Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

Abstract

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1–2 μg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 μM, MIC: 8.6 μM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure–activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use‐Dependent Inhibitors of Voltage‐Gated Sodium Channels

“…To start with, a conformational analysis was run on the protonated model of To42 in the gaseous phase following our previously developed procedures. [ 51 , 52 ] As expected for a relatively flexible molecule, a high number of conformers (22) were found within a window of 3 kcal/mol above the global minimum conformation energy. However, all conformers shared three main features:…”

“…Calculations were performed according to previously developed procedures. [ 51 , 52 ] Briefly, the model of compound 13 a was built through the atomic fragments incorporated into Spartan’20 (Wavefunction Inc., Irvine, CA, USA) inner fragment library and assuming the suggested default starting geometries. The structure was optimized by molecular mechanics MMFF force field [68] and then submitted to a Monte Carlo conformational distribution analysis using the default step sizes.…”

“…All conformers in a window of 10 Kcal/mol above the global minimum conformation were retained. Redundant conformers [52] were eliminated. The ab initio gas‐phase energy content of each survived conformation was then calculated at the RHF/6‐31G* level.…”

A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment

“…Evaluation of the anticancer activity of compounds 1-8 follows a long-standing engagement by the Genoa research group in the synthesis of pharmacologically active nitroderivatives from the initial ring-opening of nitrothiophenes 9 [36][37][38][39][40][41][42][43][44], an effort that has resulted in a number of positive results in both in vitro and in vivo experiments. For instance, appreciable antitumor activity has been found for either some modified 13 [36,[38][39][40][41][42] or some selected 14 [36,37,39,40,42]; furthermore, α-glucosidase inhibition [43] or antibacterial activity [44] has, on the one hand, exhibited in nitroheterocycles obtained from our nitrobutadiene building-blocks. On the other hand, the Cosenza research group has, in turn, recently highlighted the efficacy of a nitrocarbazole as an anti-HIV agent [11].…”

Assessment of Antibiofilm Potencies of Nervonic and Oleic Acid against Acinetobacter baumannii Using In Vitro and Computational Approaches

“…Biofilms are matrix-enclosed communities and enable bacteria to resist host defenses and antibiotics [ 1 , 2 ], and thus bacteria in biofilms can endure for extended periods and are difficult to eradicate in hospital settings [ 1 ]. Acinetobacter baumannii was ranked by the World Health Organization as a highest priority critical pathogen in 2017 and the most successful multidrug-resistant ESKAPE organism ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , A. baumannii , Pseudomonas aeruginosa , Enterobacter organisms) [ 3 , 4 , 5 ]. Moreover, A. baumannii causes a wide range of infections, including pneumonia, bacteremia, endocarditis, osteomyelitis, meningitis, and severe nosocomial wound infections, urinary tract infections, bloodstream, skin, and other soft tissue infections [ 6 , 7 , 8 ].…”