Discovery of an Azabicyclo[2.1.1]hexane Piperazinium Salt and Its Application in Medicinal Chemistry via a Rearrangement.

Herein we report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs). This bench-stable compound was found to be a versatile electrophile in a ring-opening reaction with various types of nucleophiles. Its utility as a versatile medicinal chemistry building block is further demonstrated in the synthesis of an LDD compound targeting degradation of the androgen receptor.

Discovery of 2-Sulfinyl-Diazabicyclooctane Derivatives, Potential Oral ß-Lactamase Inhibitors for Infections Caused by Serine ß-Lactamase-Producing Enterobacterales.

Coadministration of ß-lactam and ß-lactamase inhibitor (BLI) is one of the well-established therapeutic measures for bacterial infections caused by ß-lactam-resistant Gram-negative bacteria, whereas we have only two options for orally active BLI, clavulanic acid and sulbactam. Furthermore, these BLIs are losing their clinical usefulness because of the spread of new ß-lactamases, including extended-spectrum ß-lactamases (ESBLs) belonging to class A ß-lactamases, class C and D ß-lactamases, and carbapenemases, which are hardly or not inhibited by these classical BLIs. From the viewpoints of medical cost and burden of healthcare personnel, oral therapy offers many advantages. In our search for novel diazabicyclooctane (DBO) BLIs possessing a thio-functional group at the C2 position, we discovered a 2-sulfinyl-DBO derivative (2), which restores the antibacterial activities of an orally available third-generation cephalosporin, ceftibuten (CTB), against various serine ß-lactamase-producing strains including carbapenem-resistant Enterobacteriaceae (CRE). It can be orally absorbed via the ester prodrug modification and exhibits in vivo efficacy in a combination with CTB.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16'-epi-Leucophyllidine.

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler-Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C-H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16'-epi-leucophyllidine in 21 steps from commercial material.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges.

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C2- or C3-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C2- or a methylene group at the C3-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge.

Total Synthesis of Fawcettimine-Type Alkaloid, Lycojaponicumin A.

The efficient total synthesis of lycojaponicumin A (1) has been accomplished for the first time. The remarkable features of this novel strategy include the following: (1) rapid construction of tricyclic intermediate 4 through a regio- and stereoselective semipinacol ring expansion, which simplified the construction of rings A and B of 1; (2) the subsequent regio- and stereoselective formation of the highly strained rings C-E of 1 through a tandem oxa-hetero [3 + 2] cycloaddition/N-cycloalkylation.

Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability.

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal-to design an entry inhibitor with improved drug-like qualities-and warrants expanded studies to achieve this.

Synthetic approaches towards avibactam and other diazabicyclooctane ß-lactamase inhibitors.

Avibactam is a non ß-lactam ß-lactamase inhibitor that has recently been approved in association with a ß-lactam antibiotic for the treatment of severe infections caused by otherwise resistant bacteria. Its therapeutic success encouraged the development of many congeners based on its particular diazabicyclooctane scaffold. This review presents a detailed overview of the synthetic strategies that have been implemented to acces these complex bicyclic compounds with a particular focus on those that are currently on the market or in clinical trials.

Design And Synthesis Of An Azabicyclic Nucleoside Phosphoramidite For Oligonucleotide Antisense Constructs.

We report the synthesis and biophysical evaluation of an azabicycle dinucleotide with restricted γ, ß, and ε torsion angles, featuring the introduction of a piperidine ring that locks the conformation of the nucleoside into an RNA-type nucleic acid. The conceptual basis of the design is predicated upon the notion that the conformation of the phosphate group linking two RNA nucleotides can be approximated with an azabicyclic phosphoramidite which may also benefit from a unique stereoelectronic effect.

Diastereoselective FeCl3·6H2O/NaBH4 Reduction of Oxime Ether for the Synthesis of ß-Lactamase Inhibitor Relebactam.

Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.

Highly selective and wash-free visualization of resistant bacteria with a relebactam-derived fluorogenic probe.

Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine ß-lactamases (SBLs), which are the major causes of bacterial resistance to ß-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.

Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors.

We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4ß2Ki value of 10 pM and a very high α7/α4ß2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4ß2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.

Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design.

Penicillin-binding proteins (PBPs) are the targets of the ß-lactams, the most successful class of antibiotics ever developed against bacterial infections. Unfortunately, the worldwide and rapid spread of large spectrum ß-lactam resistance genes such as carbapenemases is detrimental to the use of antibiotics in this class. New potent PBP inhibitors are needed, especially compounds that resist ß-lactamase hydrolysis. Here we describe the structure of the E. coli PBP2 in its Apo form and upon its reaction with 2 diazabicyclo derivatives, avibactam and CPD4, a new potent PBP2 inhibitor. Examination of these structures shows that unlike avibactam, CPD4 can perform a hydrophobic stacking on Trp370 in the active site of E. coli PBP2. This result, together with sequence analysis, homology modeling, and SAR, allows us to propose CPD4 as potential starting scaffold to develop molecules active against a broad range of bacterial species at the top of the WHO priority list.

IID572: A New Potentially Best-In-Class ß-Lactamase Inhibitor.

Resistance in Gram-negative bacteria to ß-lactam drugs is mediated primarily by the expression of ß-lactamases, and co-dosing of ß-lactams with a ß-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New ß-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of ß-lactamases and the lack of intrinsic antibacterial activity.

Synthesis, antiproliferative activity and 2D-QSAR study of some 8-alkyl-2,4-bisbenzylidene-3-nortropinones.

AIM: Colon cancer is the third leading cause of death worldwide; therefore, there is a need for an effective therapy with lower side effects. METHODS: A series of 8-alkyl-2,4-bisbenzylidene-3-nortropinones 3 & 14-39 was prepared via Claisen-Schmidt condensation of 8-alkyl-3-nortropinones 11-13 with different aromatic aldehydes. The target compounds were screened for their antiproliferative activity. RESULTS: Most of the prepared compounds showed promising antiproliferative activity against many of 60 National Cancer Institute cell lines at 10 µM. Furthermore, 8-ethyl-2,4-bis(3,4-dimethoxybenzylidene)-8-nortropin-3-one 29 and its 3,4,5-trimethoxy analog 30 were the most active compounds against HCT116 cell line with IC50 values 0.01 and 0.46 µM, respectively. Using CODESSA-Pro software, a significant 2D-quantitative structure-activity relationship (QSAR) model was obtained. CONCLUSION: The 8-Alkyl-2,4-bisbenzylidene-8-azabicyclo[3.2.1]octan-3-one represents an interesting core for further structural optimization to obtain more promising hits.

Bioorthogonal release of sulfonamides and mutually orthogonal liberation of two drugs.

Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.

Combining a pyclen framework with conjugated antenna for the design of europium and samarium luminescent bioprobes.

The first pyclen based ligand bearing two picolinate intra-ligand charge transfer transition antennae and one acetate arm organized in a dissymmetric manner was synthesized for Eu(iii) and Sm(iii) complexation. The europium complex presents an excellent brightness and biphotonic imaging of T24-cells has been performed using Eu(iii) and the less common Sm(iii) bioprobes.

Water-Soluble Silver(I) Complexes Featuring the Hemilabile 3,7-Dimethyl-1,3,5-triaza-7-phosphabicyclo[3.3.1]nonane Ligand: Synthesis, Characterization, and Antimicrobial Activity.

This paper describes the preparation and comprehensive characterization of a series of water-soluble cationic silver(I)-centered complexes featuring the hemilabile P, N-ligand known as 3,7-dimethyl-1,3,5-triaza-7-phosphabicyclo[3.3.1]nonane (herein abbreviated as PTN(Me)) and differing types of monoanionic counterions including known biologically active sulfadiazine and triclosan. The complexes primarily differed though the number of coordinating PTN(Me) ligands. The bis-substituted Ag(I) complexes revealed P, N bidentate coordination, while the only P-monocoordination of the metal center was observed for the tris-substituted systems. The bis-ligated silver compounds were observed to quickly degrade upon photoexposure or in contact with air. In contrast, the tris-ligated complexes demonstrated greater stability, in particular, a high resistance to photo-decomposition. Calculated geometry optimized models using the density functional theory method (BP86) revealed for the bis-substituted PTN(Me) Ag(I) species that the total enthalpy of the tetrahedral C2-symmetric structure is marginally lower by -0.6 kcal mol-1 compared to the planar C2 h structure, which is analogous for the corresponding [Au(PTN(Me))2]+ complex with Δ H = -0.5 kcal mol-1. Hence both types of complexes feature free rotation of the PTN ligand about the M-P bond axis. This series of Ag(I) and bis-PTN(Me) Au(I) complexes were evaluated using the agar well diffusion test for potential antimicrobial and antifungal activity. The nature of the counterion was found to have a strong correlation with the area of microbiological growth inhibition. Silver(I) complexes bearing the deprotonated triclosan as the counterion demonstrated the greatest activity, with large zones of growth inhibition, with the tris-ligated triclosan complex obtaining of a high clearance of 42 mm against the Gram-negative Escherichia coli. In contrast, the previously reported [Au(PTN(Me))2]Cl complex demonstrated activity only against E. coli, which is lower than that observed for the silver(I) PTN(Me) species.

Synthesis of Avibactam Derivatives and Activity on ß-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria.

There is a renewed interest for ß-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their ß-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 µg mL-1 for both species). Mechanistically, ß-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.

Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins.

FK506-binding proteins (FKBPs) are evolutionarily conserved proteins that display peptidyl-prolyl isomerase activities and act as coreceptors for immunosuppressants. Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs can enhance infectivity. However, developing druglike ligands for FKBPs or Mips has proven difficult, and many FKBPs and Mips still lack biologically useful ligands. To explore the scope and potential of C5-substituted [4.3.1]-aza-bicyclic sulfonamides as a broadly applicable class of FKBP inhibitors, we developed a new synthesis method for the bicyclic core scaffold and used it to prepare an FKBP- and Mip-focused library. This allowed us to perform a systematic structure-activity-relationship analysis across key human FKBPs and microbial Mips, yielding highly improved inhibitors for all the FKBPs studied. A cocrystal structure confirmed the molecular-binding mode of the core structure and explained the affinity gained as a result of the preferred substituents. The best FKBP and Mip ligands showed promising antimalarial, antileginonellal, and antichlamydial properties in cellular models of infectivity, suggesting that substituted [4.3.1]-aza-bicyclic sulfonamides could be a novel class of anti-infectives.