 (Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 μg/mL) against Staphylococcus aureus ATCC 29213. Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 μg/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound 1b as our lead compound for comprehensive biological evaluation. As a result, compound 1b exhibited a bacteriostatic mode, and was active against a panel of Gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound 1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound 1b inhibited Staphylococcus aureus DNA gyrase (IC50: 1.81 μM) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound 1b for the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides.