The increasing threat of antimicrobial resistance to all currently available therapeutic agents has urged the development of novel antimicrobials. In this context, a series of new benzoylthiourea derivatives substituted with one or more fluorine atoms and with the trifluoromethyl group have been tested, synthesized, and characterized by IR, NMR, CHNS and crystal X-ray diffraction. The molecular docking has provided information regarding the binding affinity and the orientation of the new compounds to Escherichia coli DNA gyrase B. The docking score predicted the antimicrobial activity of the studied compounds, especially against E. coli, which was further demonstrated experimentally against planktonic and biofilm embedded bacterial and fungal cells. The compounds bearing one fluorine atom on the phenyl ring have shown the best antibacterial effect, while those with three fluorine atoms exhibited the most intensive antifungal activity. All tested compounds exhibited antibiofilm activity, correlated with the trifluoromethyl substituent, most favorable in para position.

Fifty (50) phytocompounds from several subclasses of polyphenols, chosen based on their abundance in the plant world, were analyzed through density functional methods, using computational tools to evaluate their oral availability and particular bioactivity on several cell modulators; key descriptors and molecular features related to the electron density and electrostatic potential for the lowest energy conformers of the investigated molecules were computed. An analysis of the bioactivity scores towards six cell modulators (GPCR ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor and enzyme inhibitor) was also achieved, in the context of investigating their potential side effects on the human digestive processes. Summarizing, computational results confirmed in vivo and in vitro data regarding the high bioavailability of soy isoflavones and better bioavailability of free aglycones in comparison with their esterified and glycosylated forms. However, by a computational approach analyzing Lipinski’s rule, apigenin and apigenin-7-O-rhamnoside, naringenin, hesperetin, genistein, daidzin, biochanin A and formonetin in the flavonoid series and all hydroxycinnamic acids and all hydroxybenzoic acids excepting ellagic acid were proved to have the best bioavailability data; rhamnoside derivatives, the predominant glycosides in green plants, which were reported to have the lowest bioavailability values by in vivo studies, were revealed to have the best bioavailability data among the studied flavonoids in the computational approach. Results of in silico screening on the phenolic derivatives series also revealed their real inhibitory potency on the six parameters studied, showing a remarkable similitude between the flavonoid series, while flavonoids were more powerful natural cell modulators than the phenyl carboxylic acids tested. Thus, it can be concluded that there is a need for supplementation with digestive enzymes, mainly in the case of individuals with low digestive efficiency, to obtain the best health benefits of polyphenols in humans.

Several derivatives of benzoic acid and semisynthetic alkyl gallates were investigated by an in silico approach to evaluate their potential antiviral activity against SARS-CoV-2 main protease. Molecular docking studies were used to predict their binding affinity and interactions with amino acids residues from the active binding site of SARS-CoV-2 main protease, compared to boceprevir. Deep structural insights and quantum chemical reactivity analysis according to Koopmans’ theorem, as a result of density functional theory (DFT) computations, are reported. Additionally, drug-likeness assessment in terms of Lipinski’s and Weber’s rules for pharmaceutical candidates, is provided. The outcomes of docking and key molecular descriptors and properties were forward analyzed by the statistical approach of principal component analysis (PCA) to identify the degree of their correlation. The obtained results suggest two promising candidates for future drug development to fight against the coronavirus infection.

The main goal of this chapter is to reveal the importance of molecular structure analysis with specific computational tools using quantum chemistry methods based on density functional theory (DFT) with focus on pharmaceutical compounds. A wide series of molecular properties and descriptors related with chemical reactivity is discussed and compared for small organic molecules (e.g., quinolones, oxazolidinones). Structural and physicochemical information, important for quantitative structure-property relationships (QSPR) and quantitative structure-activity relationships (QSAR) modeling analysis, obtained using Spartan 14 software Wavefunction, are reported. Thus, by a computational procedure including energy minimization and predictive calculations, values of quantum chemical parameters and molecular properties related with electronic charge distribution are reported and discussed. Frontier molecular orbitals energy diagram and their bandgap provide indications about chemical reactivity and kinetic stability of the molecules. Derived parameters (ionization potential (I), electron affinity (A), electronegativity (χ), global hardness (η), softness (σ), chemical potential (μ) and global electrophilicity index (ω)) are given. Also, graphic quantities are reported: electrostatic potential maps, local ionization potential maps and LUMO maps, as visual representation of the chemically active sites and comparative reactivity of different constitutive atoms.