Design, synthesis and bioactivity evaluation of novel pyrazole linked phenylthiazole derivatives in context of antibacterial activity.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current antibiotics requires an urgent investigation into novel classes of antimicrobial agents. This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 µg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotics. In summary, these results demonstrate that a pyrazole linked phenylthiazole scaffold has potential as a lead for further investigation to afford novel antibacterial agents.

Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores.

The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. The catalytic activity of MraY is an essential process for bacterial cell viability and growth including that of priority organisms. Muraymycins are one subclass of naturally occurring MraY inhibitors. Despite having potent antibiotic properties, the structural complexity of muraymycins advocates for simplified analogues as potential lead structures. Herein, we report a systematic structure-activity relationship (SAR) study of serine template-linked, simplified muraymycin-type analogues. This preliminary SAR lead study of serine template analogues successfully revealed that the complex structure of naturally occurring muraymycins could be easily simplified to afford bioactive scaffolds against resistant priority organisms. This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template.

Caprazamycins: Promising lead structures acting on a novel antibacterial target MraY.

The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.

Essential role of O-GlcNAcylation in stabilization of oncogenic factors.

A reversible post-translational protein modification which involves addition of N-acetylglucosamine (GlcNAc) onto hydroxyl groups of serine and/or threonine residues which is known as O-GlcNAcylation, has emerged as a potent competitor of phosphorylation. This glycosyltransfer reaction is catalyzed by the enzyme O-linked ß-N-acetylglucosamine transferase (OGT). This enzyme uses uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end product of hexosamine biosynthetic pathway, to modify numerous nuclear and cytosolic proteins. O-GlcNAcylation influences cancer cell metabolism in such a way that hyper-O-GlcNAcylation is considered as a prominent trait of many cancers, and is proposed as a major factor enabling cancer cell proliferation and progression. Growing evidence supports a connection between O-GlcNAcylation and major oncogenic factors, including for example, c-MYC, HIF-1α, and NF-κB. A comprehensive study of the roles of O-GlcNAc modification of oncogenic factors is warranted as a thorough understanding may help drive advances in cancer diagnosis and therapy. The focus of this article is to highlight the interplay between oncogenic factors and O-GlcNAcylation along with OGT in cancer cell proliferation and survival. The prospects for OGT inhibitors will also be discussed.

Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-ß (Aß) aggregated species. Recently, multiple therapies that target Aß aggregation have failed in clinical trials, since Aß aggregation is found in AD and healthy patients. Attention has therefore shifted toward the aggregation of the tau protein as a major driver of AD. Numerous inhibitors of tau-based pathology have recently been developed. Diagnosis of AD has shifted from measuring late stage senile plaques to early stage biomarkers, amyloid-ß and tau monomers and oligomeric assemblies. Synthetic peptides and some derivative structures are being explored for use as theranostic tools as they possess the capacity both to bind the biomarkers and to inhibit their pathological self-assembly. Several studies have demonstrated that O-linked glycoside addition can significantly alter amyloid aggregation kinetics. Furthermore, natural O-glycosylation of amyloid-forming proteins, including amyloid precursor protein (APP), tau, and α-synuclein, promotes alternative nonamyloidogenic processing pathways. As such, glycopeptides and related peptidomimetics are being investigated within the AD field. Here we review advancements made in the last 5 years, as well as the arrival of sugar-based derivatives.