Synthesis, Antibacterial and Cytotoxic Activities of New Thiazole Based Pyrrolidine Derivatives

In this study, some thiazole-based pyrrolidine derivatives were synthesized, characterized by FT-IR and 1H NMR spectroscopic techniques, and evaluated as potential antibacterial agents. Their antibacterial activities were evaluated by broth microdilution method and expressed as minimum inhibitory concentration; against Escherichia coli, Salmonella typhimurium, Bacillus cereus, and Staphylococcus aureus. Cytotoxicity studies of synthesized compounds were also conducted to minimize the toxic effects on healthy mammalian cells. From synthesized compounds, 4-F-phenyl derivative compound (11) has been found to inhibit Gram-positive bacteria with minimum toxicity selectively.

Investigating Curcumin/Intestinal Epithelium Interaction in a Millifluidic Bioreactor

Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells. To understand if flow can modulate the influence of curcumin on the protein’s activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of rhodamine-123 was assessed in the two systems as a function of the P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound. The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin.

A dynamic in-vitro model of the intestinal epithelium for the investigation of P-glycoprotein activity

Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells.To understand if physiological flow can modulate membrane protein activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of Rhodamine-123 assessed in the two systems as a function of P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound.The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin.

A dynamic in-vitro model of the intestinal epithelium for the investigation of P-glycoprotein activity

Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells. Aiming at understanding the role of physiological flow on the modulation of membrane protein activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of Rhodamine-123 assessed in the two systems as a function of P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound. The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin.

GC-MS Analysis of Volatile Organic Constituents of Traditionally Used Medicinal Plants from the Western Ghats of India: Blumea lanceolaria (Roxb.) Druce., Heliotropium indicum L. and Triumfetta rhomboidea Jacq.

The present study explored essential oil constituents of the medicinal plants used in traditional medicine and growing wild in the Western Ghats region of India, which is one of the 34 global biodiversity hotspots. The hydro distilled essential oils of Blumea lanceolaria (Roxb.) Druce. (Asteraceae), Heliotropium indicum L. (Boraginaceae) and Triumfetta rhomboidea Jacq. (Tiliaceae) were analyzed using gas chromatography equipped with a flame ionization detector (GC-FID) and gas chromatography coupled with mass spectroscopy (GC/MS). Thirty-six, twenty-seven, and fifty constituents were identified from the essential oils of B. lanceolaria, H. indicum, and T. rhomboidea, respectively comprising 97.3% (B. lanceolaria), 98.2% (H. indicum) and 97.6% (T. rhomboidea) of the total oil constituents. The major compounds of B. lanceolaria, H. indicum, and T. rhomboidea were identified as β-pinene (82.3%), methyl salicylate (54.3%), and β-caryophyllene (28.9%), respectively. The essential of B. lanceolaria was found to be rich in monoterpene hydrocarbons (90.4%), while H. indicum and T. rhomboidea oils were rich in phenyl derivative (72.8%) and sesquiterpene hydrocarbons (69.5%) type constituents, respectively. The common compounds viz., terpin-4-ol and eugenol were identified in the essential oils of B. lanceolaria, H. indicum, and T. rhomboidea.

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Method: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-compo Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Structural and theoretical study of four novel norcantharidine derivatives: two new cases of conditional isomorphism

Structural and theoretical studies of four novel 5,6-dehydronorcantharidine (DNCA)/norcantharidine (NCA) derivatives, namely (3aR,4S,7R,7aS)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione, C14H11NO3 (DNCA-A), (3aR,4S,7R,7aS)-2-(4-nitrophenyl)-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione, C14H10N2O5 (DNCA-NA), (3aR,4S,7R,7aS)-2-(4-nitrophenyl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione, C14H12N2O5 (NCA-NA), and (3aR,4S,7R,7aS)-2-(2-hydroxyethyl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione, C10H13NO4 (NCA-AE), are reported. The supramolecular interactions and single-crystal structural characteristics of these molecules, together with the crystal structures of four other similar molecules, i.e. NCA-A (the 4-phenyl derivative of NCA-NA), DNCA-AE (the 5,6-unsaturated derivative of NCA-AE), DNCA and NCA, were analysed. Surprisingly, DNCA-A and NCA-A, as well as DNCA–NA and NCA-NA, proved to be isomorphic, while DNCA-AE and NCA-AE, as well as DNCA and NCA, have very different crystal structures. These are very rare isostructural examples between unsaturated and saturated oxanorbornene/oxanorbornane derivatives. To further explore how noncovalent interactions (NCIs) affect the degree of isomorphism in this particular series of rigid molecules where there is a fairly limited conformational degree of freedom, all four pairs of crystal structures were analyzed in parallel. The differentiation in NCIs which entails the packing mode of similar molecules is supported by energy calculations based on real or exchanged crystal structures. Our results show that minor structural differences may result in very different supramolecular interactions, and so lead to altered packing modes in the crystalline solids. Even if isostructurality sometimes occurs, the possibility of various molecular packing types cannot be ruled out. On the other hand, isomorphism may just be the result of kinetic possibilities instead of relative thermodynamic stabilities. Though crystal structure prediction is formidable, the comparison method based on existing crystal structures and quantum calculations can be used to predict the probability of isomorphism. This understanding will help us to design new norbornene derivatives with specified structures.

Developing 9,10-anthracene Derivatives: Optical, Electrochemical, Thermal, and Electrical Characterization

Anthracene-based semiconductors are a class of molecules that have attracted interest due to their air stability, planarity, potential for strong intermolecular interactions, and favorable frontier molecular orbital energy levels. In this study seven novel 9,10-anthracene-based molecules were synthesized and their optical, electrochemical, and thermal properties were characterized, along with their single crystal arrangement. We found that functionalization of the 9,10-positions with different phenyl derivatives resulted in negligible variation in the optical properties with minor (±0.10 eV) changes in electrochemical behavior, while the choice of phenyl derivative greatly affected the thermal stability (Td > 258 °C). Preliminary organic thin film transistors (OTFTs) were fabricated and characterized using the 9,10-anthracene-based molecules as the semiconductor layer. These findings suggest that functionalization of the 9,10-position of anthracene leads to an effective handle for tuning of the thermal stability, while having little to no effect on the optical properties and the solid-state arrangement

Structure-activity relationship of flavin analogs that target the FMN riboswitch

ABSTRACTThe flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative —5FDQD— that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates. In the process, we delineated principles for productive binding to this riboswitch, thereby demonstrating the effectiveness of a coordinated structure-guided approach to designing drugs against RNA.GRAPHICAL ABSTRACTExploring the chemical structure landscape of FMN riboswitch binders.