Antibacterial and antibiofilm activity of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H pyrazoles and thiazoles in multidrug-resistant pathogens.

To find novel antibiotic drugs, six 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H derivatives named 1b, 1d (pyrazoles), 2a, 2b, 2c, and 2d (thiazoles) were evaluated in silico and in vitro. The in silico analyses were based on ADME pharmacokinetic parameters (absorption, distribution, metabolism, and excretion). The in vitro antibacterial activity was evaluated in Gram-positive and Gram-negative species (Staphylococcus aureus ATCC® 25904, Staphylococcus epidermidis ATCC® 35984, Klebsiella pneumoniae ATCC® 700603, and Acinetobacter baumannii ATCC® 19606), by determination of minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), kinetics curve, and antibiofilm assays. As results, the azoles have activity against the Gram-negative species K. pneumoniae ATCC® 700603 and A. baumannii ATCC® 19606. No antibacterial activity was observed for the Gram-positive bacteria evaluated. Thus, the azoles were evaluated against clinical isolates of K. pneumoniae carbapenemase (KPC) and A. baumannii multidrug-resistant (Ab-MDR). All azoles have antibacterial activity against Ab-MDR isolates (Gram-negative) with MIC values between 512 µg/mL and 1,024 µg/mL. Against KPC isolates the azoles 1b, 1d, and 2d present antibacterial activity (MIC = 1,024 µg/mL). In the kinetics curve assay, the 1b and 1d pyrazoles reduced significantly viable cells of Ab-MDR isolates and additionally inhibited 86.6 to 95.8% of the biofilm formation. The in silico results indicate high possibility to permeate the blood-brain barrier (2b) and was predict human gastrointestinal absorption (all evaluated azoles). Considering that the research and development of new antibiotics is a priority for drug-resistant pathogens, our study revealed the antibacterial and antibiofilm activity of novel azoles against K. pneumoniae and A. baumannii pathogens.

Bioprospection of novel synthetic monocurcuminoids: Antioxidant, antimicrobial, and in vitro cytotoxic activities.

The irrational use of medications has increased the incidence of microbial infections, which are a major threat to public health. Moreover, conventional therapeutic strategies are starting to become ineffective to treat these infections. Hence, there is a need to develop and characterize novel antimicrobial compounds. Phytochemicals are emerging as a safe and accessible alternative to conventional therapeutics for treating infectious diseases. Curcumin is extracted from the dried rhizome of the spice turmeric (Curcuma longa (Zingiberaceae)). However, the bioavailability of curcumin is low owing to its lipophilic property and thus has a low therapeutic efficacy in the host. A previous study synthesized structural variants of curcumin, which are called monocurcuminoids (CNs). CNs are synthesized based on the chemical structure of curcumin with only one methyl bridge. The biological activities of four previously synthesized CNs (CN59, CN63, CN67, and CN77), curcumin, and turmeric powder were examined in this study. Gas chromatography-tandem mass spectrometry analysis of curcumin and turmeric powder revealed similar peaks, which indicated the presence of curcumin in turmeric powder. The antioxidant activity of the test compounds was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays. The ABTS radical scavenging activities of the test compounds were similar to those of vitamin C. The minimum inhibitory concentration (MIC) values of the test compounds against seven microbial strains were in the range of 4.06-150 µg/mL. The MIC value was equal to minimum bactericidal concentration value for CN63 (150 µg/mL) and CN67 (120 µg/mL) against Staphylococcus aureus. The treatment combination of CN77 (8.75 or 4.37 µg/mL) and turmeric powder (9.37 or 4.68 µg/mL) exerted synergistic growth-inhibiting effects on Aeromonas hydrophila, Candida albicans, and Pseudomonas aeruginosa. Photodynamic therapy using 2X MIC of CN59 decreased the growth of Enterococcus faecalis by 4.18-fold compared to the control group and completely inhibited the growth of Escherichia coli. The results of the hemolytic assay revealed that the test compounds were not cytotoxic with half-maximal inhibitory concentration values ranging from 49.65-130.9 µM. The anticoagulant activity of most compounds was comparable to that of warfarin but higher than that of heparin. This indicated that these compounds target the intrinsic coagulation pathway. These results demonstrated that these CNs are a safe and promising alternative for curcumin.