Broad spectrum antimicrobial activity of dispirooxindolopyrrolidine fused acenaphthenone heterocyclic hybrid against healthcare associated microbial pathogens (HAMPs).

BACKGROUND: Healthcare-associated infections (HAI) are prime health task worldwide and issue of patient safety besides intensifying antimicrobial drug resistance. It is essential to formulate structurally fascinating novel, active and cost-effective anti-microbial drugs possessing a peculiar way of action and capable of overcoming the resistance to effectively combat this disease. MATERIALS AND METHODS: The synthesized spiro-heterocyclic hybrids (SHHs) were elucidated through spectroscopic analysis and were assessed for their in vitro antimicrobial activity by agar diffusion method and minimal inhibitory concentration (MIC) value was also determined. In addition, antioxidant potential was also evaluated through DPPH radical scavenging assays. RESULTS: The novel class of SHHs 4a and 4b displayed significant antibacterial activity against selected healthcare associated microbial pathogens (HAMPs). In addition, SHH 4b showed potent antioxidant properties. CONCLUSION: Antibacterial and antifungal activity of dispirooxindolopyrrolidine fused acenaphthenone heterocyclic hybrids were examined. Interestingly, SHH 4b exhibited potent antimicrobial activity against selected HAMPs. Further, these compounds were also showed potent antioxidant properties. These results revealed that SHH 4b is a promising lead for the development of new antimicrobial drugs.

Green Synthesis, Experimental and Theoretical Studies to Discover Novel Binders of Exosomal Tetraspanin CD81 Protein.

A new class of benzothiazole-appended quinoline derivatives (6-8) was synthesized via one-pot TPGS micellar-mediated acid-catalyzed nucleophilic addition, followed by aerobic oxidative cyclization of 3-formylquinoline-2-one (2), 3-formylquinoline-2-thione (3), and 2-azidoquinoline-3-carbaldehyde (4) individually with 2-amino thiophenol (5). The structures of the prepared compounds were confirmed using suitable spectroscopic methods complemented with single-crystal X-ray diffraction analysis. Time-dependent density functional theory-based optimization of molecular structures, bond lengths, bond angles, HOMO-LUMO energy gaps, and molecular electrostatic potential maps was theoretically computed at the B3LYP/6-311++g(d) level. The molecular docking studies recommended that 6-8 bound to the active site cavity of CD81 effectively with the binding energies of -6.9, -6.3, and -6.5 kcal mol-1, respectively. Further, MD simulation studies of compound 6 suggested that the binding resulted in the stabilization of the CD81 molecule. Thus, all theoretical predictions associated with the experimental verifications motivated to discover novel approaches for cancer therapy.

Strategy for early callus induction and identification of anti-snake venom triterpenoids from plant extracts and suspension culture of Euphorbia hirta L.

Euphorbia hirta L. from the family of Euphorbiaceae is an annual herb, which grows as a roadside weed in most tropical countries. It is prominently used by the traditional healers in rural India for the treatment of snakebites. However, the mechanisms and the major bioactive compounds behind its inhibition activity are relatively unknown. From our preliminary in silico studies, it was found that a group of pentacyclic triterpenoids from this plant are playing a major role in inhibiting the snake venom proteins. The present study was aimed at standardizing methods for obtaining callus from this medicinal plant at a much faster rate by hormone pretreatment of explants and, thus, by developing suspension cultures to obtain bioactive secondary metabolites in vitro. The results were promising that longer incubation of explants with hormone treatment showed early induction of callus. The major bioactive compounds responsible for the anti-snake venom activity were characterized from natural plant material as well as from suspension cultures, and the efficiency was found to be relatively high. The secondary metabolite analysis from suspension culture and natural plant extracts revealed that a major compound 'Taraxerol' and its derivatives was found abundant along with few other triterpenoids. This compound showed high inhibitory activity against pit viper snake venoms from our in silico studies with molecular docking tools. Hence, this study with identification of potential bioactive compounds against snake venom with standardization of In vitro culture methods would help in developing natural alternative medicine for snakebites in near future.

Domino Multicomponent Approach for the Synthesis of Functionalized Spiro-Indeno[1,2-b]quinoxaline Heterocyclic Hybrids and Their Antimicrobial Activity, Synergistic Effect and Molecular Docking Simulation.

An expedient synthesis of hitherto unexplored novel hybrid heterocycles comprising dispiropyrrolidine, N-styrylpiperidone and indeno[1,2-b]quinoxaline units has been developed via domino multicomponent 1,3-dipolar cycloaddition strategy employing a new class of azomethine ylide in ionic liquid, 1-butyl-3-methylimidazolium bromide. This domino protocol involves, 1,3-dipolar cycloaddition and concomitant enamine reaction affording the dispiropyrrolidine tethered N-styrylpiperidone hybrid heterocycles in moderate to good yield in a single step. These compounds were evaluated for their antimicrobial activity against bacterial and fungal pathogens, therein compounds 8f, 8h, and 8l displayed significant activity against tested microbial pathogens. The synergistic effect revealed that the combination of compound 8h with streptomycin and vancomycin exhibited potent synergistic activity against E. coli ATCC 25922. In addition, molecular docking simulation has also been studied for the most active compound.

Plasticity of the ligand binding pocket in the bitter taste receptor T2R7.

Bitter taste receptors (T2Rs) are a group of 25 G protein-coupled receptors (GPCRs) in humans. The cognate agonists and the mechanism of ligand binding to the majority of the T2Rs remain unknown. Here we report the first structure-function analysis of T2R7 and study the ability of this receptor to bind to different agonists by site-directed mutagenesis. Screening of ligands for T2R7 in calcium based assays lead to the identification of novel compounds that activate this receptor. Quinine, diphenidol, dextromethorphan and diphenhydramine showed substantial activation of T2R7. Interestingly, these bitter compounds showed different pharmacological characteristics. To investigate the structural features in T2R7 that might contribute to the observed differences in agonist specificities, molecular model guided ligand docking and site-directed mutagenesis was pursued. Amino acids D65, D86, W89, N167, T169, W170, S181, T255 and E271 in the ligand-binding pocket were replaced and the mutants characterized pharmacologically. Our results suggest D86, S181 and W170 present on the extracellular side of transmembrane 3 (TM3), TM5 and in extracellular loop 2 (ECL2) are essential for agonist binding in T2R7. Mutations of these amino acids lead to loss-of-function. We also identified gain-of-function residues that are agonist specific. These results suggest that agonists bind at an extracellular site rather than deep within the TM core involving residues present in both ECL2 and TM helices in T2R7. Similar to majority of the Class A GPCRs, ECL2 in T2R7 plays a significant role in agonist binding and activation.

ACI/EG eutectic mixture mediated synthesis, characterization and in vitro osteoblast differentiation assessment of spiropyrrolo[1,2-b]isoquinoline analogues.

An eco-friendly acetylcholine iodide-ethylene glycol (ACI/EG) deep eutectic mixture mediated green protocol has been developed for the synthesis of hitherto unexplored multi-functionalized linear tricyclic spiropyrrolo[1,2-b]isoquinoline analogues. The effects of the synthesized compounds on the osteoblast differentiation of hBMSC-TERT cell lines were investigated and promising results were observed with significant IC50 values. In addition, molecular modeling simulations were also performed with the 3D structure of BMP-2 to reveal binding interactions and orientations of highly potent spiropyrrolo[1,2-b]isoquinoline analogues.

Synthesis, molecular docking and biological evaluation of novel 6-(4-(4-aminophenylsulfonyl)phenylamino)-5H-benzo[a]phenothiazin-5-one derivatives.

A novel series of 6-(4-(4-aminophenylsulfonyl)phenylamino)-5H-benzo[a]phenothiazin-5-one derivatives have been synthesized and examined for their in vitro antibacterial activity against a panel of Gram-positive and Gram-negative bacteria. Among these, N-(4-(4-(5-oxo-5H-benzo[a]phenothiazin-6-ylamino)phenylsulfonyl)phenyl)-3,5-bis(trifluoromethyl)benzamide (3n) (0.4 µg/mL) and 4-ethyl-N-(4-(4-(5-oxo-5H-benzo[a]phenothiazin-6-ylamino)phenylsulfonyl)phenyl)benzamide (3l) (0.6 µg/mL) systems exhibited a potent inhibitory activity against Gram-positive organism Bacillus subtilis, when compare to the other synthesized compounds. Sparfloxacin (9.76 µg/mL), Norfloxacin (no activity) were employed as the standard drugs. An evaluation of the cytotoxicity of the title compounds (1, 2, 3a-n) revealed that they displayed low toxicity (26-115 mg/L) against cervical cancer cell line (SiHa). The results of these studies suggest that, phenothiazin-5-one derivatives are interesting binding agents for the development of new Gram-positive and Gram-negative antibacterial agents. To understand the interactions with protein receptors, docking simulation was done with crystal structures of B.subtilis (YmaH) and histone deacetylase (HDAC8) to determine the probable binding conformation.