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, Characterization and Biological Evaluation of novel (S, E)-11-[2-(arylmethylene)hydrazono] pyrrolo [2,1-c] [1,4] benzodiazepine derivatives.

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 11-hydrazinyl PBD derivatives using a multi-step synthesis. PBD-dilactam was initially produced using isatoic anhydride and (L)-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 11-hydrazinyl PBD 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, IR, GC-MS and X-ray Crystallography were used to characterize the products. Inhibition activity of the products were carried out using TEM-1, AmpC and p99 β-lactamases. National cancer Institute tested some selected compounds on 60 NCI- cell line

Syntheses and Purification of Cannabinoid Derivatives

Synthetic cannabinoids such as Δ8-Tetrahydrocannabinol (Δ8) are becoming increasingly popular. Δ8 was once studied for medicinal value and showed promise as an antiemetic. The typical synthesis of Δ8 includes a Cannabidiol (CBD) dissolved in a nonpolar solvent then reacted with a strong acid and washed in a basic solution to remove contaminants. We investigated the effects of varying the acid and solvent along with the washing method used in synthesizing Δ8 to produce novel synthetic cannabinoids and increase purity of Δ8. CBD was reacted with p-Toluenesulfonic acid monohydrate or Phosphotungstic acid dissolved in Toluene, Cyclohexene, or Cyclohexane. Samples were either washed with sodium bicarbonate or extracted from the non-polar layer when added to a biphasic solution of cyclohexane and either acetonitrile or ethanol. Samples were taken at 1-, 24-, 72-, 96-, 168-, and 288-hour increments. Samples were diluted with DCM and analyzed via GCMS. Notable cannabinoids synthesized include CBC, CBN, isomers of CBD, and unknown hydrated cannabinoids. Through comparative GCMS analysis cyclohexane was discovered to be the commercial solvent of choice. Residual cyclohexane (\u3c4%) was identified in all similar samples and poses unknown toxicity. The biphasic extraction and wash produced samples with greater purity while also reducing byproduct contamination when compared to commercial samples. This work will be useful in identifying cannabinoid byproducts in the production of Δ8 from which future drugs may be developed. This work will also be key in highlighting hidden toxic compounds related to of unregulated synthetic cannabinoid production

SYNTHESIS AND BIOLOGICAL SIGNIFICANCE OF 1,2,4-OXADIAXOLIDIN-5-ONE

SYNTHESIS AND BILOGICAL SIGNIFICANCE OF 1,2,4-OXADIAXOLIDIN-5-ONE Chimdi kalu, Austin Miller and Dr. Abbas G. Shilabin Department of Chemistry, East Tennessee State University, Johnson City, TN 37614. ABSRTACT Due to the challenge posed by microbial resistance to broad spectrum of antibiotics, there has been a great need to synthesize of a novel compound which has a different mechanism of action on microbial activity. 1,2,4-oxadiaxolidin-5-One constitute an important class of compound with tremendous potential as pharmaceutical and otherwise biologically relevance substance due to the fact that its five member ring is a configurationally stable building block. This unit is found in other compound like alkaloids, with vast medical application. This study describes the synthesis of 1,2,4-oxadiaxolidin-5-one in two-step procedure using nitroethane and benzaldehyde as starting materials to produce nitrone, which in turn undergoes 1,3- dipolar cycloaddition with phenyl isocyanate to give 1,2,4-oxadiaxolidin-5-one. The product was characterized using proton NMR and GC-MS. There is an ongoing investigation on the summary of some important inhibitory activity against class A β-lactamase by 1,2,4-oxadiaxolidin-5-one heterocyclic core structure to provide effective antimicrobial β-lactamase inhibitors, hence, solving the problem of microbial resistance to currently used antimicrobial drugs

Extraction, purification, and characterization of potential bioactive metabolites produced by Janthinobacterium lividum TAJX1901

Underexplored environments such as soil samples continue to be an untapped source of bacterial strains with great potential to produce potent secondary metabolites for medicinal applications. As a result, these microorganisms represent a broad and yet unknown reservoir of new strains capable of producing these novel natural compounds. Secondary metabolites from microorganisms have been used in antibiotic production, chemotherapy, immunosuppressants, and various industrial applications. The current research primarily seeks to perform the isolation, purification, and characterization of secondary metabolites from a soil bacterium (Janthinobacterium lividum TAJX1901). To achieve these objectives, the soil bacteria was successfully cultured on rich media agar plates followed by liquid–liquid extraction using a solvent mixture of methanol and chloroform(3:1). Various purification methods were utilized, including flash column chromatography, preparative thin layer chromatography, centrifugation, and high-performance liquid chromatography (HPLC ) using different column types and elution methods. For structural elucidation, UV/Vis analysis, infrared spectroscopy, and nuclear magnetic resonance spectroscopy were employed. The extraction resulted in a dominant violet pigment soluble in methanol. Preliminary results reveal the presence of highly conjugated, polar, and aromatic compounds. This work is relevant in the current global search for novel compounds for tackling antibiotic-resistant organisms and treating other diseases and infections

An inhibitory compound produced by a soil isolate of Rhodococcus has strong activity against the veterinary pathogen R. equi.

Complete genome sequencing of dozens of strains of the soil bacterium Rhodococcus has revealed the presence of many cryptic biosynthetic gene clusters, presumably dedicated to the production of small molecules. This has sparked a renewed interest in this underexplored member of the Actinobacteria as a potential source of new bioactive compounds. Reported here is the discovery of a potent inhibitory molecule produced by a newly isolated strain of Rhodococcus, strain MTM3W5.2. This small inhibitory molecule shows strong activity against all Rhodococcus species tested, including the veterinary pathogen R. equi, and some closely related genera. It is not active against other Gram positive or Gram negative bacteria. A screen of random transposon mutants identified a gene required to produce this inhibitory compound. This gene is a large multi-domain, type I polyketide synthase that is part of a very large multi-gene biosynthetic gene cluster in the chromosome of strain MTM3W5.2. The high resolution mass spectrum of a major chromatogram peak from a broth culture extract of MTM3W5.2 shows the presence of a compound at m/z 911.5490 atomic mass units. This compound is not detected in the culture extracts from a non-producing mutant strain of MTM3W5.2. A large gene cluster containing at least 14 different type I polyketide synthase genes is proposed to be required to synthesize this antibiotic-like compound

4-Quinolones as Noncovalent Inhibitors of High Molecular Mass Penicillin-Binding Proteins

Penicillin-binding proteins (PBPs) are important bacterial enzymes that carry out the final steps of bacterial cell wall assembly. Their DD-transpeptidase activity accomplishes the essential peptide cross-linking step of the cell wall. To date, all attempts to discover effective inhibitors of PBPs, apart from β-lactams, have not led to new antibiotics. Therefore, the need for new classes of efficient inhibitors of these enzymes remains. Guided by a computational fragment-based docking procedure, carried out on <i>Escherichia coli</i> PBP5, we have designed and synthesized a series of 4-quinolones as potential inhibitors of PBPs. We describe their binding to the PBPs of <i>E. coli</i> and <i>Bacillus subtilis</i>. Notably, these compounds bind quite tightly to the essential high molecular mass PBPs