Synthesis molecular docking and DFT studies on novel indazole derivatives.

The amide bond is an important functional group used in various fields of chemistry, including organic synthesis, drug discovery, polymers, and biology. Although normal amides are planar, and the amide has an N-C(O) bond, herein, the 26 indazole derivatives were reported via amide cross-coupling (8a-8z). Using IR, 1H NMR, 13C NMR, and mass spectrometry, all of the produced compounds were analysed. A DFT computational study was also conducted using GAUSSIAN 09-Gaussian View 6.1, which revealed that 8a, 8c, and 8s had the most substantial HOMO-LUMO energy gap. The effectiveness of indazole moieties with renal cancer-related protein (PDB: 6FEW) was assessed by docking the derivatives using Autodock 4. The analysis showed that derivatives 8v, 8w, and 8y had the highest binding energies.

Synthesis, Characterization, In Silico DFT, Molecular Docking, and Dynamics Simulation Studies of Phenylhydrazono Phenoxyquinolones for Their Hypoglycemic Efficacy.

A series of novel 24 phenylhydrazono phenoxyquinoline derivatives were synthesized with moderate to excellent yield and screened for their efficacy against the α-amylase enzyme through in silico studies. The structures were characterized using spectroscopic techniques such as 1HNMR, 13CNMR, and HREI-MS. Comprehensive computational studies including, drug-likeness and ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics (MD) simulation studies, were performed. A density functional theory study of the synthesized compounds indicated a favorable reactivity profile. The synthesized novel analogues were docked against α-amylase (PDB 6OCN) enzymes to investigate the binding interactions. Based on the docking studies, one of the compounds was found to be the hit with the highest negative binding affinity for α-amylase. A MD simulation study indicated stable binding throughout the simulation.

Palladium-Mediated Synthesis of 2-([Biphenyl]-4-yloxy)quinolin-3-carbaldehydes through Suzuki-Miyaura Cross-Coupling and Their in Silico Breast Cancer Studies on the 3ERT Protein.

A series of novel quinoline appended biaryls have been synthesized (5a-5o) by reacting various substituted boronic acids (4e-4h) with various substituted 2-(4-bromophenoxy)quinolin-3-carbaldehydes (3a-3d) through carbon-carbon bond formation. Effects of various quinoline appended biaryls (5a-5o) on the breast cancer protein 3ERT are moderate to high, as found by in silico molecular docking studies. Comparatively, all quinoline appended biaryls (5a-5o) 5h show better efficacy with a binding energy of -9.39 kcal/mol, and hydrogen bonds are Thr347, Glu353, and Arg394 in the binding pocket. Conclusively, the final novel quinoline appended biaryls (5a-5o) have been confirmed with all the spectral studies, and their efficacy has been validated with in silico studies.

Montmorillonite K10 Clay Catalyzed Synthesis of Novel ß-Aminocarbonyl Compounds and Their Biological Evaluation.

An efficient and reusable green catalyst for the synthesis of ß-aminocarbonyl compounds has been developed. In this new and greener approach, ß-aminocarbonyl compounds (1a-1r) were obtained by Montmorillonite K10 clay catalyzed reaction of aryl amines, aliphatic/aromatic aldehydes and ß-ketoesters. Molecular docking investigations were performed for all compounds (1a-1r) with the proteins PDB ID: 1JIJ and 1KZN for S. aureus and E. coli, respectively. For all compounds good to strong interactions with the active sites were observed. The biological activities of ß-aminocarbonyl compounds were further assessed for their antibacterial and antioxidant activities. The results confirmed that ß-aminocarbonyl compounds could be further developed into new drugs with potent antibacterial and antioxidant activities.

Design, Synthesis, and the Effects of (E)-9-Oxooctadec-10-en-12-ynoic Acid Analogues to Promote Glucose Uptake.

(E)-9-Oxooctadec-10-en-12-ynoic acid is found to mediate its antidiabetic activity by increasing insulin-stimulated glucose uptake in L6 myotubes by activating the phosphoinositide 3-kinase (PI3K) pathway. A simultaneous study of site-specific modification followed by structure-activity relationship provides a tremendous scope for exploiting the bioactivity of the parent molecule. Therefore, in the present study, we focused on site-specific modification of (E)-9-oxooctadec-10-en-12-ynoic acid (1) to generate multiple derivatives and extensive structure-activity relationship (SAR) studies. We have done structural base design and synthesized a series of amides from acid compound 1. Compound 1 consists of an acid functionality, which is known for its metabolism-related liabilities. The SAR has been generated using scaffolds of different antidiabetic drugs such as biguanides, sulfonylureas, thiazolidinediones/glitazones, peroxisome proliferator-activated receptors, K + ATP, α-glucosidase inhibitors, and others. Furthermore, the study demonstrates and explains the promising derivatives and importance of SAR of the compound (E)-9-oxooctadec-10-en-12-ynoic acid. In order to gain mechanistic insights, a molecular docking study was performed against PI3K, which could identify the binding modes and thermodynamic interactions governing the binding affinity. According to our research, compounds 5, 6, 27, 28, 31, 32, and 33 are the best compounds from the series having EC50 values of 15.47, 8.89, 7.00, 13.99, 8.70, 12.27, and 16.14 µM, respectively.

Design and characterisation of piperazine-benzofuran integrated dinitrobenzenesulfonamide as Mycobacterium tuberculosis H37Rv strain inhibitors.

Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv. 4d-f and 4o found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas 4a, 4c, 4j displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase.

Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids.

A series of novel benzhydryl piperazine-coupled nitrobenzenesulfonamide hybrids were synthesized with good to excellent yields. They were tested for in vitro inhibition of mycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, in vitro cytotoxicity MTT (RAW 264.7cells) assay, nutrient starvation (H37Rv strain), and ability to block Cav3.2 T-type calcium channels. Novel hybrids did not inhibit T-type calcium channels, whereas they showed excellent antituberculosis (TB) activity and low cytotoxicity with a selectivity index of >30. A direct impact of the amino acid linker was not observed. Studied hybrids exhibited good inhibition activities, and the 2,4-dinitrobenzenesulfonamide group emerged as a promising scaffold for further drug design by hybridization approaches for anti-TB therapy.

Biological Impacts of Metal(II) Complex-Based DNA Probes Derived from Bidentate N,O Donor Schiff Base Ligand.

In this article, we have reported the preparation and structural characterization of a new Schiff base ligand (E)-2-(((2,6-difluorophenyl)imino)methyl)phenol (HSBL) and its derived metal(II) complexes [Cu(SBL)2] (1), [Ni(SBL)2] (2) and [Pd(SBL)2] (3). Using various analytical and spectroscopic techniques, their structural properties have been appraised. The proposed chemical structure of HSBL has been confirmed by Single crystal XRD studies. Bidentate characteristic of HSBL and its coordination with metal(II) ions through the oxygen atom of the phenolic group and nitrogen atom of the azomethine group have been evaluated from the FT-IR spectral analysis. Pd(II) complex of HSBL (complex 3) has found to be efficient in bringing about the interaction with DNA as well as BSA molecules. The in vitro antimicrobial studies have been demonstrated that complex 3 has a superior antimicrobial activity than HSBL, complexes 1 and 2. According to the values of zone of inhibition, the antimicrobial ability has been increased in the order of 3 > 1 > 2 > HSBL. A significant decrease in percent cell viability has been suggested that complex 3 has remarkable cytotoxicity (IC50 = 15.7 ± 0.6 µg/mL) on human breast cancer (MCF-7) cells. Besides, their induced apoptosis pathway of cytotoxicity has been demonstrated by fluorescence staining techniques using AO/EB staining method. We hope this article will be very helpful for future research on the development of new anticancer agents.

New bio-sensitive and biologically active single crystal of pyrimidine scaffold ligand and its gold and platinum complexes: DFT, antimicrobial, antioxidant, DNA interaction, molecular docking with DNA/BSA and anticancer studies.

Novel gold and platinum complexes [AuL2]·Cl, 1 and [PtL2]·2Cl, 2 with ligand, 2-methoxy-6-((2-(4-(trifluoromethyl)pyrimidin-2-yl)hydrazono)methyl)phenol (HL) have been synthesized and screened for their antimicrobial, antioxidant, DNA binding and anticancer (in vitro) activities. The single crystal of ligand HL was obtained by slow evaporation technique. The molecular structure of HL was confirmed from single crystal X-ray technique. Density functional theory calculations have been performed to gain insights into the electronic structure of these metal complexes. Antimicrobial result shows that, HL and complexes (1 and 2) have good antimicrobial agents against E. coli (bacteria) and C. albicans (fungi) than others bacterial and fungal strains. Antioxidant assay results suggest that, HL and complexes (1 and 2) possess good radical scavenging activity against diverse free radicals (DPPH, SOD, NO and H2O2). The intercalative interactions of HL and complexes (1 and 2) with CT-DNA were confirmed from spectroscopic titrations and viscometric measurements. Furthermore, the interactions of prepared compounds with DNA were confirmed by molecular docking analysis. In order to understand the nature of interactions between these metal complexes and BSA protein results clearly shows that complex 1 binds better than that of complex 2. The antitumor activities of prepared products were tested against single normal and different tumor cell lines by MTT assay. These results reveal that prepared complexes (1 and 2) have significant cytotoxic effect against tumor cell lines.

Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and ß-class enzymes.

The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and ß-CA classes (VchCAα, VchCAß). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure-activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAß, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives.

Magnetic iron oxide nanoparticles (MIONs) cross-linked natural polymer-based hybrid gel beads: Controlled nano anti-TB drug delivery application.

The nanosized rifampicin (RIF) has been prepared to increase the solubility in aqueous solution, which leads to remarkable enhancement of its bioavailability and their convenient delivery system studied by newly produced nontoxic, biodegradable magnetic iron oxide nanoparticles (MIONs) cross-linked polyethylene glycol hybrid chitosan (mCS-PEG) gel beads. The functionalization of both nano RIF and mCS-PEG gel beads were studied using various spectroscopic and microscopic techniques. The size of prepared nano RIF was found to be 70.20 ± 3.50 nm. The mechanical stability and swelling ratio of the magnetic gel beads increased by the addition of PEG with a maximum swelling ratio of 38.67 ± 0.29 g/g. Interestingly, this magnetic gel bead has dual responsive assets in the nano drug delivery application (pH and the magnetic field). As we expected, magnetic gel beads show higher nano drug releasing efficacy at acidic medium (pH = 5.0) with maximum efficiency of 71.00 ± 0.87%. This efficacy may also be tuned by altering the external magnetic field and the weight percentage (wt%) of PEG. These results suggest that such a dual responsive magnetic gel beads can be used as a potential system in the nano drug delivery applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1039-1050, 2018.

Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors.

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a ß-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.

γ-Alumina Nanoparticle Catalyzed Efficient Synthesis of Highly Substituted Imidazoles.

γ-Alumina nano particle catalyzed multi component reaction of benzil, arylaldehyde and aryl amines afforded the highly substituted 1,2,4,5-tetraaryl imidazoles with good to excellent yield in less reaction time under the sonication as well as the conventional methods. Convenient operational simplicity, mild conditions and the reusability of catalyst were the other advantages of this developed protocol.

Regioselective synthesis of 2-chloroquinoline based ethyl 4-(3- hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3- carboxylates and their in-silico evaluation against P. falciparum lactate dehydrogenase.

The reaction of various substituted 2, 4-dichloroquinolines with ethyl 4-(3-hydroxyphenyl)- 2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was carried out in the presence of K2CO3 as a mild and efficient base at controlled temperature leading to novel 2-chloroquinoline based polyhydroquinoline with high regioselectivity. All the synthesized compounds were characterized using IR, NMR, Mass spectral data and then subjected to an in-silico analysis against P. falciparum lactate dehydrogenase.

Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly.

UNLABELLED: Dengue virus belongs to the virus family Flaviviridae. Dengue hemorrhagic disease caused by dengue virus is a public health problem worldwide. The viral non structural 2B and 3 (NS2B-NS3) protease complex is crucial for virus replication and hence, it is considered to be a good anti-viral target. Leaf extracts from Carica papaya is generally prescribed for patients with dengue fever, but there are no scientific evidences for its anti-dengue activity; hence we intended to investigate the anti-viral activity of compounds present in the leaves of Carica papaya against dengue 2 virus (DENV-2). We analysed the anti-dengue activities of the extracts from Carica papaya by using bioinformatics tools. Interestingly, we find the flavonoid quercetin with highest binding energy against NS2B-NS3 protease which is evident by the formation of six hydrogen bonds with the amino acid residues at the binding site of the receptor. Our results suggest that the flavonoids from Carica papaya have significant anti-dengue activities. ABBREVIATIONS: ADME - Absorption, distribution, metabolism and excretion, BBB - Blood brain barrier, CYP - Cytochrome P450, DENV - - Dengue virus, DHF - Dengue hemorrhagic fever, DSS - Dengue shock syndrome, GCMS - - Gas chromatography- Mass spectrometry, MOLCAD - Molecular Computer Aided Design, NS - Non structural, PDB - Protein data bank, PMF - Potential Mean Force.

N-(2-Fluoro-phen-yl)-2,6-dimethyl-1,3-dioxan-4-amine.

In the title compound, C12H16FNO3, the dioxane ring adopts a chair conformation with the methyl groups and amine N atom in equatorial positions. The best plane through the dioxane ring makes a dihedral angle of 43.16 (8)° with the phenyl ring. In the crystal, pairs of C-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric R 2 (2)(8) dimers, which are linked into [100] chains by further C-H⋯O hydrogen bonds. The N-H group does not participate in hydrogen bonding.

2,6-Dimethyl-N-(2-methyl-phen-yl)-1,3-dioxan-4-amine.

In the title compound, C13H19NO2, the dioxane ring adopts a chair conformation and its mean plane makes a dihedral angle of 45.36 (8)° with the phenyl ring. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers with R (2) 2(12) ring motifs. These dimers are consolidated by pairs of C-H⋯O hydrogen bonds with R (2) 2(8) ring motifs.

N-(4-Bromo-phen-yl)-2,6-dimethyl-1,3-dioxan-4-amine.

In the title compound, C12H16BrNO2, the dioxane ring adopts a chair conformation and its mean plane makes a dihedral angle of 60.63 (12)° with the 4-bromo-phenyl ring. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. These dimers are consolidated by pairs of C-H⋯O hydrogen bonds with an R 2 (2)(16) ring motif. Adjacent dimers are connected via C-H⋯O hydrogen bonds, forming infinite chains propagating along the c-axis direction.

ß-Keto esters from ketones and ethyl chloroformate: a rapid, general, efficient synthesis of pyrazolones and their antimicrobial, in silico and in vitro cytotoxicity studies.

BACKGROUND: Pyrazolones are traditionally synthesized by the reaction of ß-keto esters with hydrazine and its derivatives. There are methods to synthesize ß-keto esters from esters and aldehydes, but these methods have main limitation in varying the substituents. Often, there are a number of methods such as acylation of enolates in which a chelating effect has been employed to lock the enolate anion using lithium and magnesium salts; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize ß-keto esters from ketones like caboxylation of ketone enolates using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simple method to synthesize ß-keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence of strong bases which also requires long reaction time, use of excessive amount of reagent and inconsistent yield. These factors lead us to develop a simple method to synthesize ß-keto esters by changing the base and reagent. RESULTS: A series of ß-keto esters were synthesized from ketones and ethyl chloroformate in the presence of base which in turn are converted to pyrazolones and then subjected to cytotoxicity studies towards various cancer cell lines and antimicrobial activity studies towards various bacterial and fungal strains. CONCLUSION: The ß-keto esters from ethyl chloroformate was successfully attempted, and the developed method is simple, fast and applicable to the ketones having the alkyl halogens, protecting groups like Boc and Cbz that were tolerated and proved to be useful in the synthesis of fused bicyclic and tricyclic pyrazolones efficiently using cyclic ketones. Since this method is successful for different ketones, it can be useful for the synthesis of pharmaceutically important pyrazolones also. The synthesized pyrazolones were subjected to antimicrobial, docking and cytotoxicity assay against ACHN (human renal cell carcinoma), Panc-1 (human pancreatic adenocarcinoma) and HCT-116 (human colon cancer) cell line, and lead molecules have been identified. Some of the compounds are found to have promising activity against different bacterial and fungal strains tested.

N-(4-Fluoro-phen-yl)-2,6-dimethyl-1,3-dioxan-4-amine.

In the title compound, C12H16FNO2, the dioxane ring adopts a chair conformation with the methyl substituents and the C-N bond in equatorial orientations. Its mean plane subtends a dihedral angle of 40.17 (6)° with the benzene ring. In the crystal, weak N-H⋯F hydrogen bonds link the mol-ecules into C(7) chains propagating in [100].