CL-5343

The rise of vancomycin-resistant enterococci (VRE) as a leading cause of hospital-acquired infections underscores the urgent need for new treatment strategies. In fact, resistance has developed not only to vancomycin but also to other clinically used agents, such as daptomycin and linezolid. We propose a novel drug design approach merging tedizolid, a second-generation oxazolidinone used as an unapproved salvage therapy in clinical settings, with carbonic anhydrase inhibitors (CAIs) recently validated as functioning decolonization agents. These sulfonamide derivatives showed potent inhibition of the carbonic anhydrases from Enterococcus faecium, with K_I values in the range of 14.6-598 nM and 63.2-798 nM against EfCAα and EfCAγ. Computational simulations elucidated the binding mode of these dual-action antibiotics to the peptidyl transferase center (PTC) of the 50S ribosome subunit and bacterial CAs. A subset of six derivatives showed potent PTC-related anti-enterococcal effects against multidrug-resistant E. faecalis and E. faecium strains with some compounds outperforming both the oxazolidinone and CA inhibitor drugs (MIC values in the range 1-4 μg/mL).

Novel quinazoline–sulfonamide derivatives ( 4a ‐ n ) were synthesized and evaluated for their enzyme inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are associated with Alzheimer's diseases (AD). The target quinazoline–sulfonamides ( 4a ‐ n ) were obtained via one‐pot multicomponent reaction of 5‐amino‐1,3,4‐thiadiazole‐2‐sulfonamide ( 1 ) with substituted benzaldehydes ( 2a ‐ i ) and cyclohexane‐1,3‐diones ( 3 a , b ) under microwave irradiation. The reactions were performed using trifluoroacetic acid (TFA) as catalyst and methanol–water mixture as green solvent. All reactions were carried out in a short period of time and the products were obtained in moderate‐to‐high yields and their structures were confirmed using 1 H‐NMR, 13 C‐NMR, Fourier‐transform infrared (FT‐IR), and mass spectroscopic techniques. AChE and BChE enzyme inhibitions were obtained from the lowest Ki and IC 50 values. The lowest Ki values of compounds 4j , 4d , 4e , and 4m   were determined to be 4.84 ± 1.96 µM, 6.32 ± 1.75 µM, 7.21 ± 3.27 µM, and 7.48 ± 0.42 µM against AChE, while the lowest K i values of compounds 4d , 4f, and 4j were determined to be 4.74 ± 1.98 µM, 5.87 ± 2.11 µM, and 5.67 ± 1.96 µM against BChE, respectively. Finally, in silico molecular docking interactions were carried out by using AutoDock Vina software. The low binding energy values of the compounds ( 4a ‐ 4n ) against AChE and BChE enzymes indicated their high inhibitory effectiveness.