Design and synthesis of heterocyclic azole based bioactive compounds: Molecular structures, quantum simulation, and mechanistic studies through docking as multi-target inhibitors of SARS-CoV-2 and cytotoxicity.

Two heterocyclic azole compounds, 3-(2,3-dihydrobenzo[d]thiazol-2-yl)-4H-chromen-4-one (SVS1) and 5-(1H-indol-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (SVS2) were obtained unexpectedly from 2-aminothiophenol and 4-oxo-4H-chromene-3-carbaldehyde (for SVS1), and (E)-2-((1H-indol-3-yl)methylene)-N-methylhydrazine-1-carbothioamide in the presence of anhydrous FeCl3 (for SVS2), respectively. The compounds were well characterized by analytical and spectroscopic tools. The molecular structures of both the compounds were determined by single crystal X-ray diffraction (XRD) study. The results obtained from density functional theory (DFT) study revealed the molecular geometry and electron distribution of the compounds, which were correlated well with the three-dimensional structures obtained from the single crystal XRD. DMol3 was used to calculate quantum chemical parameters [chemical potential (µ), global hardness (η), global softness (σ), absolute electronegativity (χ) and electrophilicity index (ω)] of SVS1 and SVS2. Molecular docking study was performed to elucidate the binding ability of SVS1 and SVS2 with SARS-CoV-2 main protease and human angiotensin-converting enzyme-2 (ACE-2) molecular targets. Interestingly, the binding efficiency of the compounds with the molecular targets was comparable with that of remdesivir (SARS-CoV-2), chloroquine and hydroxychloroquine. SVS1 showed better docking energy than SVS2. The molecular docking study was complemented by molecular dynamics simulation study of SARS-CoV-2 main protease-SVS1 complex, which further exemplified the binding ability of SVS1 with the target. In addition, SVS1, SVS2 and cisplatin were assessed for their cytotoxicity against a panel of three human cancer cells such as HepG-2 (hepatic carcinoma), T24 (bladder) and EA.hy926 (endothelial), as well as Vero (kidney epithelial cells extracted from an African green monkey) normal cells using MTT assay. The results showed that SVS2 has significant cytotoxicity against HepG-2 and EA.hy926 cells with the IC50 values of 33.8 µM (IC50 = 49.9 µM-cisplatin and 8.6 µM-doxorubicin) and 29.2 (IC50 = 26.6 µM-cisplatin and 3.8 µM-doxorubicin), respectively.

Synthesis, cytotoxicity and docking studies (with SARS-CoV-2) of water-soluble binuclear Ru-p-cymene complex holding indole thiosemicarbazone ligand.

A water-soluble binuclear organometallic Ru-p-cymene complex [Ru(η6-p-cymene)(η2-L)]2 (1) was prepared from (E)-2-((1H-indol-3-yl)methylene)-N-phenylhydrazine-1-carbothioamide (HL) and [RuCl2(p-cymene)]2 in methanol at room temperature under inert atmosphere. The structure of binuclear complex was analyzed by UV-Visible, FT-IR, NMR and mass spectroscopic methods. The solid-state structure of the complex was ascertained by single crystal X-ray diffraction technique. The complex exhibited pseudo-octahedral (piano-stool) geometry around Ru(II) ion. The cytotoxic property of the ligand and complex along with cisplatin was investigated against A549-lung, MCF-7-breast, HeLa-cervical, HepG-2-liver, T24-urinary bladder and EA.hy926-endothelial cancer cells, and Vero-kidney epithelial normal cells. The complex exhibited superior activity than cisplatin against A549, HeLa and T24 cancer cells with the IC50 values of 7.70, 11.2, and 5.05 µM, respectively. The complexes were cytotoxic specifically to the cancer cells. Molecular docking studies showed good binding potential of the ligand and complex with the spike protein and main protease of SARS-CoV-2, indicating the promising role of these compounds as antiviral compounds.

Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(II)-p-cymene complexes with acylthiourea ligands-in vitro and in vivo studies.

Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 µM) and P6 (6.52 and 14.45 µM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 µM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs.

Effective inhibition of insulin amyloid fibril aggregation by nickel(II) complexes containing heterocyclic thiosemicarbazones.

The sensitivity of protein molecular structures makes them susceptible to aggregation in conditions unfavorable for the maintenance of their native folds. The aggregation of proteins leads to many disorders, but the inhibition of amyloid fibril formation using metal-containing small molecules is gaining popularity. Herein we report the effect of nickel(II) complexes (N1, N2, N3, and N4) bearing thiosemicarbazones on the inhibition of amyloid fibril formation by insulin. The interactions of the complexes with amyloid fibrils were investigated using various biophysical techniques, including light scattering, intrinsic fluorescence assay, thioflavin T (ThT) assay, and Fourier transform-infrared spectroscopy. The results revealed that the phenyl-substituted N3 was an efficient inhibitor of amyloid fibril formation and maintained the insulin in its native structure despite conditions promoting fibrillation. Nickel(II) complexes containing indole based thiosemicarbazones were efficient in inhibiting the amyloid fibril formation and maintaining the insulin in its native structure in unfavorable conditions.

Chronic Inflammatory-Modulating Potential of Cassia auriculata with Proinflammatory Cytokine IL-1beta and Its Anticancer Effect on Lung Cancer Cell Line.

BACKGROUND: Inflammation is a key element in tumor progression, over time, persistent inflammation causes damage to DNA and leads to cancer. The relationship between chronic inflammation and tumor development is well established, blocking of which can help in cancer prevention and treatment in the future. OBJECTIVE: Hence, with this background, the present study aims to evaluate the anti-inflammatory and anticancer potential of Cassia auriculata (CA) solvent fractions through in silico and in vitro means, respectively. METHODS: Generally, inflammatory mediators play a key task in chronic inflammation, following its inflection was chosen for their interactions with nine structurally varied phytoconstituents of CA identified through GCMS. The ethanolic extract of CA was assessed for its apoptotic effects on A549 lung cancer cells by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, JC-10 staining, DNA fragmentation assay and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). RESULTS: The interactions between bioactive components and target protein revealed that important molecules like 5,7-dihydroxy-2-[2-nethoxyphenyl]- 4H-1-Benzopyran-4-one, a flavonoid, and three other components can bind target interleukin 1-beta associated with lung cancer. In vitro data also confirmed that the diverse active components of CA extract might follow the intrinsic mitochondrial pathway to provoke cancer cell death. CONCLUSION: Hence, these findings strongly propose that Cassia auriculata (CA) solvent fractions could be exploited in the future to design ligands for obtaining novel leads for treating chronic inflammation linked with lung cancer, and also the extracts of CA can be recommended as a potential agent for lung cancer chemotherapy.

Synthesis of Palladium(II) Complexes via Michael Addition: Antiproliferative Effects through ROS-Mediated Mitochondrial Apoptosis and Docking with SARS-CoV-2.

Metal complexes have numerous applications in the current era, particularly in the field of pharmaceutical chemistry and catalysis. A novel synthetic approach for the same is always a beneficial addition to the literature. Henceforth, for the first time, we report the formation of three new Pd(II) complexes through the Michael addition pathway. Three chromone-based thiosemicarbazone ligands (SVSL1-SVSL3) and Pd(II) complexes (1-3) were synthesized and characterized by analytical and spectroscopic tools. The Michael addition pathway for the formation of complexes was confirmed by spectroscopic studies. Distorted square planar structure of complex 2 was confirmed by single-crystal X-ray diffraction. Complexes 1-3 were subjected to DNA- and BSA-binding studies. The complex with cyclohexyl substituent on the terminal N of thiosemicarbazone (3) showed the highest binding efficacy toward these biomolecules, which was further understood through molecular docking studies. The anticancer potential of these complexes was studied preliminarily by using MTT assay in cancer and normal cell lines along with the benchmark drugs (cisplatin, carboplatin, and gemcitabine). It was found that complex 3 was highly toxic toward MDA-MB-231 and AsPC-1 cancer cells with IC50 values of 0.5 and 0.9 µM, respectively, and was more efficient than the standard drugs. The programmed cell death mechanism of the complexes in MDA-MB-231 cancer cells was confirmed. Furthermore, the complexes induced apoptosis via ROS-mediated mitochondrial signaling pathway. Conveniently, all the complexes showed less toxicity (≥50 µM) against MCF-10a normal cell line. Molecular docking studies were performed with VEGFR2, EGFR, and SARS-CoV-2 main protease to illustrate the binding efficiency of the complexes with these receptors. To our surprise, binding potential of the complexes with SARS-CoV-2 main protease was higher than that with chloroquine and hydroxychloroquine.

Crystal structures of the Schiff base derivatives (E)-N'-[(1H-indol-3-yl)methyl-idene]isonicotino-hydrazide ethanol monosolvate and (E)-N-methyl-2-[1-(2-oxo-2H-chromen-3-yl)ethyl-idene]hydrazinecarbo-thio-amide.

The crystal structures of two title Schiff base derivatives, C15H12N4O·C2H6O (1·EtOH) and C13H13N3O2S (2), were determined at 110 and 100 K, respectively. In the crystal of compound 1·EtOH, the (E)-N'-[(1H-indol-3-yl)methyl-idene]isonicotinohydrazide and ethanol mol-ecules are linked by O-H⋯O, N-H⋯O and N-H⋯N hydrogen bonds, forming a tape structure running along the b-axis direction. The tapes are weakly linked via a C-H⋯N inter-action. In the crystal of compound 2, (E)-N-methyl-2-[1-(2-oxo-2H-chromen-3-yl)ethyl-idene]hydrazinecarbo-thio-amide mol-ecules are linked via N-H⋯O and C-H⋯O hydrogen bonds, forming a helical chain along the b-axis direction. The chains are further linked into a layer expanding parallel to (102) through C-H⋯S inter-actions.

Erratum: Crystal structure of 2-cyano-N-(furan-2-ylmeth-yl)acetamide. Corrigendum.

The address of one of the authors in the paper by Subhadramma et al. [Acta Cryst. (2015), E71, o455-o456] is corrected.[This corrects the article DOI: 10.1107/S2056989015010488.].

Crystal structure of 2-cyano-N-(furan-2-ylmeth-yl)-3-(3-nitro-phen-yl)propanamide.

In the title compound, C15H11N3O4, the acetamide group is inclined to the furan ring by 66.5 (1)°. The dihedral angle between the furan ring and the benzene ring is 66.8 (1)°. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with an R 2 (2)(12) ring motif. The dimers are linked via two pairs of C-H⋯O hydrogen bonds to the same acceptor oxygen atom, enclosing R 2 (1)(6) ring motifs, forming chains along the [101] direction.

Crystal structure of 2-cyano-N-(furan-2-ylmeth-yl)acetamide.

In the title compound, C8H8N2O2, the acetamide unit is inclined to the furan ring by 76.7 (1)°. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, generating C(4) chains along [100]. The carbonyl O atom is a bifurcated acceptor and an R (1) 2(6) ring is formed.

2,15-Dioxa-7,18,19,20,23-penta-aza-hepta-cyclo-[21.6.1.1(17,20).0(1,8).0(3,7).0(9,14).0(24,29)]hentriaconta-9,11,13,17(31),18,24,26,28-octaen-30-one.

In the title compound, C24H23N5O3, the oxindole ring system is nearly planar, with a dihedral angle between the two fused rings of 3.3 (1)°. In the fused pyrrolo-oxazole ring system, the oxazole and pyrrolidine rings adopt envelope conformations with the spiro C atom and one of the methyl-ene C atoms, respectively, as the flap atoms. In the crystal, mol-ecules are linked into a helical chain along the b axis via C-H⋯O inter-actions generating R 2 (1)(7) and R 2 (2)(8) ring motifs.