Alla Andreevna Starikova

The review describes strategies for the synthetic search for new derivatives that exhibit activity against , including those that involve modification of the structure of substances used in modern medical practice. An approach based on the use of a pyrimidine nucleus as a basis for constructing a molecule with a pronounced antibacterial effect is characterized as promising in the design of new antimicrobial agents. The importance of introducing heterocyclic substituents into the molecule, which are related to “privileged” pharmacophores, is substantiated. It is shown that the construction of the structure of compounds by introducing these fragments, which are present in the molecule of compounds exhibiting a wide range of pharmacological activity, is determined by the concept of obtaining medicinal substances with a multitarget effect. The paper presents the author’s methods for obtaining substances with an anti- effect, based on the modification of the structure of previously studied compounds by introducing a heterocyclic substituent.

   The aim of the study was to study the antimicrobial activity of new quinazoline derivatives against Staphylococcus aureus with the prediction of the structure-activity relationship.   Material and methods. Primary antimicrobial screening of new quinazoline derivatives was carried out using the serial dilution method. The number of colonies was counted using the BIOMIC V3 software and hardware complex (Giles Scientific, USA). For statistical processing of the study results, the StatTech program (Russia) was used using the parametric method with the definition of Student’s t-test with Bonferroni correction. Prediction of direct biological targets was carried out using the PASS software tool. Structural parameters and octanol/water partition coefficient (LogP) were determined using ProTox 3.0.   Results. The bacteriostatic effect of the substance VMA-23-10 against S. aureus was established in dilutions of 128, 64 and 32 μg/ml. It has been shown that VMA-23-10, distinguished by the presence of an isopropyl radical in the molecule, is characterized by greater lipophilicity. The mechanism of action of the substance VMA-23-10 was predicted.   Conclusions. The conducted study made it possible to identify the leading compound among the studied derivatives, which exhibits a bacteriostatic effect against S. aureus. The difference in lipophilicity between VMA-23-10 and other molecules studied probably determines their different ability to penetrate the cell membrane of the pathogen. The predicted probability of the effect of the compound VMA-23-10 on serine/threonine protein kinases suggests that it exhibits an antimicrobial effect due to disruption of peptidoglycan synthesis, as well as suppression of the process of biofilm formation.

Introduction. Multi-resistance of Klebsiella pneumoniae to known antimicrobial agents determines the need for urgent development of new drugs ex-hibiting an antibacterial effect. Compounds used in the treatment of non-infectious pathologies, affecting various protein targets and realizing the "anti-microbial potential", seem promising in the search for new derivatives. Of particular interest is the predicted high probability of inhibition of sterol-27-hydroxylase cytochrome P-450 (CYP27A1) by new derivatives of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione with the possibility of preventing the processes of conversion of cholesterol, as the main component of macrophage lipid rafts on which pathogen adhesion occurs. Activation of phag-ocytosis, as well as disruption of the formation of the polysaccharide capsule of K. pneumoniae, is considered one of the probable mechanisms of the antibacterial effect of the studied substances. The aim – determination of reactivity parameters and potential pharmacological activity of quinazolin-4(3H)-one and quinazolin-2,4(1H,3H)-dione deriva-tives; prediction of the mechanism of antimicrobial action of new quinazolinones against K. pneumoniae based on the formation of a complex with CYP27A1. Material and methods. The probability of CYP27A1 inhibition by new quinazolinone derivatives was predicted using the PASS program. Quantum chemical parameters were calculated using the parameterized PM7 method in the MOPAC 2016 program. The structural characteristics of the studied substances were determined using ProTox 3.0. Some pharmacokinetic parameters were assessed using the admetSAR software tool. A three-dimensional model of the protein structure of CYP27A1 was generated on the AlphaFold platform; optimal conformation and further clustering of protein sequences using the MMseqs2 and Foldseek algorithms. The determination of the energy parameters of the intermolecular complexes “quinazolinone - CYP27A1”, as well as the identification of the amino acid sites to which the quinzolinone derivative binds, was carried out using the Swiss Dock sys-tem. Results. Quantum-chemical and structural parameters of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione derivatives, as well as their intermo-lecular complexes with CYP27A1, were established, and some pharmacokinetic parameters of the studied substances were predicted. Conclusions. Control of the interaction of the compound with the lipid raft of the macrophage and an increase in the degree of penetration of the path-ogen into its cell can be considered as a probable mechanism of the antibacterial action of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione de-rivatives against Klebsiella pneumoniae. An increase in the number of naphthyl radicals in their molecule leads to a decrease in reactivity. Naphthyl rad-icals do not act as a pharmacophore of antimicrobial action against K. pneumoniae.

To date, quinazoline alkaloids of natural origin, as well as synthetic derivatives based on them, whose structure contains an aromatic heterocyclic system including a pyrimidine cycle and a benzoin ring connected to it, are promising according to the criterion of the optimal profile of pharmacological activity. Currently, several hundred compounds of the quinazoline nature have been identified with a wide range of biological activities, including psychotropic (antidepressant, antipsychotic, sedative, hypnotic, anticonvulsant, etc.), antiplatelet, hypotensive, anti-inflammatory, antioxidant and other types of activities. It has been proven that quinazoline alkaloids have an anti-infectious effect, exhibiting antibacterial, antifungal, antiparasitic, antiviral and other effects. The alkaloids of the quinazoline and quinazolinone series were originally isolated from plant sources. Currently, sources of animal and bacterial origin are used. Interest in quinazolines and quinazolinones, as compounds with a unique chemical structure and a wide range of pharmacological action, is constantly growing. The purpose of the study is to analyze the results obtained by domestic and foreign scientists in the study of the pharmacological activity of alkaloids – derivatives of quinazoline of natural origin and compounds synthesized based on their structure, as well as to assess and predict the degree of safety of use in medical practice using data from literary sources and calculated using computer modeling methods. The paper substantiates the prospects of using alkaloids of quinazolinone derivatives not only as medicines, but also as starting compounds for the synthesis of new derivatives showing pronounced activity.

Due to the rapid growth in the number of patients with diabetes in a complicated epidemiological picture, the question of the possibility of exposure of a substance to several targets becomes more important. It is noted that the most common infectious diseases in patients with diabetes mellitus are infections of the respiratory and urinary tract, skin and soft tissues, diabetic foot ulcers, otitis media and periodontal infections. Antimicrobial agents can have both direct and indirect hypoglycemic effects. Quinazolinones belonging to the group of heterocyclic derivatives exhibit a wide range of pharmacological activity. The use of the PASS program for the purpose of computer prediction of pharmacological activity showed a high probability of the hypoglycemic effect of new derivatives. The obtained results motivated the authors to search for the relationship between antimicrobial action and hypoglycemic effect within the general direction of studying the multi-targeting of drug ligands. Analysis of the literature data, as well as own studies of new quinazolinone derivative pharmacological activity make it possible to divide all ligands into functional groups that cause additional binding to the target molecule. The quinazolinone fragment, characterized by the uniqueness of its structure, can be reasonably attributed to multi-target ligands. The triazole cycle and the sulfonamide group can also purposefully bind to the target molecule. A carbamide residue, a fragment of sulfonylurea and an acetamide group, depending on the structure of the substance they are part of, can function both as a specific ligand and as a functional group involved in the stabilization of the intermediate transition state. The results obtained by the authors, as well as other researchers, allow us to formulate an assumption about the relationship between the mechanisms of antimicrobial and hyperglycemic activity.

Introduction. This article is devoted to the study of the influence of the teacher’s activity on the level of motivation of students of higher educational institutions. Purpose: to study the characteristics of the motivation of students studying in the specialty 33.05.01. “Pharmacy”. Materials and methods. The study is based on a preliminary study and analysis of data obtained by domestic scientists and presented in the sources of psychological and pedagogical literature. The implementation of the tasks set was carried out in the course of a sociological survey. The results were processed using the methods of mathematical statistics. Results. A technology has been developed to increase the motivational level of students in the form of an algorithm, introduced into the work of the teaching staff of the Department of Chemistry of the Faculty of Pharmacy in the preparation of future pharmacists. Scope. The algorithm of professional orientation of students developed by the authors can be used when teaching students in a higher educational institution. The applicability of the obtained statistically significant results as a basis for further work on increasing students’ motivation for the implementation of educational activities is substantiated. Conclusion. It was revealed that changes in the deep motives of students occurred when the teaching staff used new methods that make it possible to modernize the standard learning process, taking into account the interests and psychological characteristics of future pharmacists.

Relevance. Tuberculosis remains one of the main causes of disability and mortality from infectious diseases worldwide. The discovery of phenotypi-cally tolerant subpopulations of pathogen persisters has called into question the possibilities of known anti-tuberculosis drugs. In this connection, the search and development of new effective anti-tuberculosis drugs is an important direction in the development of modern pharmacology. Currently, it is relevant to consider substances of the quinazoline nature as antimicrobial agents that exhibit antitubercular activity. The aim of the work is computer modeling of the interaction of new derivatives of quinazoline–4(3H)–oh with NAD(H) in order to predict the possibility of influencing the fatty acid synthase (FAS) Mycobacterium. Material and methods. Modeling of intermolecular complexes in the interaction system of new derivatives of quinazoline-4(3H)–on – VMA–17–04 and VMA–13–05 with the oxidized form of NAD+ was carried out using the quantum chemical semi-empirical PM7 method implemented in the MOPAC 2016 program. Conclusions. The VMA–13–05 derivative, being in stable conformation I, forms an adduct with NAD+ having optimal energy characteristics. This inter-action can be considered as one of the stages of the biochemical pathway of suppressing the activity of FAS synthase, which takes part in the synthe-sis of mycolic acids and leads to the death of Mycobacterium cells.

An Erratum to this paper has been published: https://doi.org/10.1134/S0012500823970013

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.

Aim: To study the effect of new synthesized pyrimidine derivatives on the growth of Mycobacterium lufu (M. lufu) and Mycobacterium tuberculosis (M. tuberculosis) when cultivated on Shkolnikova’s medium.Materials and methods. The objects of research were new synthesized derivatives of 6 samples of derivatives of pyrimidine - 5-(arylmethylidene)-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-trions under laboratory codes TAG1, TAG2, TAG3, TAG4, TAG5, TAG6 and 7 samples of 5-(getarylmethylidene)-2,4,6-pyrimidine-2,4,6(1H, 3H, 5H)-trions under the laboratory codes TAG7, TAG8, TAG9, TAG10, TAG11, TAG12, TAG13. M. lufu and M. tuberculosisH37Rv strains were used as test cultures. The antimycobacterial activity of the studied compounds was studied by the method of serial dilutions.Research results. All studied compounds were found to exhibit antimycobacterial activity. The greatest inhibitory effect against M. lufu was noted for TAG1, TAG4, TAG7, TAG12, and TAG13, which was comparable to that of the reference drug dapsone. By the nature of the inhibitory effect on the growth of M. tuberculosis, the compounds under the laboratory codes TAG 1, TAG 4, TAG 7 and TAG13 were comparable to isoniazid, and the effect of the TAG3 compound was even slightly superior to the reference drug.Conclusion. Among the studied new synthesized pyrimidine derivatives, compounds under the laboratory codes TAG1, TAG4, TAG 7 and TAG13 have the most pronounced antimicrobial activity both against M. lufu and M. tuberculosis, which allows us to consider them as the most promising substances for further research on the search for antimycobacterial, including antileprosy drugs.