Design, synthesis, biological evaluation and molecular docking studies of quinoline-anthranilic acid hybrids as potent anti-inflammatory drugs.

Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.

DNA binding and cleavage, BRCA1 gene interaction, antiglycation and anticancer studies of transition metal complexes of sulfonamides.

A series of 4-((4-methylphenylsulfonamido)methyl)cyclohexanecarboxylic acid (NaMSCCA) transition metal complexes [Cu(II), Zn(II), Ni(II), Mn(II), and Co(II)] have been synthesized by precipitation method. The characterization was done by physical techniques, FT-IR spectroscopy, mass spectrometry, and NMR spectroscopy. The molecular structures of nickel (II) AZ-3 and cobalt (II) AZ-5 complexes were determined by the X-ray diffraction technique and found to crystallize in the triclinic space group P-1. The coordination geometry around the central nickel (AZ-3) and cobalt (AZ-5) atoms was square planar bipyramidal. Molecular docking was performed with duplex DNA of sequence d(CGCGAATTCGCG)2 DNA to determine the probable binding mode of compounds. Then these synthesized compounds were used to perform DNA cleavage activity through the agarose gel electrophoresis method. Among the compounds, compounds AZ-1 and AZ-2 exhibited good nuclease activity. The DNA sequence of breast-cancer suppressor gene 1 (BRCA1) was amplified through PCR and interaction studies of compounds AZ-1 and AZ-2 were performed through gel electrophoresis and fluorescence emission spectroscopy. The expression analysis of the BRCA1 gene was also performed to quantify the expression relative fold change (2^-(∆∆CT)) after treatment with compounds. All synthesized compounds were evaluated for their antioxidant and antiglycation activities and AZ-2 exhibited excellent results. The molecular docking study of these compounds was performed against the protein structure of advanced glycation end products to support the experimental results. Anticancer activity of compounds was performed through MTT assay. Copper and zinc complexes depicted the highest anticancer activity against human breast adenocarcinoma (MCF7) and human corneal epithelial cell (HCEC) cell lines.

N-Trifluoroacetylated pyrazolines: Synthesis, characterization and antimicrobial studies.

A series of N-trifluoroacetyl-2-pyrazolines have been synthesized via cyclization of chalcones in the presence of trifluoroacetic acid and hydrazine as a base. The method used for the preparation of pyrazolines was found to be an efficient one as all of the compounds were obtained in good yield (up to 79%). Various spectroscopic techniques established the structures and additionally corroborated the compounds 2a and 2e by single crystal X-ray. Newly synthesized pyrazolines were investigated for their potential as antimicrobial agents. Compound 2a displayed promising antimicrobial activity against pathogenic Escherichia coli and Pseudomonas aeruginosa. Furthermore, the mechanism of the antimicrobial activity of 2a was demonstrated with the help of scanning electron microscopy (SEM), which revealed complete damage of the bacterial cell membrane, providing dead cell debris in the milieu. The minimum inhibitory concentration (MIC) observed was 79 and 90 µM against E. coli and P. aeruginosa, respectively. Hence, these compounds might be significantly useful in antimicrobial drug development.

Sulfonamides containing curcumin scaffold: Synthesis, characterization, carbonic anhydrase inhibition and molecular docking studies.

Curcumin is a multi-functional pharmacologically safe natural agent with proven cytoprotective effects to healthy human cells. In this study, a new series of sulfonamides with curcumin scaffold were synthesized, characterized and investigated for their carbonic anhydrase isoenzyme I (human) and II (bovine) isoforms. The structures of newly synthesized compounds were described by IR, 1H NMR and 13C NMR spectral data. Compound 14 showed the Ki value of 0.99 µM with highest inhibitory activity among all other synthesized compounds against hCA-I enzyme. Similarly enzyme kinetic studies of compound 14, 16 and 30 against bCAII enzyme showed Ki values of 0.71, 0.67 and 0.71 µM respectively. Our biological assays results showed that most of active compounds have similar inhibitory activities compared to standard acetazolamide drug. The molecular docking predicted binding modes showed that these compounds bind with hCA-1 enzyme in similar fashion.

Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies.

Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study, curcumin derived azomethine, isoxazole, pyrimidines and N-substituted pyrazoles were synthesized to investigate their urease enzyme inhibition. The structures of newly synthesized compounds were described by IR, MS, 1H NMR and 13C NMR spectral data. Urease enzyme inhibition was evaluated through in vitro assays in which compound 8b was found to be the most potent (IC50 = 2.44 ± 0.07 µM) among the tested compounds. The compounds with diazine ring system except the 4d showed better urease inhibition (IC50 = 11.43 ± 0.21-19.63 ± 0.28 µM) than the standard urease inhibitor thiourea (IC50 = 22.61 ± 0.23 µM). Similarly enzyme kinetics data revealed that compounds 3c-3e and 8b were competitive inhibitors with Ki values of 20.0, 19.87, 20.23 and 19.11 µM respectively while the compounds 4b, 4c and 4e were mixed type of inhibitors with Ki values 6.72, 19.69 and 6.72 µM respectively. Molecular docking studies were also performed to identify the plausible binding modes of the most active compounds.

One Pot Selective Arylation of 2-Bromo-5-Chloro Thiophene; Molecular Structure Investigation via Density Functional Theory (DFT), X-ray Analysis, and Their Biological Activities.

Synthesis of 2,5-bisarylthiophenes was accomplished by sequential Suzuki cross coupling reaction of 2-bromo-5-chloro thiophenes. Density functional theory (DFT) studies were carried out at the B3LYP/6-31G(d, p) level of theory to compare the geometric parameters of 2,5-bisarylthiophenes with those from X-ray diffraction results. The synthesized compounds are screened for in vitro bacteria scavenging abilities. At the concentration of 50 and 100 µg/mL, compounds 2b, 2c, 2d, 3c, and 3f with IC50-values of 51.4, 52.10, 58.0, 56.2, and 56.5 µg/mL respectively, were found most potent against E. coli. Among all the synthesized compounds 2a, 2d, 3c, and 3e with the least values of IC50 77, 76.26, 79.13 µg/mL respectively showed significant antioxidant activities. Almost all of the compounds showed good antibacterial activity against Escherichia coli, whereas 2-chloro-5-(4-methoxyphenyl) thiophene (2b) was found most active among all synthesized compound with an IC50 value of 51.4 µg/mL. All of the synthesized compounds were screened for nitric oxide scavenging activity as well. Frontier molecular orbitals (FMOs) and molecular electrostatic potentials of the target compounds were also studied theoretically to account for their relative reactivity.

Recycling nanowire templates for multiplex templating synthesis: a green and sustainable strategy.

Template-directed synthesis of nanostructures has been emerging as one of the most important synthetic methodologies. A pristine nanotemplate is usually chemically transformed into other compounds and sacrificed after templating or only acts as an inert physical template to support the new components. If a nanotemplate is costly or toxic as waste, to recycle such a nanotemplate becomes highly desirable. Recently, ultrathin tellurium nanowires (TeNWs) have been demonstrated as versatile chemical or physical templates for the synthesis of a diverse family of uniform 1D nanostructures. However, ultrathin TeNWs as template are usually costly and are discarded as toxic waste in ionic species after chemical reactions or erosion. To solve the above problem, we conceptually demonstrate that such a nanotemplate can be economically recycled from waste solutions and repeatedly used as template.

Microwave Assisted Synthesis, Physicochemical, Photophysical, Single Crystal X-ray and DFT Studies of Novel Push-Pull Chromophores.

Two push-pull chromophores were synthesized by knoevenagel condensation under microwave irradiation. The structure of synthesized chromophores were established by spectroscopic (FT-IR, (1)H NMR, (13)C NMR, EI-MS) and elemental analysis. Structure of the chromophores was further conformed by X-ray crystallographic. UV-Vis and fluorescence spectroscopy measurements provided that chromophores were good absorbent and fluorescent properties. Fluorescence polarity studies demonstrated that chromophores were sensitive to the polarity of the microenvironment provided by different solvents. Physicochemical parameters, including singlet absorption, extinction coefficient, stokes shift, oscillator strength, dipole moment and flurescence quantum yield were investigated in order to explore the analytical potential of the synthesized chromophores. In addition, the total energy, frontier molecular orbitals, hardness, electron affinity, ionization energy, electrostatic potential map were also studied computationally by using density functional theoretical method.

Synthesis, crystal structures and spectroscopic properties of triazine-based hydrazone derivatives; a comparative experimental-theoretical study.

We report here a comparative theoretical and experimental study of four triazine-based hydrazone derivatives. The hydrazones are synthesized by a three step process from commercially available benzil and thiosemicarbazide. The structures of all compounds were determined by using the UV-Vis., FT-IR, NMR (1H and 13C) spectroscopic techniques and finally confirmed unequivocally by single crystal X-ray diffraction analysis. Experimental geometric parameters and spectroscopic properties of the triazine based hydrazones are compared with those obtained from density functional theory (DFT) studies. The model developed here comprises of geometry optimization at B3LYP/6-31G (d, p) level of DFT. Optimized geometric parameters of all four compounds showed excellent correlations with the results obtained from X-ray diffraction studies. The vibrational spectra show nice correlations with the experimental IR spectra. Moreover, the simulated absorption spectra also agree well with experimental results (within 10-20 nm). The molecular electrostatic potential (MEP) mapped over the entire stabilized geometries of the compounds indicated their chemical reactivates. Furthermore, frontier molecular orbital (electronic properties) and first hyperpolarizability (nonlinear optical response) were also computed at the B3LYP/6-31G (d, p) level of theory.

Crystal structure of 1-benzoyl-3-(4-fluoro-phen-yl)thio-urea.

The title compound, C14H11FN2OS, contains two mol-ecules (A and B) in the asymmetric unit, with different conformations. In mol-ecule A, the dihedral angles between the central thio-urea grouping and the phenyl and fluoro-benzene rings are 28.77 (8) and 41.82 (8)°, respectively, and the dihedral angle between the ring planes is 70.02 (9)°. Equivalent data for mol-ecule B are 8.46 (8), 47.78 (8) and 52.99 (9)°, respectively. Both mol-ecules feature an intra-molecular N-H⋯O hydrogen bond, which closes an S(6) ring. In the crystal, A+B dimers linked by pairs of N-H⋯S hydrogen bonds generate R 2 (2)(8) loops.

Synthesis, characterization, and BSA binding studies of newfangled 2-phenylacetohydrazide derivatives.

Five 2-phenylacetohydrazide derivatives (BPAH = N'-benzylidene-2-phenylacetohydrazide, HBPAH = N'-(2-hydroxybenzylidene)-2-phenylacetohydrazide), PPAH = 2-phenyl-N'-3-phenylallylideneacetohydrazide, FMPAH = N'-(furan-2-ylmethylene)-2-phenylaceto hydrazide and EPAH = N'-ethylidene-2-phenylacetohydrazide were synthesized by the condensation of 2-phenylacetohydrazide with the corresponding aldehyde. The synthesized compounds were characterized by FTIR, 1D, and 2D NMR spectroscopy. The structure of the BPAH and PPAH were analyzed by single crystal X-ray diffraction analysis and in both crystallized compounds, the molecules adopted trans geometry around the -C[bond, double bond]N- (imine) functional group. To explore the pharmacological significance of these compounds, the binding ability of these compounds with Bovine Serum Albumin (BSA) was investigated using fluorescence spectroscopy. BPAH and PPAH showed the highest binding ability while EPAH, HBPAH, and FMPAH had lower binding ability to BSA molecules. Thermodynamic parameters ΔG, ΔH°, and ΔS° demonstrated that interactions of BSA with compounds BPAH, EPAH, FMAH, and HBPAH were exothermic while for PPAH it was endothermic. The negative enthalpy and entropy of the compounds BPAH, EPAH, FMAH, and HBPAH indicated that van der Waals' forces and hydrogen bonding played a major role in stabilizing the BSA binding with the molecules. Hydrophobic interactions were predominant in the binding of PPAH with BSA tends to interact with two sets of BSA binding sites with an increase in temperature.

2-[(2-Hy-droxy-naphthalen-1-yl)methyl-idene-amino]-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile.

Two independent mol-ecules, A and B, comprise the asymmetric unit of the title compound, C(21)H(18)N(2)OS, with the difference in the angle of orientation between the naphthalene ring system and the mean plane of the cyclo-heptyl ring [16.13 (1) in A and 11.48 (5)° in B], being evident. The cyclo-heptyl ring adopts a distorted chair conformation in each mol-ecule with r.m.s. deviations of 0.2345 (4) (A) and 0.2302 (4) Š(B). Intra-molecular O-H⋯N hydrogen bonding generates planar six-membered S(6) loops with r.m.s. deviations of 0.0099 (1) (A) and 0.0286 (1) Š(B).

5-Acetyl-3-(5-phenyl-1H-pyrazol-3-yl)-1,3,4-thia-diazol-2(3H)-one monohydrate.

In the title hydrate, C13H10N4O2S·H2O, the dihedral angles between the central pyrazole ring and its pendant phenyl and thia-diazole rings are 9.93 (8) and 4.56 (7)°, respectively. In the crystal, the components are linked by N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds, generating [100] chains incorporating R 4 (4)(10) loops. A weak C-H⋯O inter-action helps to consolidate the packing.

2-(Naphthalene-2-sulfonamido)-3-phenyl-propanoic acid.

In the title compound, C(19)H(17)NO(4)S, the phenyl ring and the naphthalene ring system are oriented at a dihedral angle of 4.12 (2)° and the mol-ecule adopts a U-shaped conformation. The C(c)-C-N-S (c = carb-oxy) torsion angle is 90.98 (15)°. In the crystal, mol-ecules are linked by O-H⋯O and N-H⋯O hydrogen bonds, resulting in (100) chains incorporating centrosymmetric R(2) (2)(14) and R(2) (2)(10) loops. Weak aromatic π-π stacking is also observed [centroid-centroid separations = 3.963 (2) and 3.932 (2) Å].

1,3-Diethyl-2-sulfanyl-idene-5-(2,4,5-trimeth-oxy-benzyl-idene)-1,3-diazinane-4,6-dione.

The title compound, C18H22N2O5S, is largely planar, with an r.m.s. deviation of 0.0546 (1) Šof atoms from the mean plane through all non-H atoms except for the methyl groups. The benzene and pyrimidine-dione rings are inclined to one another at a dihedral angle of 1.41 (7)°. In the crystal, weak C-H⋯O inter-actions connect the mol-ecules into chains propagating along the b-axis direction.

2-Chloro-6-(2,3-di-chloro-benzene-sulfonamido)-benzoic acid.

In the title compound, C13H8Cl3NO4S, the aromatic rings are oriented at a dihedral angle of 68.94 (1)° and the mol-ecule adopts a V-shape. An intra-molecular N-H⋯O inter-action generates a six-membered S(6) ring motif. In the crystal, pairs of O-H⋯O hydrogen bonds involving the carb-oxy group link the mol-ecules into inversion dimers with an R 2 (2)(8) motif. N-H⋯O and non-classical C-H⋯O inter-actions connect the mol-ecules, forming sheets propagating in (100).

Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.

Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 µM. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 µM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9±1.16 to -35.1±0.13 in case of Cathepsin D, while from -24.0±0.10 to -29.5±0.10 in case of Plasmepsin-II.

Chitosan-Cu Catalyzed Novel Ferrocenated Spiropyrrolidines: Green Synthesis, Single Crystal X-ray Diffraction, Hirshfeld Surface and Antibacterial Studies.

Chitosan-bounded copper (chitosan-Cu) was introduced for green synthesis of novel ferrocenated spiropyrrolidine hybrids, namely 3'-(4-.bromobenzoyl)-5'-(4-hydroxybenzyl)-4'-ferrocenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-bromobenzoyl)-4'-ferrocenylspiro[indoline-3,2'-pyrrolidin]-2-one, in good yield. A one-pot three-component 1,3-dipolar cycloaddition reaction was employed for the formation of spiropyrrolidines from 1-(4-bromophenyl)-ferrocene-prop-2-en-1-one and azomethine ylides, which were developed in situ from tyrosine, glycine, and isatin, respectively. Various spectroscopic methods were used to establish the structures of spiropyrrolidines, and a single crystal X-ray diffraction study of a spiropyrrolidine provided additional confirmation. The crystallographic study revealed that compound 3a has one independent molecule in its unit cell, which is correlated with Hirshfeld surface analysis, and describes intramolecular contacts adversely. The highly yielded products in green conditions were determined for their antibacterial significance and were found to have good activity against Gram-positive and Gram-negative bacterial strains.

Enhancing the Photovoltaic Properties via Incorporation of Selenophene Units in Organic Chromophores with A2-π2-A1-π1-A2 Configuration: A DFT-Based Exploration.

Currently, polymer organic solar cells (POSCs) are widely utilized due to their significant application, such as low-cost power conversion efficiencies (PCEs). Therefore, we designed a series of photovoltaic materials (D1, D2, D3, D5 and D7) by the incorporation of selenophene units (n = 1-7) as π1-spacers by considering the importance of POSCs. Density functional theory (DFT) calculations were accomplished at MPW1PW91/6-311G (d, p) functional to explore the impact of additional selenophene units on the photovoltaic behavior of the above-mentioned compounds. A comparative analysis was conducted for designed compounds and reference compounds (D1). Reduction in energy gaps (∆E = 2.399 - 2.064 eV) with broader absorption wavelength (λmax = 655.480 - 728.376 nm) in chloroform along with larger charge transference rate was studied with the addition of selenophene units as compared to D1. A significantly higher exciton dissociation rate was studied as lower values of binding energy (Eb = 0.508 - 0.362 eV) were noted in derivatives than in the reference (Eb = 0.526 eV). Moreover, transition density matrix (TDM) and density of state (DOS) data also supported the efficient charge transition origination from HOMOs to LUMOs. Open circuit voltage (Voc) was also calculated for all the aforesaid compounds to check the efficiency, and significant results were seen (1.633-1.549 V). All the analyses supported our compounds as efficient POSCs materials with significant efficacy. These compounds might encourage the experimental researchers to synthesize them due to proficient photovoltaic materials.

Synthesis, structure elucidation, SC-XRD/DFT, molecular modelling simulations and DNA binding studies of 3,5-diphenyl-4,5-dihydro-1H-pyrazole chalcones.

Deoxyribonucleic acid (DNA) acts as the most important intracellular target for various drugs. Exploring the DNA binding interactions of small bioactive molecules offers a structural guideline for designing new drugs with higher clinical efficacy and enhanced selectivity. This study presents the facile synthesis of pyrazoline-derived compounds (4a)-(4f) by reacting substituted chalcones with hydrazine hydrate using formic acid. The structure elucidation of substituted pyrazoline compounds was carried out using 1H-NMR, FT-IR and elemental analyses. While the crystal structures of two compounds (4a) and (4b) have been resolved by single-crystal X-ray diffraction (SC-XRD) analysis. Hirshfeld surface analysis also endorsed their greater molecular stability. Computational calculations at DFT/B3LYP/6-311++G(d,p) were executed to compare the structural properties (bond angle and bond length) and explore reactivity descriptors, frontier molecular orbitals (FMO), Mulliken atomic charges (MAC), molecular electrostatic potential (MEP) and electronic properties. All the compounds were evaluated for DNA binding interactions by UV-Vis spectrophotometric analysis. The results revealed that compounds (4a)-(4f) bind to DNA via non-covalent binding mode having binding constant values ranging from 1.22 × 103 to 6.81 × 104 M-1. The negative values of Gibbs free energy also proved the interaction of studied compounds with DNA as a spontaneous process. The findings of molecular docking simulations depicted that these studied compounds showed significant binding interactions with DNA and these results were consistent with experimental findings. Compound (4b) was concluded as the most potent compound of the series with the highest binding constant (4.95 × 104) and strongest binding affinity (-8.48 kcal/mol).Communicated by Ramaswamy H. Sarma.