Jody Morgan

Binaphthyl‐Based Dicationic Peptoids with Therapeutic Potential

[Extract] While the cationic glycopeptide vancomycin has long been regarded as the gold standard for the treatment of recalcitrant Gram-positive bacterial infection, this position has been compromised by the emergence of resistant strains. The first report of such resistance emerged in 1988, and has subsequently widened amongst the enterococci and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA); 1, 2 cross-resistance to linezolid is also a concern. Some recent chemical strategies for overcoming this resistance have centered on other high molecular weight cyclic peptides, elegantly crafted vancomycin11 or vancomycin aglycone analogues, potent dual-action vancomycin/β-lactam hybrid antibiotics,or large vancomycin dimers. An alternative strategy is to design smaller, simpler cationic peptoids with some related design features to vancomycin which could still interact with the altered peptide-glycan cell-wall moiety in both vancomycin-resistant and -sensitive strains and thus broaden the antibacterial spectrum. Svendsen et al. designed minimal cationic peptidomimetics, and a pharmacophore has been developed for dipeptides which includes the presence of two cationic charges and two hydrophobic units of steric bulk. Subsequently, cationic tripeptide analogues were developed that demonstrated good activity against both Gram-positive (including MRSA) and Gram-negative bacteria, but were not evaluated with respect to vancomycin-resistant strains.

Antimalarial Activity of 2,4-Diaminopyrimidines

A series of 2,4and 4,6-diaminopyrimidines were prepared and evaluated for their in vitro antimalarial activity. Of the 12 compounds tested 7 showed reasonable activity with 1 having a sub-micromolar IC50.

Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists.

Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity > 50:1 noted. All analogues were screened for their ability to interact with CRH1 and CRH2 receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH2. However, several compounds were potent and selective CRH1 antagonists, most notably 13a Ki = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH1 pharmacophore (J Med. Chem., 1999, 42, 2351-2357).

Anilinopyrimidines as novel antituberculosis agents.

A selection of novel anilinopyrimidine analogues have been found to have micromolar activity against Mycobacterium tuberculosis. This could potentially generate new lead compounds in the fight against multi-drug resistant tuberculosis.

The Prevention of Preterm Labour - Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design and Development

The role of the corticotropin releasing hormone in the onset of labour and the subsequent medicinal chemistry implications of CRH antagonists for the prevention of premature birth, and identification of the CRH type 1 receptor as the target for this drug design, are reviewed here.

Identification of Aminopyrimidine Regioisomers via Line Broadening Effects in 1H and 13C NMR Spectroscopy

Substituted mono- and diamino-pyrimidines were synthesized as part of our medicinal chemistry programmes. Primary amines substituted at the 4-position exhibited room-temperature line broadening effects in both 1H and 13C NMR spectroscopy due to the presence of rotamers, but these effects were not observed for substituents in the 2-position. This provided a simple diagnostic tool for the identification of regioisomers, a determination which would otherwise have required two-dimensional experiments.

The role of naloxone in the opioid crisis

ABSTRACT Overdose due to opioid abuse is an ever increasing problem, especially in the United States, with the last few years seeing a dramatic rise in the number of synthetic opioid-related deaths. The pure opioid antagonist naloxone has been used in a clinical setting as an antidote to opioid overdose for decades. Recent data suggest that the number of patients requiring multiple doses of naloxone is growing likely caused by the increased number of intoxications with potent synthetic opioids such as fentanyl and its derivatives. Treating clinicians in both emergency departments and pre-hospital settings should be aware that they may need to escalate to higher doses of naloxone, with repeat doses or IV infusions required, when treating patients who have overdosed on synthetic opioids. Moving forward, a combination of improved access to naloxone in a pre-hospital setting, an increase in community-based training, including the likely requirement of rapid or higher dose naloxone administration for treatment of synthetic opioid overdose, and a better understanding of the toxicology of high potency synthetic opioids, are required to decrease the number of fatalities stemming from the current opioid crisis.

E-cigarettes—An unintended illicit drug delivery system

Since the introduction of electronic cigarettes (e-cigarettes) in 2003, the technology has advanced allowing for greater user modifications, with users now able to control voltage, battery power, and constituents of the e-cigarette liquid. E-cigarettes have been the subject of a growing body of research with most research justifiably focused on the chemical makeup and risk analysis of chemicals, metals, and particulates found in e-cigarette liquids and vapor. Little research to date has focused on assessing the risks associated with the drug delivery unit itself and its potential for use as an illicit drug delivery system. In light of this, a range of illicit drugs was researched focusing on pharmacodynamics, usual method of administration, the dosage required for toxicity, toxic effects, and evidence of existing use in e-cigarettes in both literature and online illicit drug forums. A systematic literature search found evidence of current use of e-cigarettes to vape almost all illicit drug types analyzed. This presents both a potential population health risk and a management issue for clinicians. It also raises the issue of policing illicit drugs due to potential altered characteristic smells and storage within e-cigarette fluids. E-cigarettes are a viable illicit drug delivery system with evidence both inside and outside of the formal medical literature detailing their potential use for drug delivery of a wide range of illicit and legal drugs.