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 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.

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.

Photo-cleavable nucleotides for primer free enzyme mediated DNA synthesis.

The synthesis, characterization and potential application of eight 3'-O modified 2'-deoxyribonucleoside triphosphates (dNTPs) are discussed. These nucleotide analogues are modified by capping the 3'-OH with a photolabile protecting group which can temporarily cease DNA strand growth and can smoothly reinitiate the growth by the photodecomposition of the protecting group and setting the 3'-OH of dNTPs free to propagate. The synthesis of 3'-O-(2-nitrobenzyl)-2'-deoxyribonucleoside triphosphates (NB-dNTPs) and 3'-O-(4,5-dimethoxy-2-nitrobenzyl)-2'-deoxyribonucleoside triphosphates (DMNB-dNTPs) is discussed in detail with structural confirmation using NMR. The UV-cleaving studies are monitored and quantified using LCMS and (1)H NMR spectral traces. The synthesised nucleotides are employed for terminating and reinitiating template-less DNA synthesis, using primer independent Terminal Deoxynucleotidyl Transferase (TdT) enzyme. The use of this photolabile nucleotide in one step stop-start DNA synthesis is a novel strategy towards the precise assembly of dNTPs with the potential to reinforce present technologies.

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.

The naturally occurring ketene acetal benesudon: total synthesis and assignment of relative and absolute stereochemistry.

The densely functionalized ketene acetal benesudon, which is a bioactive fungal metabolite, was synthesized from D-glucose by a route involving radical cyclization to form the five-membered ring, and oxidative decarboxylation to generate the key central double bond. The originally suggested stereochemistry for the quaternary center C(5) must be revised, as both C(5) epimers were prepared and a comparison with an authentic sample was made. The absolute configuration of benesudon is 4S,5R,6S.

3'-O-Caged 2'-Deoxynucleoside Triphosphates for Light-Mediated, Enzyme-Catalyzed, Template-Independent DNA Synthesis.

Synthesis, purification, and characterization of 3'-O-caged 2'-deoxyribonucleoside triphosphates (dNTPs), namely 3'-O-(2-nitrobenzyl)-2'-deoxy ribonucleoside triphosphates (NB-dNTPs) and 3'-O-(4,5-dimethoxy-2-nitrobenzyl)-2'-deoxy ribonucleoside triphosphates (DMNB-dNTPs), are discussed in detail. A total of eight 3'-O-caged dNTPs are synthesized with specific protocols depending on the nitrogenous base on the first carbon, i.e., adenine, guanine, thymine, and cytosine, as well as the photo-cleavable group, i.e, 2-nitrobenzyl and 4,5- dimethoxy-2-nitrobenzyl, to be attached in the 3'-O position. The purification of the synthesized compounds is done using ion-exchange and flash chromatography; this is followed by structural confirmation by nuclear magnetic resonance (NMR) and mass spectroscopy (MS). The efficiency of the designed compounds is tested by conducting and evaluating UV-cleaving experiments at 365 nm with proton NMR and LC-MS curves. Finally, the application of the 3'-O-cagged dNTPs in template-independent, enzyme-catalyzed, photo-mediated oligonucleotide synthesis is demonstrated. © 2017 by John Wiley & Sons, Inc.

Synthesis of the core structure of the fungal metabolite benesudon: use of oxidative decarboxylation.

[chemical reaction: see text]. The core structure (5) of the fungal metabolite benesudon (1) was synthesized, the key step being oxidative decarboxylation of acid 17.