In Silico Design and In Vitro Assessment of Bicyclic Trifluoromethylated Pyrroles as New Antibacterial and Antifungal Agents.

QSAR studies on the number of compounds tested as S. aureus inhibitors were performed using an interactive Online Chemical Database and Modeling Environment (OCHEM) web platform. The predictive ability of the developed consensus QSAR model was q2=0.79±0.02. The consensus prediction for the external evaluation set afforded high predictive power (q2=0.82±0.03). The models were applied to screen a virtual chemical library with anti-S. aureus activity. Six promising new bicyclic trifluoromethylated pyrroles were identified, synthesized and evaluated in vitro against S. aureus, E. coli, and A. baumannii for their antibacterial activity and against C. albicans, C. krusei and C. glabrata for their antifungal activity. The synthesized compounds were characterized by 1H, 19F, and 13C NMR and elemental analysis. The antimicrobial activity assessment indicated that trifluoromethylated pyrroles 9 and 11 demonstrated the greatest antibacterial and antifungal effects against all the tested pathogens, especially against multidrug-resistant strains. The acute toxicity of the compounds to Daphnia magna ranged from 1.21 to 33.39 mg/L (moderately and slightly toxic). Based on the docking results, it can be suggested that the antibacterial and antifungal effects of the compounds can be explained by the inhibition of bacterial wall component synthesis.

In Silico, in Vitro and in Vivo Study of Substituted Imidazolidinone Sulfonamides as Antibacterial Agents.

New substituted imidazolidinone sulfonamides have been developed using a rational drug design strategy. Predictive QSAR models for the search of new antibacterials were created using the OCHEM platform. Regression models were applied to verify a virtual chemical library of new imidazolidinone derivatives designed to have antibacterial activity. A number of substituted imidazolidinone sulfonamides as effective antibacterial agents were identified by QSAR prediction, synthesized and characterized by spectral and elemental, and tested in vitro. Six studied compounds have shown the highest in vitro antibacterial activity against Gram-negative E. coli and Gram-positive S. aureus multidrug-resistant strains. The in vivo acute toxicity of these imidazolidinone sulfonamides based on the LC50 value ranged from 16.01 to 44.35 mg/L (slightly toxic compounds class). The results of molecular docking suggest that the antibacterial mechanism of the compounds can be associated with the inhibition of post-translational modification processes of bacterial peptides and proteins.

Inhibition of glutathione S-transferases by photoactive calix[4]arene α-ketophosphonic acids.

Calix[4]arenes bearing photoactive α-ketophosphonic acid groups at the upper rim of the macrocycle were synthesized and evaluated as inhibitors of glutathione S-transferases. Irradiation at 365 nm increased the inhibition effects of some macrocyclic compounds on GSTP1-1 by more than two orders of magnitude. Calix[4]arene bis-α-ketophosphonic acids substituted at the lower rim by n-propyl or n-butyl groups showed IC50 values in the low micromolar range. Kinetics of the irreversible inhibition was described by pseudo-first-order rate constants dependent on inhibitor concentration. The values of second-order rate constants were higher for glutathione S-transferase from human placenta than for the enzyme from equine liver. Molecular docking suggested that photoactive macrocyclic compounds cover the active site of glutathione S-transferase, providing the possibility to modify the catalytically important amino acid residues during irradiation.