PIDA/I2-mediated photo-induced aerobic N-acylation of sulfoximines with methylarenes.

A visible-light-promoted, PIDA/I2-mediated acylation of NH-sulfoximines with methylarenes as an acyl source has been achieved. This transition metal and photosensitizer-free approach provides easy access to N-acylsulfoximines via oxidative coupling of sulfoximines with easily available methylarenes without using any peroxide source. Mechanistic investigations suggest the intermediacy of radicals and the importance of molecular oxygen.

Base-Promoted Synthesis of S-Arylisothiazolones via Intramolecular Dehydrative Cyclization of α-Keto-N-acylsulfoximines.

A base (Et3N)-promoted synthesis of 1,4-diarylisothiazolones from α-keto-N-acylsulfoximines has been achieved. The reaction proceeds via α-hydrogen abstraction from sulfoximine, followed by an intramolecular nucleophilic attack at the keto carbonyl to form a tert-hydroxy isothiazolone intermediate. The 1,4-substituted isothiazolone is obtained after dehydration via an E1cB path. This one-pot synthesis of isothiazolinones has a broad substrate scope, has a high atom economy, and provides products with good yields. The ΔELUMO-HOMO is calculated using Gaussian 16 at the B3LYP/6-31G(d,p) level of theory.

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel ß-Lactam-Metallo-ß-Lactamase Inhibitors.

Virulent Enterobacterale strains expressing serine and metallo-ß-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop ß-lactamase inhibitors to counter this resistance. Currently, serine ß-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-ß-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived ß-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-ß-lactamase (NDM-1) and Verona Integron-encoded Metallo-ß-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

NIS-initiated photo-induced oxidative decarboxylative sulfoximidation of cinnamic acids.

N-Iodosuccinimide catalyzed, visible-light-induced oxidative decarboxylative cross-coupling between cinnamic acids and NH-sulfoximines is presented. This strategy results in the formation of α-keto-N-acyl sulfoximines via the construction of two new CO bonds and one C-N bond. The in situ-generated N-iodosulfoximine serves as the light-absorbing species in the absence of any external photosensitizer. The keto carbonyl and amidic carbonyl oxygen in the resulting product originate from dioxygen and water respectively.

N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity.

Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram - Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 showed high antimycobacterial activity with MIC value of 4-8 µg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC50 = 15 µg/mL; compound 15 IC50 = 65 µg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.

Synthesis of novel 1,2,4-thiadiazinane 1,1-dioxides via three component SuFEx type reaction.

Herein, we report the preparation of 1,2,4-thiadiazinane 1,1-dioxides from reaction of ß-aminoethane sulfonamides with dichloromethane, dibromomethane and formaldehyde as methylene donors. The ß-aminoethane sulfonamides were obtained through sequential Michael addition of amines to α,ß-unsaturated ethenesulfonyl fluorides followed by further DBU mediated sulfur(vi) fluoride exchange (SuFEx) reaction with amines at the S-F bond.