The Evaluation of Isatin 3-Hydrazone Derivatives toward Biofilm Regulation

In the current methodology of fighting infections, antibiotics are used to eliminate the invading bacteria. A result of this process is constantly evolving antibiotic-resistant bacteria. If we hope to be more effective at preventing disease, we must shift the way we view microbial treatment. One novel method of preventing bacterial proliferation is the modulation of biofilm. Many bacteria can produce a biofilm; an extracellular substance that provides protection and antibiotic resistance to the bacteria. Attacking this biofilm and allowing the body’s natural defenses to clear out the bacteria is one promising way to treat bacterial infections while avoiding adaptive bacterial mutation. Isatin has been shown to regulate biofilm and thus exhibits properties similar to quorum sensing molecules. Additionally, isatin derived from indole which is a known quorum sensing molecule. Previous studies have shown that hydrazone and oxime derivatives of isatin have antimicrobial properties, which make them targets of interest in testing the ability of isatins to regulate biofilms. Within this study, a library of these compounds was created and tested against E. coli, P. aeruginosa, S. aureus to determine the OD600 correlation, minimum inhibitory concentration and the effect the compounds have on biofilm formation. For E. coli it was found that a compound was found to inhibit while others promoted. For P. aeruginosa, it was found that a compound was found to inhibit biofilm production, while two others were found to be promoters. Compounds were found to be biofilm inhibitors for S. aureus, while a compound was found to be a promoter

Alternative Extraction Method of Guanidine Metabolites from Marine Sponge, Ptilocaulis spiculifer

Marine sponges are known for their use of biologically active allelopathic compounds. With almost every species of sponge having been shown to produce some chemical with medicinal properties, their survival is becoming increasingly important. Current extraction methods used by research teams require a large sample relative to the size of the sponge, which threatens the survival of the organism. 1 Ptilocaulis sp., or the orange tree sponge, is known to produce guanidine metabolites. This derivative has demonstrated biological activity against cell lines of leukemia, uterine, and cervical cancer.2 3 In this study we have developed a method for the chemical extraction of active metabolites from the ambient water containing a sponge. Preliminary data suggests the metabolite was found both using the traditional methods and using the water extraction. The organic extracts were used to test against L1210 leukemia cells for biological activity

Saving the Synapse: Assessing Opioid Receptors as Therapeutic Targets in the Management of Opioid Addiction

Understanding drug physiology at the synaptic level is crucial for the design and delivery of treatments for individuals facing opioid addiction. Opioids are analgesic drugs that can agonize endogenous opioid receptors at the neuronal synapse and inhibit signal transduction through pain modulatory pathways, making opioids a popular drug choice for clinical pain management. However, chronic exposure to opioids induces physical and chemical changes in the synapse, resulting in receptor expression downregulation and decreased neurotransmitter synthesis. Downregulation produces a diminished responsiveness to the drug and decreased neurotransmitter release fosters drug dependence, thus contributing to addiction and withdrawal symptoms. These physiological changes are difficult to reverse, thus making addiction treatment and withdrawal management difficult to accomplish. The current project aims to elucidate the effect of opioids at the synapse in order to further understand the processes behind current addiction treatments through a medicinal chemistry perspective. Through investigation of primary literature concerning opioid activity and neuronal target defense mechanisms, we hope explore strategies for novel drug development in order to counteract the physical, mental, and behavioral consequences of chronic opioid use. As rates of opioid addiction continue to rise, more research is needed to enhance the recovery of individuals facing opioid addiction as well as bring attention to the perils of over-prescribing opioids in clinical settings

Investing aliphatic phosphazenes as quaternary ammonium cation (QACs) mimics

Our lab is interested in various medicinal chemistry projects that intersect chemistry and biology. The biological focus of our lab is primarily that of anti-bacterial treatments. More particularly, I am interested in compounds that may be alternative treatments to traditional antibiotics. One alternative treatment that my post-doctoral lab focused on was the inhibition of bacterial biofilms. Over 80% of bacterial infections in the body are caused not by the presence of bacteria, since they are most often present constantly, but when bacteria manage to form biofilms. It is this biofilm that often provides the bacteria some safety from external pressures (such as antibiotics, our immune system, temperature, pH changes, etc.). The ability to prevent or even disperse the presence of bacterial biofilms presents an interesting alternative treatment that is less susceptible to bacterial resistance

Synthesis of Substituted Stilbene Probes Towards the Investigation of Antagonistic Effects Observed with 3,5-Substituted Paraben Derivatives

In practice, antagonistic xenoestrogen compounds have been used as drugs to treat cancer. Traditional strategies, include preparation of estrogen receptor antagonists exhibiting high affinity for the receptor while preventing rearrangement of the AF-2 binding domain. In a potentially new strategy, substituted parabens have proven to act as antagonists but do not bear the large sidechain associated with this common antagonist strategy. Weak phenolic interactions make determining such paraben binding confirmations and mode of action difficult. To investigate these activities associated with hindered phenolic compounds, substituted bisphenol probes have been synthesized via Witting protocols to produce a series of stilbene derivatives. Herein we present the synthesis of such substituted stilbenes. A model system was used to test the synthesis of many different molecules, with success towards one of the probes. Further work will need to completed to complete synthesis of all the probes to allow for testing using TR-FRET and ELISA assays. Antagonism is expected to arise from similar disruption in the role of H12 in the AF-2 ligand binding domain albeit due to alternative binding interactions

Synthesis and antimicrobial evaluation of gallate esters

Parabens are esters of p-hydroxybenzoates that are commonly found in everyday consumer products as well as pharmaceuticals. They are often used in commercial products to prevent bacterial growth as well as to provide extended shelf life, but have been shown to activate estrogen receptors in vivo, a contributing factor in human breast cancer proliferation. Our lab has previously generated a multitude of paraben derivatives that do not mimic estrogen. Many of these derivatives have other safety concerns, but gallate esters appear to have the least hazardous properties. The oestrogenic and antimicrobial properties of the gallate ester family are not currently understood; therefore, our lab set out to synthesize the non-commercially available gallate esters through Fischer esterification. Both synthesized and commercial gallate esters (methyl through dodecyl esters) were subsequently screened by serial dilution for the minimum inhibitory concentration (MIC) against Staphylococcus epidermidis and Serratia marcescens as representatives of Gram-positive and Gram-negative bacteria respectively. Our results indicate that increasing alkyl chain length improves the MIC against Gram-positive bacteria, with dodecyl gallate being the most effective antimicrobial agent at 32 µg/mL. These observed MIC values were improved relative to commercially available amoxicillin and erythromycin (no inhibition observed). Both compounds of interest and known antimicrobial agents were ineffective against Gram-negative bacterial growth. Additionally, the results of this study can be used to further evaluate the effectiveness of paraben ester derivatives in prevention of cancer cell development as well as antimicrobial agents

Decarboxylative Generation of 2‑Azaallyl Anions: 2‑Iminoalcohols via a Decarboxylative Erlenmeyer Reaction

Condensation between the tetrabutylammonium salt of 2,2-diphenylglycine and aldehydes results in a decarboxylative Erlenmeyer reaction, affording 1,2-diaryl-2-iminoalcohols as a mixture of diastereomers in good yields. The diastereomeric ratio shifts over time, with the <i>anti</i> diastereomer and the <i>syn</i> oxazolidine tautomer serving as the kinetic and thermodynamic products, respectively. Addition of Lewis acids can catalyze the rates of reaction and product equilibration. The results highlight the stereochemical promiscuity of 1,2-diaryl-2-iminoalcohols in the presence of Lewis acids and Brønsted bases

Disconnecting the Estrogen Receptor Binding Properties and Antimicrobial Properties of Parabens through 3,5-Substitution

Commercially utilized parabens are employed for their antimicrobial properties, but a weak binding to the estrogen receptor alpha (ER_α) may lead to breast cancer in some applications. Modification of the paraben scaffold should allow for a disconnection of these observed properties. Toward this goal, various 3,5-substituted parabens were synthesized and assessed for antimicrobial properties against <i>S. aureus</i> as well as competitive binding to the ER_α. The minimum inhibitory concentration assay confirmed retention of antimicrobial activity in many of these derivatives, while all compounds exhibited decreased xenoestrogen activity as determined by a combination of competitive enzyme linked immunosorbent assay (ELISA), proliferation, and estrogen receptor binding assay. Thus, these changes to the paraben scaffold have led to a multitude of paraben derivatives with antimicrobial properties up to 16 times more active than the parent paraben and that are devoid or significantly diminished of potential breast cancer causing properties

Palladium-Catalyzed Decarboxylative Generation and Asymmetric Allylation of α‑Imino Anions

A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (<i>S,S</i>)-<i>f</i>-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines