s-Triazine Derivatives Functionalized with Alkylating 2-Chloroethylamine Fragments as Promising Antimicrobial Agents: Inhibition of Bacterial DNA Gyrases, Molecular Docking Studies, and Antibacterial and Antifungal Activity.

The spectrum of biological properties of s-triazine derivatives is broad and includes anti-microbial, anti-cancer, and anti-neurodegenerative activities, among others. The s-triazine molecule, due to the possibility of substituting three substituents, offers many opportunities to obtain hybrid compounds with a wide variety of activities. A group of 1,3,5 triazine derivatives containing a dipeptide, 2-ethylpiperazine, and a methoxy group as substituents was screened for their antimicrobial activity. An in vitro study was conducted on pathogenic bacteria (E. coli, S. aureus, B. subtilis, and M. luteus), yeasts (C. albicans), and filamentous fungi (A. fumigatus, A. flavus, F. solani, and P. citrinum) via microdilution in broth, and the results were compared with antibacterial (Streptomycin) and antifungal (Ketoconazole and Nystatin) antibiotics. Several s-triazine analogues have minimal inhibitory concentrations lower than the standard. To confirm the inhibitory potential of the most active compounds against gyrases E. coli and S. aureus, a bacterial gyrases inhibition assay, and molecular docking studies were performed. The most active s-triazine derivatives contained the -NH-Trp(Boc)-AlaOMe, -NH-Asp(OtBu)-AlaOMe, and -NH-PheOMe moieties in their structures.

Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents.

Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds (1-18) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (hDHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds 13-14 (49.89% and 43.85%) and 17-18 (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2, and poly (dG-dC)2. With the exception of compounds 9 (IC50 = 56.05 µM) and 11 (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against hDHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards hDHFR. Derivatives 2, 6, 13, 14, and 16 were found to be the most potent hDHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30.

On-The-Fly Kinetics of the Hydrogen Abstraction by Hydroperoxyl Radical: An Application of the Reaction Class Transition State Theory.

A Reaction Class Transition State Theory (RC-TST) is applied to calculate thermal rate constants for hydrogen abstraction by OOH radical from alkanes in the temperature range of 300-2500 K. The rate constants for the reference reaction C2H6 + ∙OOH → ∙C2H5 + H2O2, is obtained with the Canonical Variational Transition State Theory (CVT) augmented with the Small Curvature Tunneling (SCT) correction. The necessary parameters were obtained from M06-2X/aug-cc-pVTZ data for a training set of 24 reactions. Depending on the approximation employed, only the reaction energy or no additional parameters are needed to predict the RC-TST rates for other class representatives. Although each of the reactions can in principle be investigated at higher levels of theory, the approach provides a nearly equally reliable rate constant at a fraction of the cost needed for larger and higher level calculations. The systematic error is smaller than 50% in comparison with high level computations. Satisfactory agreement with literature data, augmented by the lack of necessity of tedious and time consuming transition state calculations, facilitated the seamless application of the proposed methodology to the Automated Reaction Mechanism Generators (ARMGs) programs.

Kinetics of the Hydrogen Abstraction PAH + •OH → PAH Radical + H2O Reaction Class: An Application of the Reaction Class Transition State Theory (RC-TST) and Structure-Activity Relationship (SAR).

A reaction class transition state theory (RC-TST) augmented with structure-activity relationship (SAR) methodology is applied to predict high-pressure limit thermal rate constants for hydrogen abstraction by •OH radical from polycyclic aromatic hydrocarbons (PAHs) reaction class in the temperature range of 300-3000 K. The rate constants for the reference reaction of C6H6 + •OH → C6H5 + H2O is calculated by the canonical variational transition state theory (CVT) with small curvature tunneling (SCT). Only the reaction energy is needed to predict RC-TST rates for other processes within the family, the parameters needed were obtained from M06-2X/cc-pVTZ data for a training set of 34 reactions. The systematic error of the resulting RC-TST rates is smaller than 50% in comparison with explicit rate calculations, which facilitates application of the proposed methodology to the automated reaction mechanism generators (ARMGs) schemes.

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs.

A new series of trimethoprim (TMP) analogs containing amide bonds (1-6) have been synthesized. Molecular docking, as well as dihydrofolate reductase (DHFR) inhibition assay were used to confirm their affinity to bind dihydrofolate reductase enzyme. Data from the ethidium displacement test showed their DNA-binding capacity. Tests confirming the possibility of DNA binding in a minor groove as well as determination of the association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2 and poly (dG-dC)2. Additionally, the mechanism of action of the new compounds was studied. In conclusion, some of our new analogs inhibited DHFR activity more strongly than TMP did, which confirms, that the addition of amide bonds into the analogs of TMP increases their affinity towards DHFR.