Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem

Concise Total Synthesis of (−)-Erinapyrone B from D-(+)-Malic Acid

<div><p></p><p>A convenient and facile enantioselective synthesis of (−)-erinapyrone B from commercially available D-(+)-malic acid has been achieved in seven steps. One of the key steps in this synthesis was the one-pot reaction of palladium(II)-mediated Wacker-type oxidative cyclization in the presence of a catalytic amount of <i>p</i>-toluenesulphonic acid (<i>p</i>-TsOH) which has been found to be effective for the preparation of enantiopure 2,3-dihydro-4<i>H</i>-pyran-4-one from the corresponding enantiopure β-hydroxyenone via enantio-enriched diketohydroxy intermediate.</p> <p>[Supplementary materials are available for this article. Go to the publisher's online edition of <i>Synthetic Communications®</i> for the following free supplemental resource(s): Full experimental and spectral details.]</p> </div

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active

Suzuki–Miyaura coupling of quinazolines containing an unprotected NH₂ group: Synthesis and biological testing of quinazoline derivatives

<p>A robust approach to 4-amino quinazoline bi-aryl compounds was developed through Suzuki–Miyaura coupling reaction of quinazoline containing an unprotected NH₂ group and arylboronic acids. Pd(dcpf)Cl₂ was found to be an efficient catalyst for the reaction. All the compounds were evaluated for antimicrobial activity against gram-positive and gram-negative bacteria and fungi. One of the compounds, <b>3l</b>, found to be more active against <i>Candida albicans</i> than the standard Miconazole.</p

Novel Imidazoline Antimicrobial Scaffold That Inhibits DNA Replication with Activity against Mycobacteria and Drug Resistant Gram-Positive Cocci

Bacterial antimicrobial resistance is an escalating public health threat, yet the current antimicrobial pipeline remains alarmingly depleted, making the development of new antimicrobials an urgent need. Here, we identify a novel, potent, imidazoline antimicrobial compound, SKI-356313, with bactericidal activity against <i>Mycobacterium tuberculosis</i> and Gram-positive cocci, including vancomycin-resistant <i>Enterococcus faecium</i> (VRE) and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). SKI-356313 is active in murine models of <i>Streptococcus pneumoniae</i> and MRSA infection and is potently bactericidal for both replicating and nonreplicating <i>M. tuberculosis.</i> Using a combination of genetics, whole genome sequencing, and a novel target ID approach using real time imaging of core macromolecular biosynthesis, we show that SKI-356313 inhibits DNA replication and displaces the replisome from the bacterial nucleoid. These results identify a new antimicrobial scaffold with a novel mechanism of action and potential therapeutic utility against nonreplicating <i>M. tuberculosis</i> and antibiotic resistant Gram-positive cocci