Selected Electrosynthesis of 3-Aminopyrazoles from α,ß-Alkynic Hydrazones and Secondary Amines.

An available and simple electromediated cyclization method for 3-amino-substituted pyrazoles by using α,ß-alkynic hydrazone and secondary amine is described. The strategy utilizes KI as an electrolyte in an undivided cell with a constant current, generating the desired products in moderate-to-good yield. The method features selective amination at the 3-position of the pyrazole skeleton. The results indicate that α,ß-alkynic hydrazones functionalized with aromatic groups and secondary amines functionalized with electron-rich groups were better tolerated in this transformation.

Improved synthesis and evaluation of preclinical pharmacodynamic parameters of a new monocyclic ß-lactam DPI-2016.

Monocyclic ß-lactams are stable to a number of ß-lactamases and are the focus of researchers for the development of antibacterial drugs, particularly against Enterobacterales. We recently synthesized and reported the bactericidal activity of diverse series of aztreonam appended with amidine moieties as siderophores. One of the derivatives exhibiting the highest MIC value in vitro was selected for further preclinical studies. The compound DPI-2016 was reassessed for its synthetic routes and methods that were improved to find the maximum final yields aimed at large-scale synthesis. In addition, the results of the pharmacological studies were determined with reference to aztreonam. It has been found that the compound DPI-2016 showed comparable or slightly improved ADMET as well as pharmacokinetic parameters to aztreonam. It is estimated that the compound could be a potential lead for further clinical evaluation.

Recent Developments to Cope the Antibacterial Resistance via ß-Lactamase Inhibition.

Antibacterial resistance towards the ß-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new ß-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, ß-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first ß-lactamase inhibitor (BLI), clavulanic acid. Over the years, ß-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D ß-lactamases. Boronic acids have shown promise in coping with Ambler class B ß-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- ß-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic ß-Lactams.

BACKGROUND: Mononcyclic ß-lactams are regarded as the most resistant class of ß-lactams against a series of ß-lactamases, although they possess limited antibacterial activity. Aztreonam, being the first clinically approved monobactam, needs broad-spectrum efficacy through structural modification. OBJECTIVE: We strive to synthesize a number of monocyclic ß-lactams by varying the substituents at N1, C3, and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. METHODS: Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using the broth microdilution method against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime, and meropenem, existing clinical antibiotics. RESULTS: All compounds 23a-g showed higher antibacterial activities (MIC 0.25 µg/mL to 64 µg/mL) against tested strains as compared to aztreonam (MIC 16 µg/mL to >64 µg/mL) and ceftazidime (MIC >64 µg/mL). However, all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains compared to meropenem. CONCLUSION: Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 µg/mL to 2 µg/mL) to meropenem (MIC 1 µg/mL to 2 µg/mL) in the case of seven bacterial species. Therefore, compound 23d may be a valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.

ß-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes.

The diazabicyclooctane (DBO) scaffold is the backbone of non-ß-lactam-based second generation ß-lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1-23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in vitro. All compounds did not show antibacterial activity when tested alone (MIC >64 mg/L), however, they exhibited a moderate inhibition activity in the presence of meropenem by lowering its MIC values. The compound A12 proved most potent among the other counterparts against all bacterial species with MIC from <0.125 mg/L to 2 mg/L, and is comparable to avibactam against both E. coli strains with a MIC value of <0.125 mg/L.

Synthesis and antibacterial evaluation of new monobactams.

Monobactams play an important role in antibiotic drug discovery. Based on the structural characteristics of aztreonam and its biological targets, six new monobactam derivatives (2a-c and 3a-c) were synthesized and their in vitro antibacterial activities were investigated. Compounds 2a-c showed higher activities against tested gram-negative bacteria than that of parent aztreonam. Monobactam 2c exhibited the most potent activities, with MIC ranging from 0.25 to 2 µg/mL against most bacteria.

Synthesis of layered double hydroxide/poly(N-isopropylacrylamide) nanocomposite hydrogels with excellent mechanical and thermoresponsive performances.

Nanocomposite (NC) hydrogels of positively charged layered double hydroxide (LDH) single-layer nanosheet (SLNS) cross-linked poly(N-isopropylacrylamide) (PNIPAM) were synthesized. Especially, the LDH SLNSs used here were pre-synthesized via an aqueous synthetic route without using organic solvents and modifiers. The obtained LDH/PNIPAM NC hydrogels were characterized using XRD, SEM, TEM, and DSC. The mechanical and thermoresponsive properties were determined using tensile, compression, and swelling/deswelling tests. Interestingly, different network structures are observed for the NC hydrogels along the horizontal and vertical directions; those along the horizontal direction exhibit a fine and uniform sponge-like network structure while those along the vertical direction exhibit a hierarchical layered architecture. Compared with the conventional N,N'-methylene bisacrylamide cross-linked PNIPAM hydrogel, the NC hydrogels exhibit extraordinary deformability and stretchability and obviously improved thermoresponsive swelling/deswelling characteristics. Furthermore, the fracture elongation observed here is obviously higher than those reported for negatively charged clay/PNIPAM NC hydrogels. With the increase in the LDH content from 0.8 to 2.0 wt%, the fracture strength and the compressive strength at an 85% strain increase from 23.5 to 37.2 kPa and from 0.15 to 0.57 MPa, respectively, while the fracture elongation decreases from 2689 to 2202%. The mechanism for the improved mechanical performances of the NC hydrogels is discussed. To the best of our knowledge, this is the first report on LDH/PNIPAM hydrogels. This work provides a green synthesis route for LDH-containing NC hydrogels. The new NC hydrogels may have great potential applications such as in tissue engineering, drug vehicles, and sorbents.