Evaluation of xanthene-appended quinoline hybrids as potential leads against antimalarial drug targets.

A series of fused heterocycle xanthene-appended quinoline 6a-n was successfully synthesized with regioselectivity and characterized using IR, 1H NMR, 13C NMR, and mass spectral data. Molecular docking was performed to find the binding efficacy of all these newly synthesized compounds towards thirteen antimalarial drug targets. Molecular dynamics simulation was carried out to predict the stability of the ligand-bound complex in a solvent medium. Blind and site-directed docking with compounds 6a-n against 13 drug targets revealed most of the ligands to have a good binding affinity with the targets. Analysis on the basis of binding energy, binding modalities of the ligands, intermolecular interactions, and pharmacophore, we identified only one of the ligand-receptor complexes to provide better results. Molecular dynamic simulation of the selected receptor-ligand complex revealed that the synthesized compound had a better binding affinity with the receptor than the native ligand complex. Further analysis of the synthesized ligand in the laboratory may prove promising results in the search for potential antimalarial drugs.

Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors.

Herein we describe the design, synthesis and anticancer evaluation of a series of 2,3-dihydroimidazo[2,1-b]thiazoles as dual kinase inhibitors of IGF1R and EGFR. A series of saturated dihydroimidazo[2,1-b] thiazoles were synthesized to understand the structure-activity relationship. Further, the key modifications were performed to improve drug like properties of the series. A 2-oxa-6-azaspiro [3.3] heptane moiety was incorporated as a bioisosteric replacement of morpholine on dihydroimidazo[2,1-b] thiazole scaffold.Subsequent structure-activity relationship (SAR) studies identified several compounds with nM range of activity. The compound 18a shows promising activity, IC50 = 52 nM against IGF1R and IC50 = 35.5 nM against EGFR with descent PK profile. The identified leadshows promising activity against both wild type and the T790M mutant forms of enzymes.

Rationally designed imidazole derivative as colorimetric and fluorometric sensor for selective, qualitative and quantitative cyanide ion detection in real time samples.

A new imidazole derivative of 1,2-diaminoanthraquinone and fluorene-2-carboxaldehyde was designed as a sensor B2 to selectively detect the cyanide (CN-) ion through colorimetric and/or fluorometric methods. The photochemical characterizations of sensor B2 were tested using absorption and emission spectral studies in CH3CN-H2O (8:2) semi-aqueous medium. An excited state proton transfer process (ESIPT) was proved by theoretical and spectral studies. The colorimetric and fluorescence detection limit of CN- ion was found to be 5.3 × 10-6 M and 4.11 × 10-8 M, respectively. 1H NMR titration, electrochemical and DFT studies were supported the removal of -NH proton from B2. In order to utilize this sensor in real-time applications, we developed a test cassette which is coated with sensor B2 detected the presence of CN- ion in the food sample with endogenous cyanide ion.

Synthesis, DNA binding and in-vitro cytotoxicity studies on novel bis-pyrazoles.

A new series of bis-pyrazoles 6a-t were synthesized from 3,5-dimethyl pyrazole using sequential approach. All these compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral data. The interaction of newly synthesized bis-pyrazoles with DNA was investigated through molecular docking and absorption spectroscopic technique. Among all bis-pyrazoles compounds, the 6h compound showed lower conformational energy through in silico analysis. The interaction of each molecule in this series 6a-t with the various concentrations of DNA was examined through the UV-visible spectroscopic studies. The UV-visible spectroscopy studies on the specific binding of compound 6a, 6b, 6g, 6h, 6d, 6i, 6k, 6n, 6s with DNA have exhibited spectral shifts and the results were discussed. In further the compounds 6a-t were subjected to the in-vitro cytotoxicity studies against human pancreatic adenocarcinoma, human non-small cell lung carcinoma cell lines. Among the screened compounds, N-(3-isopropoxy-1-isopropyl-4-(3,5-dimethyl-1H-pyrazol-1-yl)-1H-pyrazol-5-yl)cyclobutane carboxamide and N-(5'-Isopropoxy-2'-isopropyl-3,5-dimethyl-2'H-[1,4'] bipyrazolyl-3'-yl)-dimethane sulfonamide were found as lead molecules since they have exhibited promising activity against both the cancer cell lines used in this study, whereas the compounds 4-(trifluoromethyl)-N-(3-isopropoxy-1-isopropyl-4-(3,5-dimethyl-2H-pyrrol-2-yl)-1H-pyrazol-5-yl)benzamide and 2,6-difluoro-N-(3-isopropoxy-1-isopropyl-4-(3,5-dimethyl-2H-pyrrol-2-yl)-1H-pyrazol-5-yl) benzamide were found to be active against the pancreatic cell line only. Rest all the other compounds were found to exhibit moderate to good activity towards both the cell lines.

Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents.

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 µg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents.

12-(3,4,5-Tri-meth-oxy-phen-yl)-2,3,4,12-tetra-hydro-1H-5-oxa-tetra-phen-1-one: crystal structure and Hirshfeld surface analysis.

In the title compound, C26H24O5, the pyran ring has a flattened-boat con-formation, with the 1,4-related ether O and methine C atoms lying 0.1205 (18) and 0.271 (2) Å, respectively, above the least-squares plane involving the doubly bonded C atoms (r.m.s deviation = 0.0208 Å). An envelope conformation is found for the cyclo-hexene ring, with the flap atom being the middle methyl-ene C atom, lying 0.616 (2) Šout of the plane defined by the remaining atoms (r.m.s. deviation = 0.0173 Å). The fused four-ring system is approximately planar, with the dihedral angle between the least-squares planes through the cyclo-hexene and naphthyl rings being 10.78 (7)°. The tris-ubstituted benzene ring occupies a position almost perpendicular to the pyran ring [dihedral angle = 83.97 (4)°]. The most prominent feature of the packing is the formation of zigzag supra-molecular chains mediated by aryl-C-H⋯O(meth-oxy) inter-actions; chains are connected into a three-dimensional architecture by methyl-ene- and methyl-C-H⋯π inter-actions. The prevalence of C-H⋯O and C-H⋯π inter-actions is confirmed by an analysis of the Hirshfeld surface. A comparison with related structures suggests that the mol-ecular conformation of the title compound is relatively robust with respect to varying substitution patterns at the methine C atom of the pyran ring.

Synthesis, characterization of (3E)-1-(6-chloro-2-methyl-4-phenyl quinolin-3-Yl)-3-aryl prop-2-en-1-ones through IR, NMR, single crystal X-ray diffraction and insights into their electronic structure using DFT calculations.

3E-1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)-3-arylprop-2-en-1-ones were synthesized and characterized by FTIR, (1)H NMR, (13)C NMR, HSQC, DEPT-135. In addition the compound 3E-1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one was subjected to the single crystal X-ray diffraction studies. Density functional theory calculations were carried out for this chalcone and its derivatives to investigate into their electronic structure, chemical reactivity, linear and non-linear optical properties. The structure predicted from DFT for chalcone is in good agreement with the structure from XRD measurement.

Synthesis of 4-hydroxy-2(1H)-quinolone derived chalcones, pyrazolines and their antimicrobial, in silico antimalarial evaluations.

A few derivatives of 3-(4,5-dihydro-5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-hydroxyquinolin-2(1H)-ones (5a-j) that are synthesized from 4-hydroxy-3-(3-arylacryloyl)quinolin-2(1H)-ones (4a-j) by microwave-assisted synthesis are screened for their antimicrobial, in silico antimalarial activities. Among the tested compounds 4h and 5d were found to have a potent antimalarial activity than the standards, and the others are found to show considerable antimalarial activity and moderate antimicrobial activity.

Growth, spectral, optical, thermal, surface analysis and third order nonlinear optical properties of an organic single crystal: 1-(2-Methyl-6-nitro-4-phenyl-3-quinolyl) ethanone.

Single crystal of 1-(2-Methyl-6-nitro-4-phenyl-3-quinolyl) ethanone was grown using slow evaporation solution growth technique. Single crystal X-ray diffraction study reveals the lattice parameters of the grown crystal. The modes of vibration of different molecular groups present in 2M6NQE were identified by FTIR spectral analysis. Its optical behavior was examined through UV-vis-NIR absorption and PL emission spectrum. They signify that the crystal has transparency in the region between 383 and 1100 nm. The PL spectrum of the title compound shows green emission in the crystal. From the thermal analysis, 2M6NQE has found to be thermally stable up to 263°C, and the melting point of the material is 170°C. The estimations of third order non-linear optical properties like non-linear absorption coefficient (ß), non-linear refractive index (n2) and susceptibility [χ(3)] were calculated using Z-scan technique. It has observed that, crystal exhibits reverse saturation absorption and self-defocusing performance. Etching study was carried out for the grown crystal using different solvents.

Growth, optical, luminescence, thermal and mechanical behavior of an organic single crystal: 3-Acetyl-2-methyl-4-phenylquinolin-1-ium chloride.

A single crystal of 3-acetyl-2-methyl-4-phenylquinolin-1-ium chloride has grown by slow evaporation solution growth technique using ethanol as solvent. The structural, thermal, optical and mechanical property has studied for the grown crystal. Single crystal XRD revealed that the crystal belongs to monoclinic system with space group P21/c. The presences of Functional groups in the crystallized material have confirmed using the FTIR vibrational spectrum. The optical absorbance spectrum recorded from 190 to 1100nm shows the cut-off wavelength occurs at 371nm. The material shows its transparency in the entire region of the visible spectrum. The photoluminescence spectrum shows the ultraviolet and blue emission in the crystal. Thermogravimetric and differential thermal analysis reveal the thermal stability of the grown crystal. Etching study shows the grown mechanism and surface features of the crystal. Vickers microhardness studies have carried out on the (01-1) plane to understand the mechanical properties of the grown crystal. The hardness of the title compound increases on increasing the load. The Meyer's index number (n), and the stiffness constants for different loads has calculated and reported.

(2E)-3-(6-Chloro-2-meth-oxy-quinolin-3-yl)-1-(2,4-di-methyl-quinolin-3-yl)prop-2-en-1-one.

The mol-ecule of the title compound, C24H19ClN2O2, is bent, with the dihedral angle between the terminal quinoline ring systems being 63.30 (5)°. The quinolinyl residues are connected by an almost planar prop-2-en-1-one bridge (r.m.s. deviation = 0.022 Å), with the dihedral angles between this plane and the appended quinolinyl residues being 75.86 (7) and 38.54 (7)°. The C atom of the meth-oxy group is close to coplanar with its attached ring [deviation = 0.116 (2) Å]. In the crystal, a three-dimensional architecture is constructed by meth-yl-carbonyl C-H⋯O inter-actions and π-π inter-actions between centrosymmetrically related quinolinyl residues [centroid-to-centroid separations 3.5341 (10) and 3.8719 (9) Å].

(2E)-3-(2-Chloro-8-methyl-quinolin-3-yl)-1-(2,4-di-methyl-quinolin-3-yl)prop-2-en-1-one.

In the mol-ecule of the title compound, C24H19ClN2O, the terminal quinolinyl residues are close to perpendicular to each other [dihedral angle 83.72 (4)°]. The quinolinyl residues are connected by and inclined to the prop-2-en-1-one bridge, with the Car-Car-C-C (ar = aromatic) torsion angles being 71.01 (17) and 20.6 (2)°. The crystal structure features phen-yl-carbonyl C-H⋯O inter-actions and π-π inter-actions between centrosymmetrically related quinolinyl residues [3.5341 (10) and 3.8719 (9) Å], which together lead to a three-dimensional architecture.

(2E)-3-(2-Chloro-8-methyl-quinolin-3-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one.

In the title compound, C29H21ClN2O, there is a twist in the bridging prop-2-en-1-one group [C=C-C=O torsion angle = 22.7 (2)°]. The quinolinyl residues form a dihedral angle of 86.92 (4)°, indicating an almost perpendicular relationship. In the crystal, supra-molecular layers in the bc plane are stabilized by C-H⋯π and π-π inter-actions [centroid-centroid distance = 3.4947 (7) Å].

(2E)-3-(6-Chloro-2-meth-oxy-quinolin-3-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one acetone monosolvate.

In the title solvate, C29H21ClN2O2·C3H6O, a prop-2-en-1-one bridge links two quinolinyl residues; the latter are almost perpendicular [dihedral angle = 78.27 (6)°]. The dihedral angle between the quinonyl ring system and its pendant phenyl group is 59.78 (8)°. A small twist in the bridging prop-2-en-1-one group is noted [O=C-C=C torsion angle = -10.6 (3)°]. In the crystal, a three-dimensional architecture arises as a result of C-H⋯O and π-π stacking [centroid-centroid distances = 3.5504 (12)-3.6623 (12) Å].

(2E)-3-(2-Chloro-benzo[h]quinolin-3-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one.

In the title compound, C32H21ClN2O, an almost planar (r.m.s. deviation = 0.033 Å) prop-2-en-1-one bridge links quinolinyl and benzoquinolinyl residues; the latter are twisted out of the plane of the bridge [dihedral angles = 75.94 (5) and 20.20 (5)°, respectively]. In the crystal, a three-dimensional architecture arises as a result of C-H⋯O, C-H⋯π and π-π [centroid-centroid distances involving pyridine rings = 3.5806 (7)-3.7537 (7) Å] interactions.

(2E)-3-(2-Chloro-7-methyl-quinolin-3-yl)-1-(6-chloro-2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one ethanol monosolvate.

In the title ethanol solvate, C29H20Cl2N2O·C2H5OH, the quinolinyl residues form a dihedral angle of 46.41 (4)° with each other, and each is inclined [Cp-C-C=O and C=C-C-Cp (p = pyridyl) torsion angles = 54.8 (2) and 144.44 (19)°, respectively] with respect to the almost planar bridging prop-2-en-1-one residue [O=C-C=C torsion angle = -4.1 (3)°]. The ethanol solvent mol-ecule is disordered over two positions of equal occupancy and is located close to a centre of inversion. These mol-ecules reside in cavities defined by the organic mol-ecules, which are connected into a three-dimensional architecture by C-H⋯Cl, C-H⋯O and C-H⋯N inter-actions, as well as π-π contacts [inter-centroid distances = 3.5853 (10) and 3.8268 (11) Å], each involving pyridyl rings.

10a-Hy-droxy-9-(4-meth-oxy-phen-yl)-3,4,5,6,7,8a,9,10a-octa-hydro-1H-xanthene-1,8(2H)-dione.

In the title compound, C(20)H(22)O(5), the tetra-hydro-pyran, cyclo-hexene and cyclo-hexane rings of the xanthene ring system adopt half-chair, half-boat and chair conformations, respectively. The mean plane of the four roughly planar atoms of the tetra-hydro-pyran ring (r.m.s. deviation = 0.111 Å) forms a dihedral angle of 82.91 (4)° with the meth-oxy-benzene group. In the crystal, mol-ecules are linked via O-H⋯O and C-H⋯O hydrogen bonds into sheets lying parallel to the ac plane. The crystal is further consolidated by weak C-H⋯π inter-actions.

Diisobutyl 4-(3-eth-oxy-4-hy-droxy-phen-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxyl-ate.

The asymmetric unit of the title compound, C(25)H(35)NO(6), contains two independent mol-ecules. In each mol-ecule, the 1,4-dihydro-pyridine ring adopts a flattened boat conformation. The dihedral angles between the 1,4-dihydro-pyridine and benzene rings are 87.55 (7) and 87.23 (7)°. In one of these mol-ecules, one of the isobutyl groups is disordered over two sets of sites, with an occupancy ratio of 0.890 (2):0.110 (2). In the crystal, mol-ecules are linked through N-H⋯O, O-H⋯O and C-H⋯O hydrogen bonds forming two-dimensional networks parallel to the ab plane. The crystal structure is further stabilized by weak C-H⋯π inter-actions.

Diethyl 2,6-dihy-droxy-4-(3-nitro-phen-yl)-2,6-bis-(trifluoro-meth-yl)piperidine-3,5-dicarboxyl-ate.

In the title compound, C(19)H(20)F(6)N(2)O(8), the eth-oxy and ethyl groups are disordered over two sets of sites, with occupancy ratios of 0.212 (18):0.788 (18) and 0.746 (6):0.254 (6), respectively. The piperidine ring adopts a chair conformation. In the mol-ecule, intra-molecular O-H⋯O hydrogen bonds form two S(6) ring motifs. In the crystal, mol-ecules are linked via O-H⋯O and C-H⋯O hydrogen bonds, forming dimers.

9-(4-Hy-droxy-phen-yl)-3,3,6,6-tetra-methyl-4,5,6,9-tetra-hydro-3H-xanthene-1,8(2H,7H)-dione.

In the title compound, C(23)H(26)O(4), the two cyclo-hexene rings adopt envelope conformations whereas the pyran ring adopts a boat conformation. In the crystal, pairs of inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into inversion dimers.