Chalcone-based Turn-Off Chemosensor for Selective and Susceptible Detection of Fe2+ Ions: Spectroscopic and DFT Investigations.

Herein, in this report we are introducing newly synthesized chalcone derivative, "(E)-1-phenyl-3-(4-((5-(((Z)-thiophen-2-ylmethylene)amino)-1,3,4-thiadiazol-2-yl)thio)phenyl)prop-2-en-1-one" (5), as a chemosensor to detect Fe2+ metal ions in HEPES buffer solution of pH 7.5. Spectroscopic techniques were used to confirm the synthesized sensor. To determine the chemical reactivity and molecular stability of the probe, a frontier molecular orbitals investigation was carried out. A molecular electrostatic potential map was investigated to know the binding site of 5 for metal ion coordination. The theoretical absorption and fluorescence emission properties were estimated and correlated with the experimental observations. The sensor showed excellent selectivity for Fe2+ compared to all other studied metal ions. The fluorescence binding studies were carried out by adding different amounts of Fe2+ ions for a fixed concentration of probe 5. The inclusion of Fe2+ ions resulted in a decrease in fluorescence intensity with a bathochromic shift of emission wavelength of 5 due to the 5-Fe2+ complexation. The binding affinity value for the probe was found to be 576.2 M-1 with the help of the Stern-Volmer plot. The Job's plot and mass spectra supported the 2:1 (5: Fe2+) stoichiometry of complex formation. The detection limit and limit of quantification of 5 for Fe2+ were calculated to be 4.79 × 10-5 M and 14.54 × 10-5 M. Further, in addition to this, the photophysical parameters such as fluorescence lifetime of 5 and 5-Fe2+ complex measured to be 0.1439 and 0.1574 ns. The quantum yield of 5 and 5-Fe2+ was found to be 0.0398 and 0.0376. All these experimental findings revealed that probe 5 has excellent selectivity and sensitivity for Fe2+ ions.

In vitro α-amylase and α-glucosidase inhibition study of dihydropyrimidinones synthesized via one-pot Biginelli reaction in the presence of a green catalyst.

A green catalyst WELPSA-catalyzed three-component condensation (Biginelli) process involving an aldehyde, barbituric/thiobarbituric/1,3-dimethylbarbituric acid, and urea/thiourea/guanidine hydrochloride in a single pot in presence of a green solvent for the production of DHPM have been presented. The catalyst is reusable and this methodology is scalable. By using the in vitro experiments, the antidiabetic potentiality of synthesized compounds that inhibit α-amylase along with α-glucosidase efficiencies was assessed. All the synthesized compounds except for 4a and 4e, showed the most significant inhibition for α-amylase and α-glucosidase activities. Among the synthesized DHPM compounds, 4c and 4b exhibited significant inhibition profiles compared to the standard antidiabetic drug acarbose. Furthermore, synthesized substances' energy-minimized structures, 3D structures, and DFT calculations were performed using Gaussian 09 software, hybrid models, and MM2 force approaches. Strong hydrogen bonds with amino acid residues Arg-672, Arg-600, Trp-613, Asp-404, Asp-282, and Asp-616 indicate that an α-glucosidase-inhibitory peptide may have hypoglycemic efficacy confirmed by the molecular docking study of the synthesized DHPM.

Synthesis, antimycobacterial, cytotoxicity, anti-inflammatory, in silico studies and molecular dynamics of pyrazole-embedded thiazolidin-4-one hybrids.

In the present investigation, we devolved and synthesized a new series of pyrazole-embedded thiazolidin-4-one derivatives (9a-p) with the goal to produce promising antitubercular leads. The in vitro antimycobacterial activity of the synthesized compounds was tested against replicating and nonreplicating Mtb H37Rv strains. With MIC ranging from 3.03 to 22.55 µg/ml, five compounds (9a, 9c, 9d, 9e, and 9f) emerged as promising antitubercular agents. The active molecules were nontoxic to normal Vero cells. All the synthesized compounds were evaluated for in vitro anti-inflammatory studies. Compounds 9a, 9b, 9c, 9h, and 9i exhibited excellent anti-inflammatory efficacy. Docking study was performed to understand the binding pattern of the significantly active compound 9a with 1P44.

Potential Fluorinated Anti-MRSA Thiazolidinone Derivatives with Antibacterial, Antitubercular Activity and Molecular Docking Studies.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 µg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 µg/mL), and 4f (MIC 0.39 and 0.79 µg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

In vitro and in silico studies of fluorinated 2,3-disubstituted thiazolidinone-pyrazoles as potential α-amylase inhibitors and antioxidant agents.

As part of our effort to identify potent α-amylase inhibitors, in the present study, a novel series of fluorinated thiazolidinone-pyrazole hybrid molecules were prepared by the condensation of 3-(aryl/benzyloxyaryl)-pyrazole-4-carbaldehydes with fluorinated 2,3-disubstituted thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and liquid chromatography-mass spectrometry data. All the compounds were screened for their α-amylase inhibitory and free radical scavenging activities by DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS methods. Among the tested compounds, compound 8g emerged as a promising α-amylase inhibitor with IC50 = 0.76 ± 1.23 µM, and it was found to be more potent than the standard drug acarbose (IC50 = 0.86 ± 0.81 µM). Compounds 8b and 8g showed strong free radical scavenging activity compared to the standard butylated hydroxyl anisole. The kinetic study of compound 8g revealed the reversible, classical competitive inhibition mode on the α-amylase enzyme. Molecular docking and dynamic simulations studies were performed for the most potent compound 8g, which displayed remarkable hydrogen bonding with the α-amylase protein (PDB ID: 1DHK).

Novel pyrazole-clubbed thiophene derivatives via Gewald synthesis as antibacterial and anti-inflammatory agents.

The aim of this study was to synthesize newer potent Schiff bases by condensing 2-amino-5-(2,4-dichlorophenyl)thiophene-3-carbonitrile and 1,3-disubstituted-1H-pyrazole-4-carbaldehydes, and to investigate their biological activity. The compounds were synthesized via Gewald synthesis and characterized by spectral data and elemental analyses. They were screened for their in vitro antibacterial and anti-inflammatory activities. The synthesized compounds were also evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate Alamar Blue assay. Compounds 8b, 8c, 8f, 8g, 8k, 8n, and 8o showed promising antibacterial activity. The interactions between the substituted pyrazoles and bovine protein showed promising anti-inflammatory activity. The experimental results revealed compound 8a as a promising antitubercular agent. Hemolytic assays confirmed that the compounds are nontoxic, with percentage hemolysis ranging from 3.6 to 20.1, at a concentration of 1 mg/ml. The results suggest that the pyrazole ring and the substitution pattern on the heterocyclic moiety have an effect on the bioactivity.

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-(SUBSTITUTED PHENYL)-2-(5H-[1,2,4]TRIAZINO[5,6-b]INDOL-3-YLSULFANYL)ACETAMIDES AS ANTIMICROBIAL, ANTIDEPRESSANT AND ANTICONVULSANT AGENTS.

A new series of N-Aryl-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides were synthesized by condensation of tricyclic compound 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione with chloro N-phenylacetamides. The tricyclic compound was obtained by condensation of Isatin with thiosemicarbazide. Chloro N-phenylacetamides were obtained from different substituted anilines. Their structures were characterized by IR, 1H NMR, LC-MS and elemental analyses. Newly synthesized compounds were screened for antimicrobial, antidepressant and anticonvulsant activities. Preliminary results indicated that most of the compounds showed lesser MIC value than the standard drug used when tested for antimicrobial activity. Some of the compounds were endowed with very good antidepressant and anticonvulsant activity.

Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors.

Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases. Here, we report the structure-based designing and synthesis of two distinct series of novel Sirt1 inhibitors, benzimidazole mono-peptides and amino-acid derived 5-pyrazolyl methylidene rhodanine carboxylic acid. The compounds were evaluated for in vitro enzyme-based and cell-based Sirt1 inhibition assay, and cytotoxic-activity in both liver and breast cancer cells. The tryptophan conjugates i.e.13h (IC50 = 0.66 µM, ΔG bind = -1.1 kcal mol-1) and 7d (IC50 = 0.77 µM, ΔG bind = -4.4 kcal mol-1) demonstrated the maximum efficacy to inhibit Sirt1. The MD simulation unveiled that electrostatic complementarity at the substrate-binding-site through a novel motif "SLxVxP(V/F)A" could be a cause of increased Sirt1 inhibition by 13h and 13l over Sirt2 in cell-based assay, as compared to the control Ex527 and 7d. Finally, this study highlights novel molecules 7d and 13h, along with a new key hot-spot in Sirt1, which could be used as a starting lead to design more potent and selective sirtuin inhibitors as a potential anticancer molecule.

1-Chloro-4-(3,4-dichloro-phen-yl)-3,4-dihydro-naphthalene-2-carbaldehyde.

The title compound, C(17)H(11)Cl(3)O, was synthesized via the Vilsmeier-Haack reaction. The dihydro-naphthalene ring system is non-planar, the dihedral angle between the two fused rings being 10.87 (13)°; it forms a dihedral angle of 81.45 (10)° with the dichloro-phenyl ring. The crystal structure features inter-molecular C-H⋯O hydrogen bonds.

2-[4-(Methyl-sulfon-yl)phen-yl]acetonitrile.

In the title compound, C(9)H(9)NO(2)S, the benzene ring and the acetonitrile group are approximately coplanar, with a C-C-C-C torsion angle of 1.1 (3)° between them. In the crystal, mol-ecules are linked via inter-molecular C-H⋯O hydrogen bonds into layers parallel to (001).

Methyl 2-[2-(benzyl-oxycarbonyl-amino)-propan-2-yl]-5-hy-droxy-6-meth-oxy-pyrimidine-4-carboxyl-ate.

In the title compound, C(18)H(21)N(3)O(6), a pyrimidine derivative, the dihedral angle between the benzene and pyrimidine rings is 52.26 (12)°. The carboxyl-ate unit is twisted with respect to the pyrimidine ring, making a dihedral angle of 12.33 (7)°. In the crystal, mol-ecules are linked by a pair of O-H⋯O hydrogen bonds, forming an inversion dimer. The dimers are stacked into columns along the b axis through weak C-H⋯O inter-actions.

Benzyl N-{2-[5-(4-chloro-phen-yl)-1,2,4-oxadiazol-3-yl]propan-2-yl}carbamate.

In the title 1,2,4-oxadiazole derivative, C(19)H(18)ClN(3)O(3), the 1,2,4-oxadiazole ring makes dihedral angles of 12.83 (8) and 4.89 (8)°, respectively, with the benzyl and 4-chloro-phenyl rings, while the dihedral angle between the benzyl and 4-chloro-phenyl rings is 11.53 (7)°. In the crystal, mol-ecules are linked by N-H⋯N hydrogen bonds into helical chains along the b axis. A weak C-H⋯π inter-action is also present.

1-{4-Chloro-2-[2-(2-fluoro-phen-yl)-1,3-dithio-lan-2-yl]phen-yl}-2-methyl-1H-imidazole-5-carbaldehyde.

There are two mol-ecules in the asymmetric unit of the title imidazole derivative, C(20)H(16)ClFN(2)OS(2). In one mol-ecule, the dithiol-ane ring is disordered over two positions in a 0.849 (9):0.151 (10) ratio. The imidazole ring makes dihedral angles of 79.56 (9) and 18.45 (9)° with the 4-chloro-phenyl and 2-fluoro-phenyl rings, respectively, in one mol-ecule; in the other mol-ecule, the corresponding angles are 82.72 (9) and 17.39 (10)°. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions and these linked mol-ecules are stacked along the b axis by π-π inter-actions with a centroid-centroid distance of 3.4922 (11) Å. In addition, π-π inter-actions between the imidazole and 2-fluoro-phenyl rings are also observed, with centroid-centroid distances of 3.4867 (11) and 3.4326 (10) Å. The crystal is further consolidated by weak C-H⋯π inter-actions. Cl⋯S [3.5185 (8) Å], C⋯O [3.192 (3) Å] and C⋯C [3.326 (2)-3.393 (3) Å] short contacts are also observed.

(5E)-5-(4-Meth-oxy-benzyl-idene)-2-(piperidin-1-yl)-1,3-thia-zol-4(5H)-one.

In the title compound, C(16)H(18)N(2)O(2)S, the piperidine ring adopts a chair conformation. The central 4-thia-zolidinone ring makes dihedral angles of 12.01 (7) and 51.42 (9)°, respectively, with the benzene ring and the least-squares plane of the piperidine ring. An intra-molecular C-H⋯S hydrogen bond stabilizes the mol-ecular structure and generates an S(6) ring motif. In the crystal, mol-ecules are linked into a tape along the c axis by inter-molecular C-H⋯O hydrogen bonds.

3-{1-[4-(2-Methyl-prop-yl)phen-yl]eth-yl}-4-phenyl-1H-1,2,4-triazole-5(4H)-thione.

In the title compound, C(20)H(23)N(3)S, the central 1,2,4-triazole ring makes dihedral angles of 69.76 (9) and 81.69 (8)°, respectively, with the phenyl and benzene rings. In the crystal, mol-ecules are linked into a centrosymmetric dimer by a pair of inter-molecular N-H⋯S hydrogen bonds, generating an R(2) (2)(8) ring motif.

N-(2-Chloro-phen-yl)-2-({5-[4-(methyl-sulfan-yl)benz-yl]-4-phenyl-4H-1,2,4-triazol-3-yl}sulfan-yl)acetamide.

In the title mol-ecule, C(24)H(21)ClN(4)OS(2), the central 1,2,4-triazole ring forms dihedral angles of 89.05 (9), 86.66 (9) and 82.70 (10)° with the chloro-substituted benzene ring, the methyl-sulfanyl-substituted benzene ring and the phenyl ring, respectively. In the crystal, mol-ecules are linked into sheets parallel to (100) by inter-molecular N-H⋯N and weak C-H⋯O hydrogen bonds.

N'-(4-Fluoro-benzyl-idene)-2-(4-fluoro-phen-yl)acetohydrazide.

In the title compound, C(15)H(12)F(2)N(2)O, the dihedral angle between the two benzene rings is 48.73 (8)°. The hydrazine group is twisted slightly, with a C-N-N-C torsion angle of 172.48 (12)°. In the crystal, mol-ecules are connected by strong N-H⋯O and weak C-H⋯O hydrogen bonds, forming supra-molecular chains along the c axis. The structure is consolidated by π-π [centroid-centroid separation = 3.6579 (10) Å] and C-H⋯π inter-actions.

N'-(4-Chloro-benzyl-idene)-2-[4-(methyl-sulfan-yl)phen-yl]acetohydrazide.

In the title compound, C(16)H(15)ClN(2)OS, the hydrazine group is twisted slightly: the C-N-N-C torsion angle is 175.46 (13)°. The dihedral angle between the two terminal aromatic rings is 87.01 (8)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops. The dimers are further linked by weak C-H⋯π inter-actions.

(5E)-5-(2,4-Dichloro-benzyl-idene)-2-(piperidin-1-yl)-1,3-thia-zol-4(5H)-one.

In the title compound, C(15)H(14)Cl(2)N(2)OS, the piperidine ring adopts a chair conformation. The dihedral angle between the thia-zolidine ring and the dichloro-benzene ring is 9.30 (4)°; this near coplanar conformation is stabilized by the formation of an intra-molecular C-H⋯S hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming [001] chains. Weak π-π inter-actions [centroid-centroid separation = 3.5460 (5) Å] consolidate the structure.

Pyridine- and Thiazole-Based Hydrazides with Promising Anti-inflammatory and Antimicrobial Activities along with Their In Silico Studies.

A new class of compounds formed by the linkage of -C(O)-NH- with pyridine and thiazole moieties was designed, synthesized, and characterized by various spectral approaches. The newly characterized compounds were evaluated for their antimicrobial as well as anti-inflammatory properties. The in vitro anti-inflammatory activity of these compounds was evaluated by denaturation of the bovine serum albumin method and showed inhibition in the range of IC50 values-46.29-100.60 µg/mL. Among all the tested compounds, compound 5l has the highest IC50 value and compound 5g has the least IC50 value. On the other hand, antimicrobial results revealed that compound 5j showed the lowest MIC values and compound 5a has the highest MIC values. Furthermore, molecular docking of the active compounds demonstrated a better docking score and interacted well with the target protein. Physicochemical parameters of the titled compounds were found suitable in the reference range only. The in silico molecular docking study revealed their COX-inhibitory action. Compound 5j emerged as a significant bioactive molecule among the synthesized analogues.