Mining for antifungal agents to inhibit biofilm formation of Candida albicans: A study on green synthesis, antibiofilm, cytotoxicity, and in silico ADME analysis of 2-amino-4H-pyran-3-carbonitrile derivatives.

Candida albicans (C. albicans) biofilm infections are quite difficult to manage due to their resistance against conventional antifungal drugs. To address this issue, there is a desperate need for new therapeutic drugs. In the present study, a green and efficient protocol has been developed for the synthesis of 2-amino-4H-pyran-3-carbonitrile scaffolds 4a-i, 6a-j, and 8a-g by Knoevenagel-Michael-cyclocondensation reaction between aldehydes, malononitrile, and diverse enolizable C-H activated acidic compounds using guanidinium carbonate as a catalyst either under grinding conditions or by stirring at room temperature. This protocol is operationally simple, rapid, inexpensive, has easy workup and column-free purification. A further investigation of the synthesized compounds was conducted to examine their antifungal potential and their ability to inhibit the growth and development of biofilm-forming yeasts like fungus C. albicans. According to our findings, 4b, 4d, 4e, 6e, 6f, 6g, 6i, 8c, 8d, and 8g were found to be active and potential inhibitors for biofilm infection causing C. albicans. The inhibition of biofilm by active compounds were observed using field emission scanning electron microscopy (FESEM). Biofilm inhibiting compounds were also tested for in vitro toxicity by using 3T3-L1 cell line, and 4b, 6e, 6f, 6g, 6i, 8c, and 8d were found to be biocompatible. Furthermore, the in silico ADME descriptors revealed drug-like properties with no violation of Lipinski's rule of five. Hence, the result suggested that synthesized derivatives could serve as a useful aid in the development of novel antifungal compounds for the treatment of fungal infections and virulence in C. albicans.

Novel alkyl-substituted 4-methoxy benzaldehyde thiosemicarbazones: Multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting mental ability and interrupts neurocognitive functions. Treating multifactorial conditions of AD with a single-target-directed drug is highly difficult. Thus, a multi-target-directed ligand (MTDL) development strategy has been developed as a promising approach for the treatment of AD. Herein, we have synthesized two novel thiosemicarbazones as MTDLs and reported their bioactivities against diverse neuropathological events involved in AD. In vitro studies revealed that both compounds exhibited promising anticholinesterase activity (AChE, IC50 = 15.98 µM, MZET and IC50 = 30.23 µM, MZMT), well supported by a detailed computational study. Both analogs have shown good thermodynamic behaviour and stability through interactions with characteristic amino acid residues throughout simulation of 100 ns against acetylcholinesterase enzyme. In an electrophysiology assay, these analogs have shown a characteristic inhibitory response against the GluN1-1a + GluN2B subunit of N-methyl-D-aspartate receptors. Pre-treatment of BV-2 microglial cells with MZET effectively decreased nitrite production compared to nitrite produced by lipopolysaccharide-treated cells alone. Further, the effect of MZMT and MZET on autophagy regulation was determined using stably transfected SH-SY5Y neuroblastoma cells. MZET significantly enhanced the autophagy flux in neuroblastoma cells. A significant decrease in copper-catalysed oxidation of amyloid-ß in presence of synthesized thiosemicarbazones was also observed. Collectively, our findings indicated that these analogs have potential as effective anti-AD candidates and can be used as a prototype to develop more safer multi-targeted anti-AD drugs.

An insight into the morphology of DNA compaction induced by homobinuclear Ru(II) polypyridyl complexes.

Binuclear Ru(II) polypyridyl complexes [Ru2(NN)4(BIPMB)]4+ (1-4), where N-N = 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), dipyrido [3,2-d:2',3'-f] quinoxaline (dpq), and dipyrido[3,2-a:2',3'-c]phenazine (dppz), have been synthesized using suitable precursors and bridging ligand (BIPMB), where BIPMB = 3,3'-bis-{(imidazol-1-yl)-[4,5-f]-1,10-phenanthroline) methyl}-1,1'-biphenyl. The binding mode and affinity of complexes 1-4 with Calf Thymus DNA (CT-DNA) were determined by absorption and steady-state fluorescence spectroscopy. The decrease in viscosity of CT-DNA on sequential addition of these complexes indicated DNA condensation and the result was corroborated by circular dichroism (CD). The nanosized globular aggregates of CT-DNA induced by complexes 1-4 were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements. The gel electrophoretic mobility studies revealed the small orderly particles of supercoiled plasmid pBR322 DNA induced by these complexes. Additionally, the morphology and size of compact plasmid DNA condensates were studied by DLS and atomic force microscopy (AFM). The complexes were moderately cytotoxic against MCF-7 cells.

Fixed-dose Combination of Metoprolol, Telmisartan, and Chlorthalidone for Essential Hypertension in Adults with Stable Coronary Artery Disease: Phase III Study.

INTRODUCTION: The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of metoprolol, telmisartan, and chlorthalidone in patients with essential hypertension and stable coronary artery disease (CAD) who showed inadequate response to dual therapy. METHODS: In this phase III, open-label, multicenter study, 254 adults with stable CAD having uncontrolled hypertension despite being treated with FDC of metoprolol (25/50 mg) and telmisartan (40 mg) were included. Patients received either of the following FDC for 24 weeks: metoprolol (25 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC1; n = 139) or metoprolol (50 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC2; n = 115) tablets once daily. The FDCs were developed using the novel Wrap Matrix™ platform technology. Primary endpoint assessed the mean change in seated diastolic blood pressure (SeDBP) and seated systolic blood pressure (SeSBP) from baseline to 24 weeks. Secondary efficacy endpoints included proportion of patients achieving < 90 mmHg SeDBP (SeDBP responder) and < 140 mmHg SeSBP (SeSBP responder) at weeks 12, 16, 20, and 24. Safety was assessed throughout the study. RESULTS: A total of 243 (95.70%) patients completed study. The mean change in BP from baseline (FDC1, 155/96 mmHg; FDC2, 165/98 mmHg) to week 24 (FDC1, 128/82 mmHg; FDC2, 131/83 mmHg) was statistically significant (both groups p < 0.0001). Within FDC1 and FDC2, the mean change from baseline to week 24 in SeDBP (82.60 mmHg and 83.09 mmHg) and SeSBP (128.07 mmHg and 131.29 mmHg) was statistically significant (both groups p < 0.0001). At week 24, in FDC1, 80.15% and 84.73% were SeDBP and SeSBP responders, respectively; in FDC2, 79.46% and 74.11% were SeDBP and SeSBP responders, respectively. No serious adverse events or deaths were reported. CONCLUSION: Triple FDCs of metoprolol, telmisartan, and chlorthalidone were considered effective and well tolerated in patients with hypertension who respond inadequately to dual therapy. CLINICAL TRIAL REGISTRATION: CTRI/2016/11/007491.

The increasing prevalence of hypertension in India requires immediate attention. To adequately manage blood pressure and ensure compliance to medications, innovative treatment options involving combination therapy with three or more drugs to treat hypertension need to be explored. Fixed-dose combination (FDC) of three antihypertension drugs, viz., metoprolol, telmisartan, and chlorthalidone, were tested in Indian patients who could not respond adequately to dual treatment. The rationale behind using a combination of three drug types was to take advantage of the complementary actions of each drug class for an enhanced treatment effect. The two variants of FDCs were tested in 254 adults with the most common form of heart disease, i.e., stable coronary artery disease. Changes in seated diastolic and systolic blood pressure (SeDBP and SeSBP) were measured to assess the effectiveness of the FDC. The mean changes in SeDBP and SeSBP were statistically significant by the end of the study, i.e., it determined that results are not explainable by chance alone. A greater proportion of patients (range 74­84%) achieved their target BPs with the FDC used in the study. The FDC variants were well tolerated without any reports of serious adverse events or deaths. Overall, this triple combination therapy option was effective and considered safe to be administered to hypertensive Indian adults with stable coronary artery disease who did not respond adequately to dual antihypertension therapy.

Tris-heteroleptic ruthenium(II) polypyridyl complexes: Synthesis, structural characterization, photophysical, electrochemistry and biological properties.

Three water-soluble tris-heteroleptic ruthenium(II) polypyridyl complexes [Ru(bpy)(phen)(bpg)]2+ (1), [Ru(bpy)(dppz)(bpg)]2+ (2), and [Ru(phen)(dppz)(bpg)]2+ (3) (where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, dppz = dipyrido[3,2-a:2',3'-c] phenazine, bpg = 4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f] [1,10] phenanthroline-6,13-dione) have been synthesized and characterized. Molecular structures of complexes 1 and 3 are confirmed by single crystal X-ray structure determination. Interaction of complexes 1-3 with DNA is explored by various spectroscopic techniques. The complexes 1-3 show solvent dependent photophysical properties. Complexes 2 and 3 show extensive "molecular light switch" effect for DNA. The complexes 1-3 are low toxic towards HeLa (human cervical cancer) and HL-60 (human promyelocytic leukemia) cell lines. Further, the cellular uptake of complexes 2 and 3 by cells shows that complexes mainly localised on the nucleus of the cells.

Heterostructural CuO-ZnO Nanocomposites: A Highly Selective Chemical and Electrochemical NO2 Sensor.

A simple one-step chemical method is employed for the successful synthesis of CuO(50%)-ZnO(50%) nanocomposites (NCs) and investigation of their gas sensing properties. The X-ray diffraction studies revealed that these CuO-ZnO NCs display a hexagonal wurtzite-type crystal structure. The average width of 50-100 nm and length of 200-600 nm of the NCs were confirmed by transmission electron microscopic images, and the 1:1 proportion of Cu and Zn composition was confirmed by energy-dispersive spectra, i.e., CuO(50%)-ZnO(50%) NC studies. The CuO(50%)-ZnO(50%) NCs exhibit superior gas sensing performance with outstanding selectivity toward NO2 gas at a working temperature of 200 °C. Moreover, these NCs were used for the indirect evaluation of NO2 via electrochemical detection of NO2 - (as NO2 converts into NO2 - once it reacts with moisture, resulting into acid rain, i.e., indirect evaluation of NO2). As compared with other known modified electrodes, CuO(50%)-ZnO(50%) NCs show an apparent oxidation of NO2 - with a larger peak current for a wider linear range of nitrite concentration from 20 to 100 mM. We thus demonstrate that the as-synthesized CuO(50%)-ZnO(50%) NCs act as a promising low-cost NO2 sensor and further confirm their potential toward tunable gas sensors (electrochemical and solid state) (Scheme 1).

Photochemical hydrogen evolution from water by a 1D-network of octahedral Ni6L8 cages.

A self-assembled M6L8 type cage-connected 1D-coordination network of formula {[Ni6(MeSi(3py)3)8Cl9(H2O)2]Cl3·16H2O}∞ (1) was obtained from a 3-pyridyl substituted silane ligand MeSi(3py)3. This complex shows significantly high performance for the electrocatalytic and photocatalytic hydrogen evolution reaction (HER) in water. A maximum turnover number (TON) of 2824 has been observed for photocatalytic HER after 69 h.

Coordination polymers of CdII and PbII derived from bipyridine-glycoluril: influence of metal-ion size and counter-ions.

Two new one-dimensional (1D) coordination polymers (CPs), namely catena-poly[[[aquacadmium(II)]-bis(µ-4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione)] bis(perchlorate) dihydrate], {[Cd(C14H10N6O2)2(H2O)](ClO4)2·2H2O}n or {[Cd(BPG)2(H2O)](ClO4)2·2H2O}n, 1, and catena-poly[[lead(II)-bis(µ-4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione)] bis(perchlorate) dihydrate], {[Pb(C14H10N6O2)2](ClO4)2·2H2O}n or {[Pb(BPG)2](ClO4)2·2H2O}n, 2, have been synthesized using bipyridine-glycoluril (BPG; systematic name: 4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione), a urea-fused tecton, in a mixed-solvent system. The CdII ion in 1 is heptacoordinated and the PbII ion in 2 is hexacoordinated, with the CdII ion adopting a pentagonal bipyramidal geometry and the PbII ion adopting a distorted octahedral geometry. Both CPs form infinite linear chain structures which are hydrogen bonded to each other leading to the formation of three-dimensional supramolecular network structures. Topological analysis of CPs 1 and 2 reveals that the structures exhibit 1D chain-like arrangements in an AB-AB sequence and shows platonic uniform 2-connected uninodal topologies. Furthermore, a comparative analysis of a series of structures based on the BPG ligand indicates that the size of the metal ion and the types of counter-ions used have a great influence on the resulting frameworks and properties.

A copper(ii)-coordination polymer based on a sulfonic-carboxylic ligand exhibits high water-facilitated proton conductivity.

Proton conduction ability has been investigated in a new Cu(ii) based coordination polymer (CP), {[Cu2(sba)2(bpg)2(H2O)3]·5H2O}n (1), synthesized using the combination of 4-sulfobenzoic acid (4-Hsba) and bipyridine-glycoluril (BPG) ligands. Single crystal X-ray structure determination revealed that 1 features 1D porous channels encapsulating a continuous array of water molecules. Proton conductivity measurements reveal a high conductivity value of 0.94 × 10-2 S cm-1 at 80 °C and 95% RH. The activation energy (Ea) of 0.64 eV demonstrates that the solvate water, coordinated water and hydrophilic groups in the channels promote the mobility of protons in the framework. Water sorption measurements exhibited hysterical behaviour with a high uptake value of 379.07 cm3 g-1. Time-dependent measurements revealed that the proton conductivity is retained even after 12 h of measurements. The proton conduction mechanism was validated by ab initio electronic structure calculations using the Nudged Elastic Band (NEB) method with molecular dynamics (MD) simulation studies. The theoretical activation energy is calculated to be 0.54 eV which is in accordance with the experimental value.

Acetylcholinesterase and Aß Aggregation Inhibition by Heterometallic Ruthenium(II)-Platinum(II) Polypyridyl Complexes.

Two heteronuclear ruthenium(II)-platinum(II) complexes [Ru(bpy)2(BPIMBp)PtCl2]2+ (3) and [Ru(phen)2(BPIMBp)PtCl2]2+ (4), where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and BPIMBp = 1,4'-bis[(2-pyridin-2-yl)-1H-imidazol-1-ylmethyl]-1,1'-biphenyl, have been designed and synthesized from their mononuclear precursors [Ru(bpy)2(BPIMBp)]2+ (1) and [Ru(phen)2(BPIMBp)]2+ (2) as multitarget molecules for Alzheimer's disease (AD). The inclusion of the cis-PtCl2 moiety facilitates the covalent interaction of Ru(II) polypyridyl complexes with amyloid ß (Aß) peptide. These multifunctional complexes act as inhibitors of acetylcholinesterase (AChE), Aß aggregation, and Cu-induced oxidative stress and protect neuronal cells against Aß-toxicity. The study highlights the design of metal based anti-Alzheimer's disease (AD) systems.

Excited State Interaction of Ruthenium (II) Imidazole Phenanthroline Complex [Ru(bpy)2 ipH]2+ with 1,4-Benzoquinone: Simple Electron Transfer or Proton-Coupled Electron Transfer?

The unidirectional proton coupled electron transfer (PCET) from the excited state of Ru(II) imidazole phenanthroline complex [Ru(bpy)2 ipH]2+ to 1,4-benzoquinone, was studied by steady-state (SS) and time-resolved (TR) fluorescence and transient absorption (TA) measurements. The pKa (9.7) and pKa * (8.6) values of the complex suggest that it behaves as a photoacid on excitation. The difference in the quenching rates obtained from SS and TR fluorescence studies indicate participation of both dynamic quenching and static quenching involving the hydrogen bonded ipH ligand of [Ru(bpy)2 ipH]2+ with the 1,4-benzoquinone quencher, formed in the ground state. Within the hydrogen bonded complex, the ruthenium centre acts as the electron donor, while the ipH ligand acts as the proton donor to the hydrogen bonded 1,4-benzoquinone that acts simultaneously both as the electron and proton acceptor. It is proposed that the static quenching in the hydrogen bonded [Ru(bpy)2 ipH]2+ -1,4-benzoquinone pairs occurs involving the PCET mechanism, while the dynamic quenching occurs through the simple ET mechanism, on diffusional encounter of the isolated 1,4-benzoquinone with the excited [Ru(bpy)2 ipH]2+ complex. The occurrence of broad TA bands around 420-430 nm suggests formation of both 1,4-benzoquinone radical anion as well as the 1,4-benzosemiquinone radical by the interaction of excited [Ru(bpy)2 ipH]2+ with 1,4-benzoquinone, thus supporting the ET process in the studied system.

Light-driven Hydrogen Evolution from Water by a Tripodal Silane Based CoII6L18 Octahedral Cage.

The octahedral cage assembly [CoII6L18Cl6(H2O)6]Cl6 has been synthesized in a single-step reaction by using a polypyridyl-functionalized tripodal silane ligand. The electrochemical behavior of the cage in water exhibits the pH dependence of potential as well as catalytic current indicating the possible involvement of proton-coupled electron transfer in H2 evolution. Electrocatalytic hydrogen evolution from an aqueous buffered solution gave a turnover frequency of 16 h-1. Further, this cage assembly has been explored as a photocatalyst (blue light irradiation λ 469 nm) for the evolution of H2 from water in the presence of Ru(bpy)32+ as a photosensitizer and ascorbic acid as a sacrificial electron donor. This catalytic reaction is found to be pseudo first order with a turnover frequency of 20.50 h-1.

A ruthenium water oxidation catalyst containing a bipyridine glycoluril ligand.

A mononuclear ruthenium complex [Ru(tpy)(bpg)H2O]2+ bearing a bipyridine glycoluril where bpg = 4b,5,7,7a-tetrahydro-4b,7a-nepiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthro-line-6,13-dione acts as a robust water oxidation catalyst (WOC) at pH = 1 using Ce(iv) as a sacrificial oxidant. The turn over number (TON) for water oxidation is found to be ∼5 times higher than the parent complex [Ru(tpy)(bpy)H2O]2+ where tpy = 2,2':6',2''-terpyridine; bpy = 2,2'-bipyridine. The presence of intermolecular H-bonding groups and the electronic effect of the functionalized bipyridine ligand may play a significant role in water oxidation.

Proton conduction in a hydrogen-bonded complex of copper(ii)-bipyridine glycoluril nitrate.

Bipyridine glycoluril (BPG), a urea-fused bipyridine tecton, forms a square-pyramidal secondary building unit with copper(ii) which further self-assembles to give a porous hydrogen-bonded complex. This complex displays a high proton conductivity of 4.45 × 10-3 S cm-1 at 90 °C and 95% relative humidity (RH). Chains consisting of coordinated water, solvent water and nitrate anions embedded in the complex are responsible for high proton conduction. The proton conduction pathway was corroborated by ab initio electronic structure calculations with molecular dynamics (MD) simulations using the Nudged Elastic Band (NEB) method. The theoretical activation energy estimated to be 0.18 eV is in close agreement with the experimental value of 0.15 eV which evidences a Grotthuss proton hopping mechanism. We thus demonstrate that the hydrogen-bonded complex encapsulating appropriate counter ions, coordinated water and solvent water molecules exhibts superprotonic conductivity.

Honeycomb-like Ordered Assembly of DNA Induced by Flexible Binuclear Ruthenium(II)-Polypyridyl Complexes.

A series of binuclear ruthenium(II)-polypyridyl complexes of the type [Ru2 (N-N)4 (BPIMBp)]4+ , in which N-N is 2,2'-bipyridine (bpy; 1), 1,10-phenanthroline (phen; 2), dipyrido[3,2-d:2',3-f] quinoxaline (dpq; 3), dipyrido[3,2-a:2',3'-c] phenanzine (dppz; 4), and 1,4'-bis[(2-pyridin-2-yl)-1H-imidazol-1-yl)methyl]-1,1'-biphenyl (BPIMBp) is a bridging ligand, have been synthesized and characterized. These complexes are charged (4+) cations and flexible due to the -CH2 group of the bridging ligand and possess terminal ligands with variable intercalative abilities. The interaction of complexes 1-4 with calf thymus DNA (CT-DNA) was explored by using UV/Vis absorption spectroscopy, steady-state emission, emission quenching with K4 [Fe(CN)6 ], ethidium bromide displacement assay, Hoechst displacement assay, and viscosity measurements and revealed a groove-binding mode for all the complexes through a spacer and an intercalative mode for complexes 3 and 4. A decrease in the viscosity of DNA revealed bending and coiling of DNA, an initial step toward aggregation. Interestingly, a distinctive honeycomb-like ordered assembly of the DNA-complex species was visualized by fluorescence microscopy in the solution state. The use of SEM and AFM confirmed the disordered self-organization of the DNA-complex adduct on evaporation of the solvent. The small orderly nanosized DNA aggregates were confirmed by means of circular dichroism, dynamic light scattering (DLS), and TEM. These complexes are moderately cytotoxic against three different cell lines, namely, MCF-7, HeLa, and HL-60.

Ruthenium(II) polypyridyl complexes with hydrophobic ancillary ligand as Aß aggregation inhibitors.

The synthesis, spectral and electrochemical characterization of the complexes of the type [Ru(NN)2(txbg)](2+) where NN is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), dipyrido [3,2-d:2',3f] quinoxaline (dpq) (3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4) which incorporate the tetra-xylene bipyridine glycoluril (txbg) as the ancillary ligand are described in detail. Crystal structures of ligand txbg and complex 2 were solved by single crystal X-ray diffraction. Thioflavin T (ThT) fluorescence and Transmission Electron Microscopy (TEM) results indicated that at micromolar concentration all complexes exhibit significant potential of Aß aggregation inhibition, while the ligand txbg displayed weak activity towards Aß aggregation. Complex 1 showed relatively low inhibition (70%) while complexes 2-4 inhibited nearly 100% Aß aggregation after 240 h of incubation. The similar potential of complexes 2-4 and absence of any trend in their activity with the planarity of polypyridyl ligands suggests there is no marked effect of planarity of coligands on their inhibitory potential. Further studies on acetylcholinesterase (AChE) inhibition indicated very weak activity of these complexes against AChE. Detailed interactions of Aß with both ligand and complex 2 have been studied by molecular modeling. Complex 2 showed interactions involving all three polypyridyl ligands with hydrophobic region of Aß. Furthermore, the toxicity of these complexes towards human neuroblastoma cells was evaluated by MTT assay and except complex 4, the complexes displayed very low toxicity.

Antiproliferative activity of ruthenium(ii) arene complexes with mono- and bidentate pyridine-based ligands.

A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester groups and chlorido ancillary ligands were synthesised and structurally characterised. The complexes have a distorted tetrahedral piano-stool geometry. The binding interaction was studied with calf thymus DNA (CT-DNA) by absorption titration, viscosity measurement, thermal melting, circular dichroism, ethidium bromide displacement assay and DNA cleavage of plasmid DNA (pBR322), investigated by gel electrophoresis. The dichlorido complexes bind covalently to DNA in the dark, similar to cisplatin, while the monochlorido complexes bind covalently on irradiation, similar to cisplatin analogues. The compounds are selectively cytotoxic against several tumour cell lines and show specific nonlinear correlation between dose and activity. This phenomenon is closely related to their potential to act preferentially as inhibitors of cell division.

Copper(ii) mixed-ligand polypyridyl complexes with doxycycline - structures and biological evaluation.

Mixed-ligand Cu(ii) complexes of the type [Cu(doxycycline)(L)(H2O)2](NO3)2, where doxycycline = [4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] and L = 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4) have been synthesised and characterised by structural, analytical, and spectral methods. The single-crystal X-ray structures of 1 and 2 exhibited two different geometries, distorted square-pyramidal and octahedral respectively as well as different coordination modes of doxycycline. Complexes 2-4 exhibit prominent plasmid DNA cleavage at significantly low concentrations probably by an oxidative mechanism. Matrix Metalloproteinase (MMP-2) inhibition studies revealed that all complexes inhibit MMP-2 similar to doxycycline which is a well-known MMP inhibitor with 3 being the most potent. IC50 values of doxycycline and 1-4 against MCF-7 (human breast cancer) and HeLa cell lines were almost equal in which 3 showed the highest efficiency (IC50 = 0.46 ± 0.05 µM), being consistent with its increased MMP inhibition potency. The antimalarial activities of these complexes against the chloroquine-sensitive Plasmodium falciparum NF54 and chloroquine-resistant Plasmodium falciparum Dd2 strains reveal that complex 3 exhibited a higher activity than artesunate drug against the chloroquine-resistant Dd2 strain.

Ruthenium(II) polypyridyl complex as inhibitor of acetylcholinesterase and Aß aggregation.

Two ruthenium(II) polypyridyl complexes [Ru(phen)3](2+) (1) and [Ru(phen)2(bxbg)](2+) (2) (where phen = 1,10 phenanthroline, bxbg = bis(o-xylene)bipyridine glycoluril) have been evaluated for acetylcholinesterase (AChE) and Amyloid-ß peptide (Aß) aggregation inhibition. Complex 2 exhibits higher potency of AChE inhibition and kinetics and molecular modeling studies indicate that ancillary ligand plays significant role in inhibitory potency exhibited by complex 2. The inhibitory effect of these complexes on Aß (1-40) aggregation is investigated using Thioflavin T fluorescence and Transmission Electron Microscopy. Both complexes efficiently inhibit Aß (1-40) aggregation and are negligibly toxic to human neuroblastoma cells. This is the first demonstration that ruthenium(II) polypyridyl complexes simultaneously inhibit AChE and Aß aggregation.

Synthesis, optimization, and characterization of silver nanoparticles from Acinetobacter calcoaceticus and their enhanced antibacterial activity when combined with antibiotics.

BACKGROUND: The development of nontoxic methods of synthesizing nanoparticles is a major step in nanotechnology to allow their application in nanomedicine. The present study aims to biosynthesize silver nanoparticles (AgNPs) using a cell-free extract of Acinetobacter spp. and evaluate their antibacterial activity. METHODS: Eighteen strains of Acinetobacter were screened for AgNP synthesis. AgNPs were characterized using various techniques. Reaction parameters were optimized, and their effect on the morphology of AgNPs was studied. The synergistic potential of AgNPs on 14 antibiotics against seven pathogens was determined by disc-diffusion, broth-microdilution, and minimum bactericidal concentration assays. The efficacy of AgNPs was evaluated as per the minimum inhibitory concentration (MIC) breakpoints of the Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: Only A. calcoaceticus LRVP54 produced AgNPs within 24 hours. Monodisperse spherical nanoparticles of 8-12 nm were obtained with 0.7 mM silver nitrate at 70°C. During optimization, a blue-shift in ultraviolet-visible spectra was seen. X-ray diffraction data and lattice fringes (d =0.23 nm) observed under high-resolution transmission electron microscope confirmed the crystallinity of AgNPs. These AgNPs were found to be more effective against Gram-negative compared with Gram-positive microorganisms. Overall, AgNPs showed the highest synergy with vancomycin in the disc-diffusion assay. For Enterobacter aerogenes, a 3.8-fold increase in inhibition zone area was observed after the addition of AgNPs with vancomycin. Reduction in MIC and minimum bactericidal concentration was observed on exposure of AgNPs with antibiotics. Interestingly, multidrug-resistant A. baumannii was highly sensitized in the presence of AgNPs and became susceptible to antibiotics except cephalosporins. Similarly, the vancomycin-resistant strain of Streptococcus mutans was also found to be susceptible to antibiotic treatment when AgNPs were added. These biogenic AgNPs showed significant synergistic activity on the ß-lactam class of antibiotics. CONCLUSION: This is the first report of synthesis of AgNPs using A. calcoaceticus LRVP54 and their significant synergistic activity with antibiotics resulting in increased susceptibility of multidrug-resistant bacteria evaluated as per MIC breakpoints of the CLSI standard.