Biochemical Basis of the Antimicrobial Activity of Quinazolinone Derivatives in the Light of Insights into the Features of the Chemical Structure and Ways of Binding to Target Molecules. A Review

• Published in: Doklady. Chemistry 2023-05, Vol.510 (1), p.107-129
• Main Authors: Samotrueva, M. A., Starikova, A. A., Bashkina, O. A., Tsibizova, A. A., Borisov, A. V., Merezhkina, D. V., Tyurenkov, I. N., Ozerov, A. A.
• Format: Article
• Language: English
• Subjects: Antiinfectives and antibacterials; Antimicrobial agents; Cell membranes; Chemical bonds; Chemical reactions; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Complex compounds; Efflux; Histidine; Hydrogen bonds; Industrial Chemistry/Chemical Engineering; Kinases; Pathogens; Penicillin; Pharmaceuticals; Pharmacology; Proteins; Quinazolinones; Signalling systems
• ISSN: 0012-5008; 1608-3113
• DOI: 10.1134/S0012500823600463

The review characterizes the role of the basic targets of antibacterial agents: efflux pumps, enzymes (DNA gyrases as a subclass of topoisomerases, homoserine transacetylase, various classes of sortases, aromatase, lipoteichoic synthase, polyketide synthase, pantothenate synthetase, acetyl-CoA carboxylase, sensory histidine kinase, kinase, cyclooxygenase, etc.), penicillin-binding protein, quorum sensing systems, and adhesins in significant biochemical processes of pathogen maintenance and virulence manifestation. It has been demonstrated that a chemical can exhibit the antimicrobial effect when it binds to protein molecules responsible for pathogenicity of a microorganism. The role of quinazolinone derivatives exhibiting high reactivity and stability in chemical processes and characterized by a wide spectrum of pharmacological activity, including antimicrobial activity with respect to various Gram-positive and Gram-negative bacteria, has been determined. It has been shown that structural changes induced by introducing various substituents contribute to a change in the degree of hydrophilicity and, as a result, determine a different degree of penetration of the drug through the cell membrane, the ability to form intermediate complex compounds stabilized by a system of hydrogen bonds, as well as by van der Waals and stacking interactions, with enzymatic targets, receptor regulatory proteins, and signaling systems of pathogen cells. The results of mathematical modeling of the mechanism of action of the compounds synthesized by the authors of the article are discussed. The possibility of creating a pharmaceutical with a pronounced antimicrobial activity by combining the quinazolinone core with various heterocyclic derivatives is assessed. The considered regularities are of practical importance for the researchers in the field of medicinal chemistry, organic synthesis, biotechnology, clinical pharmacology, and pharmaceutical chemistry and technology, whose efforts are aimed at designing a new drug.