Synthesis of 2-Carbamoyl-4-Oxo-1,5-Diazabicyclo [3.2.1] Octane Derivatives as a Possible Inhibitors of Serine β-Lactamases

Antibiotic resistance is becoming ever more severe due in part to the increasing use of antibiotic drugs. One significant contributor to this problem is the production of β-lactamase enzymes that provide resistance to common β-lactam antibiotics. The scope of this research is to synthesize and study the β-lactamase inhibitors of 2-carbamoyl-4-oxo-1,5-diazabicyclo [3.2.1] octane derivatives. Currently the research process is in the beginning stages of synthesizing three compounds: (R)-hexahydro-6-oxopyrimidine-4-carboxylic acid (1a), hexahydro-2,2-dimethyl-6-oxopyrimidine-4-carboxylic acid (1b) and hexahydro-6-oxo-2-phenylpyrimidine-4-carboxylic acid (1c). The future steps are to synthesize (R) -3-(methoxycarbonyl)-hexahydro-6-oxopyrimidine-4-carboxylic acid (2a), (R)-dimethyl tetrahydro-4-oxopyrimidine-1,6(2H)-dicarboxylate (3a) and (R)-methyl hexahydro-6-oxopyrimidine-4-carboxylate (4a). All the compounds will be evaluated for the inhibitory activities against pure TEM-1 and P99 β-lactamase

Isolation and Structural Determination of Bioactive Metabolites Produced by a Soil Bacterium, Arthrobacter sp. TAJX1902

As antimicrobial resistance persistently disrupts the treatment of microbial infection, identifying novel drugs with novel modes of action is critical to getting ahead of resistance. The primary goal of this project is to extract and identify novel chemical products produced by Arthrobacter sp. TAJX1902, particularly antimicrobial metabolites. Although underexplored, Arthrobacter sps. have been shown to produce bioactive compounds of great versatility; one such is a depsipeptide with quorum-sensing inhibitory activity.1 In this research, Arthrobacter sp. TAJX1902 isolated from a soil sample showed inhibitory activity against a filamentous indicator-type bacterium and a violacein-producing Janthinobacterium sp. A. sp. TAJX1902 was cultured using rich medium broth and agar and extracted with solvents of varying polarity. Characterization of purified bioactive compounds from A. sp. TAJX1902 was done via spectroscopic techniques, including 1D and 2D-NMR spectroscopy, FTIR, and GCMS analysis. The A. sp. TAJX1902 was found to produce pyrrolo[1,2-a]pyrazine-1,4-dione,hexahydro-3-(2-methylpropyl), and five other bioactive cyclic dipeptides (CDP)

Synthesis and Evaluation of 1,2,4-oxadiazolidinones: The Search for Potential non-β-lactam β-lactamase Inhibitors.

β-lactam antibiotics have been the most widely used drug of choice to combat infectious disease caused by bacteria. Unfortunately, the effectiveness of these antibiotics is drastically threatened by bacterial β-lactamases. β-lactamases are currently responsible for the resistance to most β-lactam antibiotic drugs. For decades, β-lactam β-lactamases inhibitors have been used to reduce bacterial resistance, however, in this study, we will employ the use of 1,2,4-oxadiazolidinone derivatives as a non-β-lactam β-lactamases inhibitor against TEM-1 and P99 β-lactamases. The significance of oxadiazolidinone is the prominent five-membered ring in its structure, which is configurationally stable and present in other biologically active compounds such as linezolid and avibactam. Oxadiazolidinones were synthesized in two steps procedure using nitroalkanes and benzaldehyde as starting materials to produce nitrones, which in turn undergo 1,3- dipolar cycloaddition with substituted isocyanates to give the desired 1,2,4-oxadiazolidin analogs (2a, 2b, 2c and 3). Each product was purified and characterized using 1H NMR and 13C NMR, GC-MS, IR, and UV/Vis analysis. Following their successful synthesis and structural elucidation, they were tested with TEM-1 and P99 serine β-lactamase using Nitrocefin as the substrate to ascertain their effectiveness against β-lactamase. 2a, 2b, 2c and 3 showed inhibition ranging from 12-38 %

Specificity and Mechanism of Mandelamide Hydrolase Catalysis

The best-studied amidase signature (AS) enzyme is probably fatty acid amide hydrolase (FAAH). Closely related to FAAH is mandelamide hydrolase (MAH), whose substrate specificity and mechanism of catalysis are described in this paper. First, we developed a convenient chromogenic substrate, 4-nitrophenylacetamide, for MAH. The lack of reactivity of MAH with the corresponding ethyl ester confirmed the very limited size of the MAH leaving group site. The reactivity of MAH with 4-nitrophenyl acetate and methyl 4-nitrophenyl carbonate, therefore, suggested formation of an “inverse” acyl-enzyme where the small acyl-group occupies the normal leaving group site. We have interpreted the specificity of MAH for phenylacetamide substrates and small leaving groups in terms of its active site structure, using a homology model based on a FAAH crystal structure. The relevant structural elements were compared with those of FAAH. Phenylmethylboronic acid is a potent inhibitor of MAH (Ki = 27 nM), presumably because it forms a transition state analogue structure with the enzyme. O-Acyl hydroxamates were not irreversible inactivators of MAH but some were found to be transient inhibitors

Synthesis and Biological Activity of Fused tetracyclic Pyrrolo[2,1-C][1,4]Benzodiazepines

Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1–13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines

R10. First in class (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs as selective CB2 modulators targeting neurodegenerative disorders

Corresponding author (NCNPR): Mohamed A. Ibrahim, [email protected]://egrove.olemiss.edu/pharm_annual_posters/1009/thumbnail.jp

SYNTHESIS OF PYRROLO[2,1-c] [1,4] BENZODIAZEPINE -11- HYDRAZINYL DEVRIVATIES AS A POTENTIAL ANTIMICROBIAL AGENT

SYNTHESIS OF PYRROLO[2,1-c] [1,4] BENZODIAZEPINE -11- HYDRAZINYL DEVRIVATIES AS A POTENTIAL ANTIMICROBIAL AGENT David Mingle and Abbas G. Shilabin Department of Chemistry, East Tennessee State University, Johnson City, TN 37614, USA ABSTRACT Pyrrolo [2,1-c] [1,4] benzodiazepine (PBD) is a class of natural products obtained from various actinomycetes which have both anti-tumor and antibiotic activities. They can bind to specific sequences of DNA that can trigger a biological response which is of pharmacological interest. PBD can also prevent cell division leading to death of the bacteria. This research focuses on the synthesis of novel PBD-11-hydrazinyl derivatives using a multi step synthesis. PBD-dilactam was initialy produced using isatoic anhydride and (S)-proline which was then converted to the PBD-thiolactam using Lawesson\u27s reagent. Reaction of thiolactam with hydrazine in ethanol afforded PBD-11-hydrazinyl in good yield. Condensation of PBD-11-hydrazinyl with aldehydes possessing various substitutions was performed to generate (S,E)-11-[2-(phenylmethylene)hydrazono]-1,2,3,10,11,11a-hexahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one. 1H-NMR , 13C-NMR , DEPT and GC-MS were used to characterize the products. Inhibition activity of the products were carried out using TEM-1 and p99 β-lactamases. Microbial activity will be conducted in collaboration with Natural Product Center at University of Mississippi on the final products

Extraction and Partial Purification of an Antibiotic-like Compound From the Soil Bacterium Rhoddococcus Strain KCHXC3

Rhodococcus bacteria have many secondary metabolic pathways that may produce novel natural products. The bacterium Rhodococcus strain KCHXC3 was isolated from a soil sample collected near Kingsport, Tennessee and was found to produce an inhibitory compound active against a broad array of bacterial species, including the Gram negative pathogen Shigella. The aim of this research is to extract and purify the compound for future structure elucidation. A mixture of compounds from 3 month old agar plates inoculated with strain KCHXC3 was extracted using ethyl acetate. The crude extract was then partially purified utilizing a Sephadex LH-20 column, followed by an analytical NH2 HPLC column. This purification resulted in a dried crystalline-like active compound that is white in color and needle-like in shape. Structural studies such as NMR and GC-MS were performed in order to determine the purity of this solid