pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2021-9-4-318-329pmedpharm-885Research ArticleФАРМАКОЛОГИЯ И КЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯPHARMACOLOGY AND CLINICAL PHARMACOLOGYИЗУЧЕНИЕ АНТИМИКРОБНОЙ АКТИВНОСТИ НОВЫХ ХИНАЗОЛИН-4(3Н)-ОНОВ ПО ОТНОШЕНИЮ К STAPHYLOCOCCUS AUREUS И STREPTOCOCCUS PNEUMONIAEANTIMICROBIAL ACTIVITY STUDY OF NEW QUINAZOLIN-4(3H)-ONES AGAINST STAPHYLOCOCCUS AUREUS AND STREPTOCOCCUS PNEUMONIAEhttps://orcid.org/0000-0001-5336-4455СамотруеваМ. А.SamotruevaM. A.

доктор медицинских наук, профессор, заведующая кафедрой фармакогнозии, фармацевтической технологии и биотехнологии 

Doctor of Sciences (Medicine), Professor, Head of the Department of Pharmacognosy, Pharmaceutical Technology and Biotechnology

ms1506@mail.ruhttps://orcid.org/0000-0002-4721-0959ОзеровА. А.OzerovA. A.

доктор химических наук, профессор, заведующий кафедрой фармацевтической и токсикологической химии 

Doctor of Sciences (Chemistry), Professor, Head of the Department of Pharmaceutical and Toxicological Chemistry

prof_ozerov@yahoo.comhttps://orcid.org/0000-0002-5210-5248СтариковаА. А.StarikovaA. A.

ассистент кафедры химии фармацевтического факультета 

Assistant, Department of Chemistry, Faculty of Pharmacy

alhimik.83@mail.ruhttps://orcid.org/0000-0002-3867-8330ГабитоваН. М.GabitovaN. M.

ассистент кафедры фармакогнозии, фармацевтической технологии и биотехнологии ФГБОУ ВО «Астраханский государственный медицинский университет» Минздрава России, младший научный сотрудник ФГБУ «НИИЛ» Минздрава России

Assistant, Department of Pharmacognosy, Pharmaceutical Technology and Biotechnology, Astrakhan State Medical University, Junior Researcher of Scientific Research Institute for the Study of Leprosy

narmina85@inbox.ruhttps://orcid.org/0000-0002-9848-7149МережкинаД. В.MerezhkinaD. V.

аспирант кафедры фармацевтической и токсикологической химии

Postgraduate student, Department of Pharmaceutical and Toxicological Chemistry

merezhkinad@mail.ruhttps://orcid.org/0000-0002-9994-4751ЦибизоваА. А.TsibizovaA. A.

кандидат фармацевтических наук, доцент кафедры фармакогнозии, фармацевтической технологии и биотехнологии

Candidate of Sciences (Pharmacy), Associate Professor, Department of Pharmacognosy, Pharmaceutical Technology and Biotechnology

sasha3633@yandex.ruhttps://orcid.org/0000-0001-7574-3923ТюренковИ. Н.TyurenkovI. N.

доктор медицинских наук, профессор, член-корреспондент Российской академии наук, заведующий кафедрой фармакологии и фармации Института непрерывного медицинского и фармацевтического образования факультета усовершенствования врачей

Doctor of Sciences (Medicine), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Pharmacology and Pharmacy of the Institute of Continuous Medical and Pharmaceutical Education, the Faculty of Advanced Training of Physicians, Volgograd State Medical University

fibfuv@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Астраханский государственный медицинский университет» Министерства здравоохранения Российской Федерации 414000, Россия, г. Астрахань, ул. Бакинская, 121РоссияАstrakhan State Medical University 121, Bakinskaya Str., Astrakhan, Russia, 414000Russian Federation1. Федеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской Федерации 400131, Россия, г. Волгоград, пл. Павших Борцов, 1 2. Государственное бюджетное учреждение «Волгоградский медицинский научный центр» 400131, Россия, г. Волгоград, пл. Павших Борцов, 1Россия1. Volgograd State Medical University 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131 2. Volgograd Medical Research Center 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131Russian Federation1. Федеральное государственное бюджетное образовательное учреждение высшего образования «Астраханский государственный медицинский университет» Министерства здравоохранения Российской Федерации 414000, Россия, г. Астрахань, ул. Бакинская, 121 2. Федеральное государственное бюджетное учреждение «Научно-исследовательский институт по изучению лепры» Министерства здравоохранения Российской Федерации 414057, Россия, г. Астрахань, пр. Николая Островского, 3Россия1. Аstrakhan State Medical University 121, Bakinskaya Str., Astrakhan, Russia, 414000 2. Scientific Research Institute for the Study of Leprosy 3, Nikolay Ostrovsky Ave., Astrakhan, Russia, 414057Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской Федерации 400131, Россия, г. Волгоград, пл. Павших Борцов, 1РоссияVolgograd State Medical University 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131Russian Federation20210809202194318329Copyright © Самотруева М.А., Озеров А.А., Старикова А.А., Габитова Н.М., Мережкина Д.В., Цибизова А.А., Тюренков И.Н., 20212021Самотруева М.А., Озеров А.А., Старикова А.А., Габитова Н.М., Мережкина Д.В., Цибизова А.А., Тюренков И.Н.Samotrueva M.A., Ozerov A.A., Starikova A.A., Gabitova N.M., Merezhkina D.V., Tsibizova A.A., Tyurenkov I.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/885

Производные хиназолин-4(3Н)-она, проявляющие широкий спектр фармакологической активности, представляют перспективный класс веществ, используемых для получения антибактериальных средств, что особенно актуально в условиях возникновения резистентности патогенных микроорганизмов к используемым в медицине лекарственным препаратам. Доказано, что соединения, имеющие в молекуле нафтильный радикал, а также амидную группу, связанную с бензольным кольцом, в качестве заместителей хиназолинона, характеризуются выраженной противомикробной активностью в отношении Staphylococcus aureus и Streptococcus pneumoniae.

Цель

Цель. Первичный микробиологический скрининг антимикробной активности in vitro новых производных хиназолин-4(3Н)-она по отношению к Staphylococcus aureus и Streptococcus pneumoniae, а также оценка взаимосвязи между проявляемым фармакологическим действием и структурным преобразованием молекулы вещества, липофильностью и возможностью формирования устойчивости к ним.

Материалы и методы

Материалы и методы. Экспериментальные исследования были выполнены с использованием общеизвестных нозокомиальных возбудителей инфекционно-воспалительных заболеваний Staphylococcus aureus и Streptococcus pneumoniae методом серийных разведений.

Результаты

Результаты. Соединение, содержащее в структуре нафтильный радикал, вносящий вклад в увеличение гидрофобности вещества и его растворимости в мембране бактериальной клетки, обладает бактериостатическим действием как в отношении Staphylococcus aureus, так и к Streptococcus pneumoniae. Сходный фармакологический эффект проявляет производное с амидной группой в качестве заместителя хиназолинонового ядра, связанной с фенильным радикалом, которая, вероятно, способствует увеличению степени связывания с активными сайтами ферментов, принимающих участие в процессах репликации ДНК и синтеза белков. Очевидно, повышенная липофильность, способствующая лучшему связыванию с белком оттока, не может служить объективной характеристикой возможности возникновения резистентности патогенов к данному веществу.

Заключение

Заключение. Среди синтезированных соединений были выявлены вещества-лидеры, проявляющее антимикробную активность в отношении Staphylococcus aureus и Streptococcus pneumoniae. Оценка химического строения позволила обосновать их фармакологическое действие и сделать выводы о возможности развития устойчивости к нему у микробных клеток.

Quinazolin-4(3H)-one derivatives exhibiting a wide spectrum of a pharmacological activity, represent a promising class of substances used to obtain antibacterial agents, which is especially important in the context of the emergence of pathogenic microorganisms’ resistance to drugs used in medicine. It has been proved that compounds having a naphthyl radical in the molecule, as well as an amide group bound to the benzene ring as quinazolinone substituents, are characterized by a pronounced antimicrobial activity against Staphylococcus aureus and Streptococcus pneumoniae.

The aim of the research is a primary microbiological screening of the in vitro antimicrobial activity of new quinazolin-4(3H)-one derivatives against Staphylococcus aureus and Streptococcus pneumoniae, as well as the assessment of the relationship between the pharmacological effect and the structural transformation of the substance molecule, lipophilicity and the possibility of forming resistance to them.

Materials and methods

Materials and methods. The experimental studies have been carried out using well-known nosocomial pathogens of infectious and inflammatory diseases Staphylococcus aureus and Streptococcus pneumoniae by a serial dilution method.

Results

Results. A compound containing a naphthyl radical in its structure, which contributes to an increase in the hydrophobicity of the substance and its solubility in the membrane of a bacterial cell, has a bacteriostatic effect against both Staphylococcus aureus and Streptococcus pneumoniae. A similar pharmacological effect is exhibited by a derivative with an amide group as a substituent of the quinazolinone nucleus linked to a phenyl radical, which probably contributes to an increase in the degree of binding to active sites of enzymes involved in the DNA replication, and protein synthesis. Obviously, the increased lipophilicity, which promotes better binding to the efflux protein, cannot serve as objective characteristics of the emergence possibility of the pathogen’s resistance to this substance.

Conclusion

Conclusion. Among the synthesized compounds, the leading substances that exhibit an antimicrobial activity against Staphylococcus aureus and Streptococcus pneumonia, have been identified. The assessment of the chemical structure made it possible to substantiate their pharmacological action and draw conclusions about the possibility of developing resistance to it in microbial cells.

производные хиназолинонаантимикробная активностьсоединение-лидерэлектронодонорные центрыактивный сайт ферментаминимальная подавляющая концентрацияминимальная ингибирующая концентрациябактериостатическое действиебактерицидная активностьрезистентностьАТФ-зависимый эффлюксный насосплазмидытранспозоныбольшой мобильный элементquinazolinone derivativesantimicrobial activitylead-compoundelectron-donating centersenzyme active siteminimum inhibitory concentrationminimum suppressing concentrationbacteriostatic actionbactericidal activityresistanceATP-dependent efflux pumpplasmidstransposoneslarge mobile elementДанная работа выполнена в рамках государственного задания Министерства здравоохранения РФ в части проведения НИР по теме «Поиск и разработка перспективных соединений с антибактериальной активностью среди производных пиримидина для создания лекарственных препаратов» 48.2-2021.This work was carried out within the framework of the state assignment of the Ministry of Health of the Russian Federation in terms of conducting research on the topic “Search and development of promising compounds with antibacterial activity among pyrimidine derivatives for the creation of drugs” 48.2-2021.ReferencesAbrusán G., Marsh J.A. Ligands and receptors with broad binding capabilities have common structural characteristics: An antibiotic design perspective // J. Med. Chem. – 2019. – Vol. 62. – Р. 9357−9374. DOI: 10.1021/acs.jmedchem.9b00220.Abrusán G, Marsh JA. Ligands and Receptors with Broad Binding Capabilities Have Common Structural Characteristics: An Antibiotic Design Perspective. J Med Chem. 2019 Nov 14;62(21):9357–74. DOI: 10.1021/acs.jmedchem.9b00220.Beyzaei H., Ghasemi B. In vitro Antibacterial evaluation of newly synthesized heterocyclic compounds against Streptococcus Pneumoniae // Journal of Sciences, Islamic Republic of Iran. – 2018. – Vol. 29, No.3. – Р. 211–220. DOI: 10.22059/JSCIENCES.2018.67436.Beyzaei H, Ghasemi B. In vitro Antibacterial evaluation of newly synthesized heterocyclic compounds against Streptococcus Pneumoniae. Journal of Sciences, Islamic Republic of Iran. 2018; 29(3):211–20. DOI: 10.22059/JSCIENCES.2018.67436.Цибизова А.А., Ясенявская А.Л., Озеров А.А., Самотруева М.А., Тюренков И.Н. Оценка острой токсичности нового пиримидинового производного // Астраханский медицинский журнал. – 2021. – Т. 16, № 1. – С. 82–87. DOI: 10.17021/2021.16.1.82.87.Tsibizova AA, Yasenyavskaya AL, Ozerov AA, Samotrueva MA, Tyurenkov IN. Acute toxicity assessment a new pyrimidine derivative. Astrakhan medical journal. 2021;16(1):82–87. DOI: 10.17021/2021.16.1.82.87. RussianJampilek J. Heterocycles in Medicinal Chemistry // Molecules. – 2019. -Vol. 24. – Art. No.3839. DOI: 10.3390/molecules24213839.Jampilek J. Heterocycles in Medicinal Chemistry. Molecules. 2019 Oct 25;24(21):3839. DOI: 10.3390/molecules24213839.Patel P.R., Joshi H., Shah U., Bapna M., Patel B. New generation of quinazolinone derivatives as potent antimicrobial agents // Asian Pac. J. Health Sci. – 2021. – Vol. 8, No.2. – Р. 61–66. DOI: 10.21276/apjhs.2021.8.2.12.Patel PR, Joshi H, Shah U, Bapna M, Patel B. New generation of quinazolinone derivatives as potent antimicrobial agents. Asian Pac J Health Sci. 2021;8(2):61–6. DOI: 10.21276/apjhs.2021.8.2.12.Etebu E., Arikekpar I. Antibiotics: Classification and mechanisms of action with emphasis on molecular perspectives // Int. J. Appl. Microbiol. Biotechnol.Res. – 2016. – Vol. 4. – Р. 90–101.Etebu E, Arikekpar I. Antibiotics: Classification and mechanisms of action with emphasis on molecular perspectives. Int. J. Appl. Microbiol. Biotechnol.Res. 2016;4:90–101.Alanazi A.M., Abdel-Aziz A.A.M., Shawer T.Z., Ayyad R.R., Al-Obaid A.M., Al-Agamy M.H.M., Maarouf A.R., El-Azab A.S. Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies // Journal of Enzyme Inhibition and Medicinal Chemistry. – 2016. – Vol. 31, No.5. – Р. 721–735. DOI: 10.3109/14756366.2015.1060482.Alanazi AM, Abdel-Aziz AA, Shawer TZ, Ayyad RR, Al-Obaid AM, Al-Agamy MH, Maarouf AR, El-Azab AS. Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies. J Enzyme Inhib Med Chem. 2016 Oct;31(5):721–35. DOI: 10.3109/14756366.2015.1060482.El-Sayed N.N.E., Al-Otaibi T.M., Alonazi M., Masand V.H., Barakat A., Almarhoon Z.M., Ben Bacha A. Synthesis and characterization of some new quinoxalin-2(1H)-one and 2-methyl-3H-quinazolin-4-one derivatives targeting the onset and progression of CRC with SRA, Molecular Docking, and ADMET analyses // Molecules. – 2021. – Vol. 26. – Art. No.3121. DOI: 10.3390/molecules26113121.El-Sayed NNE, Al-Otaibi TM, Alonazi M, Masand VH, Barakat A, Almarhoon ZM, Ben Bacha A. Synthesis and Characterization of Some New Quinoxalin-2(1H)-one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SRA, Molecular Docking, and ADMET Analyses. Molecules. 2021 May 23;26(11):3121. DOI: 10.3390/molecules26113121.Hassan K.A., Liu Q., Elbourne L.D.H., Ahmad I., Sharples D., Naidu V., Chan C.L., Li L., Harborne S.P.D., Pokhrel A., Postis V.L.G., Goldman A., Henderson P.J.F., Paulsen I.T. Pacing across the membrane: the novel PACE family of efflux pumps is widespread in gram-negative pathogens // Research in Microbiology. – 2018. – Vol. 169. – P. 450–454. DOI: 10.1016/j.resmic.2018.01.001.Hassan KA, Liu Q, Elbourne LDH, Ahmad I, Sharples D, Naidu V, Chan CL, Li L, Harborne SPD, Pokhrel A, Postis VLG, Goldman A, Henderson PJF, Paulsen IT. Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram-negative pathogens. Res Microbiol. 2018 Sep–Oct;169(7–8):450–4. DOI: 10.1016/j.resmic.2018.01.001.Vila J., Moreno-Morales J., Balleste-Delpierre C. Current landscape in the discovery of novel antibacterial agents // Clinical Microbiology and Infection. – 2020. – Vol. 26. – P. 596–603. DOI: 10.1016/j.cmi.2019.09.015.Vila J, Moreno-Morales J, Ballesté-Delpierre C. Current landscape in the discovery of novel antibacterial agents. Clin Microbiol Infect. 2020 May;26(5):596–603. DOI: 10.1016/j.cmi.2019.09.015.Nagaraja V., Godbole A.A., Henderson S.R., Maxwell A. DNA topoisomerase I and DNA gyrase as targets for TB therapy // Drug Discovery Today. – 2017. – Vol. 22, Nо. 3. – P. 510–518. DOI: 10.1016/j.drudis.2016.11.006.Nagaraja V, Godbole AA, Henderson SR, Maxwell A. DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discovery Today. 2017;22(3):510–8. DOI: 10.1016/j.drudis.2016.11.006.D’Atanasio N., Capezzone de Joannon A., Di Sante L., Mangano G., Ombrato R., Vitiello M., Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors // Plos One. – 2020. – Vol. 15, No. 2. – Р. 1–21. DOI: 10.1371/journal.pone.0228509.D’Atanasio N, Capezzone de Joannon A, Di Sante L, Mangano G, Ombrato R, Vitiello M, Bartella C, Magarò G, Prati F, Milanese C, Vignaroli C, Di Giorgio FP, Tongiani S. Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors. PLoS One. 2020 Feb 19;15(2):e0228509. DOI: 10.1371/journal.pone.0228509.Karaman R., Jubeh B., Breijyeh Z., Karaman R. Resistance of gram-positive bacteria to current antibacterial agents and overcoming approaches // Molecules. – 2020. – Vol. 25, No.12. – Art. No.2888. DOI: 10.3390/molecules25122888.Karaman R, Jubeh B, Breijyeh Z. Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches. Molecules. 2020 Jun 23;25(12):2888. DOI: 10.3390/molecules25122888.Lepak A.J., Seiler P., Surivet J.P., Ritz D., Kohl C., Andes D.R. In vivo pharmacodynamic target investigation of two bacterial topoisomerase inhibitors, ACT-387042 and ACT-292706, in the neutropenic murine thigh model against Streptococcus pneumoniaeand Staphylococcus aureus // Antimicrobial Agents and Chemotherapy. – 2016. – Vol. 60, No. 6. – Р. 3626–3632. DOI: 10.1128/AAC.00363-16.Lepak AJ, Seiler P, Surivet JP, Ritz D, Kohl C, Andes DR. In Vivo Pharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus. Antimicrob Agents Chemother. 2016 May 23;60(6):3626–32. DOI: 10.1128/AAC.00363-16.Li L., Wang Q., Zhang H., Yang M., Khan M.I., Zhou X. Sensor histidine kinase is a β-lactam receptor and induces resistance to β-lactam antibiotics // Microbiology. – 2016. – Vol. 113, No.6. – P. 1648–1653. DOI: 10.1073/pnas.1520300113.Li L, Wang Q, Zhang H, Yang M, Khan MI, Zhou X. Sensor histidine kinase is a β-lactam receptor and induces resistance to β-lactam antibiotics. Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):1648–53. DOI: 10.1073/pnas.1520300113.Qiao Y., Srisuknimit V., Rubino F., Schaefer K., Ruiz N., Walker S., Kahne D. Lipid II overproduction allows direct assay of transpeptidase inhibition by β-lactams // Nat Chem Biol. – 2017. – Vol. 13, No.7. – Р. 793–798. DOI: 10.1038/nchembio.2388.Qiao Y, Srisuknimit V, Rubino F, Schaefer K, Ruiz N, Walker S, Kahne D. Lipid II overproduction allows direct assay of transpeptidase inhibition by β-lactams. Nat Chem Biol. 2017 Jul;13(7):793–8. DOI: 10.1038/nchembio.2388.Janardhanan J., Bouley R., Martнnez-Caballero S., Peng Z., Batuecas-Mordillo M., Meisel J.E., Ding D., Schroeder V.A., Wolter W.R., Mahasenan K.V., Hermoso J.A., Mobashery S., Chang M. The quinazolinone allosteric inhibitor of PBP 2a synergizes with piperacillin and tazobactam against methicillin-resistant Staphylococcus aureus // Antimicrobial Agents and Chemotherapy. – 2019. – Vol. 63, No.5. – Р. 1–12. DOI: 10.1128/AAC.02637-18.Janardhanan J, Bouley R, Martínez-Caballero S, Peng Z, Batuecas-Mordillo M, Meisel JE, Ding D, Schroeder VA, Wolter WR, Mahasenan KV, Hermoso JA, Mobashery S, Chang M. The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2019 Apr 25;63(5):e02637–18. DOI: 10.1128/AAC.02637-18.Liu J., Chen D., Peters B.M., Li L., Li B., Xu Z., Shirliff M.E. Staphylococcal chromosomal cassettes mec (SCCmec): A mobile genetic element in methicillin-resistant Staphylococcus aureus // Microbial Pathogenesis. – 2016. – Vol. 101. – Р. 56–67. DOI: 10.1016/j.micpath.2016.10.028.Liu J, Chen D, Peters BM, Li L, Li B, Xu Z, Shirliff ME. Staphylococcal chromosomal cassettes mec (SCCmec): A mobile genetic element in methicillin-resistant Staphylococcus aureus. Microb Pathog. 2016 Dec;101:56–67. DOI: 10.1016/j.micpath.2016.10.028.Cai Z.Q., Jin Z.S., Zheng D.Q, Hou L., Huang G.W., Tian J.Q., Wang G.J. Synthesis of several new quinazolin-4-amines containing p-toluenesulfonate moiety // Journal of chemical research. – 2016. – Vol. 40. – Р. 573–575. DOI: 10.3184/174751916X14725679922221.Cai ZQ, Jin ZS, Zheng DQ, Hou L, Huang GW, Tian JQ, Wang GJ. Synthesis of several new quinazolin-4-amines containing p-toluenesulfonate moiety. Journal of chemical research. 2016;40:573–5. DOI: 10.3184/174751916X14725679922221.Khan I., Zaib S., Batool S., Abbas N., Ashraf Z., Iqbal J., Saeed A. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification // Bioorg. Med. Chem. – 2016. – Vol. 24. – Р. 2361–2381. DOI: 10.1016/j.bmc.2016.03.031.Khan I, Zaib S, Batool S, Abbas N, Ashraf Z, Iqbal J, Saeed A. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification. Bioorg Med Chem. 2016 Jun 1;24(11):2361–81. DOI: 10.1016/j.bmc.2016.03.031.Badshah S.L., Ullah A. New developments in non-quinolone-based antibiotics for the inhibition of bacterial gyrase and topoisomerase IV // European Journal of Medicinal Chemistry. – 2018. – Vol. 152. – Р. 393–400. DOI: 10.1016/j.ejmech.2018.04.059.Badshah SL, Ullah A. New developments in non-quinolone-based antibiotics for the inhibiton of bacterial gyrase and topoisomerase IV. Eur J Med Chem. 2018 May 25;152:393–400. DOI: 10.1016/j.ejmech.2018.04.059.Qian Y., Allegretta G., Janardhanan J., Peng Z., Mahasenan K.V., Lastochkin E., Gozun M.M.N., Tejera S., Schroeder V.A., Wolter W.R., Feltzer R., Mobashery S., Chang M. Exploration of the structural space in 4(3H)-quinazolinone antibacterials // J Med Chem. – 2020. – Vol. 63, No.10. – Р. 5287–5296. DOI: 10.1021/acs.jmedchem.0c00153.Qian Y, Allegretta G, Janardhanan J, Peng Z, Mahasenan KV, Lastochkin E, Gozun MMN, Tejera S, Schroeder VA, Wolter WR, Feltzer R, Mobashery S, Chang M. Exploration of the Structural Space in 4(3H)-Quinazolinone Antibacterials. J Med Chem. 2020 May 28;63(10):5287–5296. DOI: 10.1021/acs.jmedchem.0c00153.Masri A., Anwar A., Khan N.A., Shahbaz M.S., Khan K.M., Shahabuddin S., Siddiqui R. Antibacterial effects of quinazolin-4(3H)-one functionalized-conjugated silver nanoparticles // Antibiotics. – 2019. – Vol. 8. – Р. 179. DOI: 10.3390/antibiotics8040179.Masri A, Anwar A, Khan NA, Shahbaz MS, Khan KM, Shahabuddin S, Siddiqui R. Antibacterial Effects of Quinazolin-4(3H)-One Functionalized-Conjugated Silver Nanoparticles. Antibiotics (Basel). 2019 Oct 9;8(4):179. DOI: 10.3390/antibiotics8040179.Bouley R., Ding D., Peng Z., Bastian M., Lastochkin E., Song W., Suckow M.A., Schroeder V.A., Wolter W.R., Mobashery S., Chang M. Structure−activity relationship for the 4(3H) quinazolinoneantibacterials // Journal of Medicinal Chemistry. – 2016. – Vol. 59. – P. 5011–5021. DOI: 10.1021/acs.jmedchem.6b00372.Bouley R, Ding D, Peng Z, Bastian M, Lastochkin E, Song W, Suckow MA, Schroeder VA, Wolter WR, Mobashery S, Chang M. Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials. J Med Chem. 2016 May 26;59(10):5011–21. DOI: 10.1021/acs.jmedchem.6b00372.Nakano S., Fujisawa T., Ito Y., Chang B., Matsumura Y., Yamamoto M., Suga S., Ohnishi M., Nagao M. Penicillin-binding protein typing, antibiotic resistance gene identification, and molecular phylogenetic analysis of meropenem-resistant Streptococcus pneumoniaeserotype 19A-CC3111 strainsin Japan // Antimicrob Agents Chemother. – 2019. – Vol. 63. – Р. 1–9. DOI: 10.1128/AAC.00711-19.Nakano S, Fujisawa T, Ito Y, Chang B, Matsumura Y, Yamamoto M, Suga S, Ohnishi M, Nagao M. Penicillin-Binding Protein Typing, Antibiotic Resistance Gene Identification, and Molecular Phylogenetic Analysis of Meropenem-Resistant Streptococcus pneumoniae Serotype 19A-CC3111 Strains in Japan. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00711–19. DOI: 10.1128/AAC.00711-19.Brouwers R., Vass H., Dawson A., Squires T., Tavaddod S., Allen R.J. Stability of β-lactam antibiotics in bacterial growth media // PLoS One. – 2020. – Vol. 15, No.7. – Р. e0236198. DOI: 10.1371/journal.pone.0236198.Brouwers R, Vass H, Dawson A, Squires T, Tavaddod S, Allen RJ. Stability of β-lactam antibiotics in bacterial growth media. PLoS One. 2020 Jul 20;15(7):e0236198. DOI: 10.1371/journal.pone.0236198.Ligozzi M., Galia L., Bertoncelli A., Mazzariol A. Intrinsic role of coagulase negative staphylococcinor A-like efflux system in fluoroquinolones resistance // AIMS Microbiology. – 2017. – Vol. 3, No.4. – Р. 908–914. DOI: 10.3934/microbiol.2017.4.908.Marco L, Liliana G, Anna B, Annarita M. Intrinsic role of coagulase negative staphylococci norA-like efflux system in fluoroquinolones resistance. AIMS Microbiol. 2017 Nov 14;3(4):908–914. DOI: 10.3934/microbiol.2017.4.908.Ankireddy A.R., Rambabu G., Balaraju T., Banothu V., Gundla P.L., Addepally U., Mantipally M. Synthesis, characterization and antibacterial activity of some novel C-7-Substituted-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine derivatives // Der PharmaChemica. – 2018. – Vol. 10, No.11. – Р. 40–48.Ankireddy AR, Rambabu G, Balaraju T, Banothu V, Gundla PL, Addepally U, Mantipally M. Synthesis, characterization and antibacterial activity of some novel C-7-Substituted-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine derivatives. Der PharmaChemica. 2018;10(11):40–8.Ghorab M.M., Alqahtani A.S., Soliman A.M., Askar A.A. Novel N-(Substituted) thioacetamide quinazolinone benzene sulfonamides as antimicrobial agents // International Journal of Nanomedicine. – 2020. – Vol. 15. – Р. 3161–3180. DOI: 10.2147/IJN.S241433.Ghorab MM, Alqahtani AS, Soliman AM, Askar AA. Novel N-(Substituted) Thioacetamide Quinazolinone Benzenesulfonamides as Antimicrobial Agents. Int J Nanomedicine. 2020 May 5;15:3161–80. DOI: 10.2147/IJN.S241433.De Rosa M., Verdino A., Soriente A., Marabotti A. The Odd Couple(s): An overview of Beta-Lactam antibiotics bearing more than one pharmacophoric group // Int. J. Mol. Sci. – 2021. – Vol. 22. – Р. 2–21. DOI: 10.3390/ijms22020617.De Rosa M, Verdino A, Soriente A, Marabotti A. The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group. Int J Mol Sci. 2021 Jan 9;22(2):617. DOI: 10.3390/ijms22020617.Kahlmeter G., Brown D. F. J., Goldstein F. W., MacGowan A. P., Mouton J. W., Odenholt I., Rodloff A., Soussy C-J., Steinbakk M., Soriano F., Stetsiouk O. European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing // Clinical Microbiology and Infection. – 2006. – Vol. 12, No. 6. – Р. 501–503. DOI:10.1111/j.1469-0691.2006.01454.x.Kahlmeter G, Brown DF, Goldstein FW, MacGowan AP, Mouton JW, Odenholt I, Rodloff A, Soussy CJ, Steinbakk M, Soriano F, Stetsiouk O. European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing. Clin Microbiol Infect. 2006 Jun;12(6):501–3. DOI: 10.1111/j.1469-0691.2006.01454.x.Turnidge J., Kahlmeter, G., Kronvall, G. Statistical characterisation of bacterial wild-type MIC value distributions and the determination of epidemiological cut-off values // ClinMicrobiol Infect. – 2006. – Vol. 12, No.5. – Р. 418–425. DOI:10.1111/j.1469-0691.2006.01377.x.Turnidge J, Kahlmeter G, Kronvall G. Statistical characterisation of bacterial wild-type MIC value distributions and the determination of epidemiological cut-off values. Clin Microbiol Infect. 2006 May;12(5):418–25. DOI: 10.1111/j.1469-0691.2006.01377.x.Лужнова С.А., Воронков А.В., Кодониди И.П., Габитова Н.М., Храпова А.В., Бель С. Активность новых производных 1,3-диазинона-4 и их нециклических предшественников в отношении Staphilococcus aureus // Астраханский медицинский журнал. – 2017. – Т. 12, № 2. – С. 56–63.Luzhnova SA, Voronkov AV, Kodonidi IP, Gabitova NM, Hrapova AV, Billel Souda. ACTIVITY OF NEW DERIVATIVES OF 1,3-DIAZINON-4 AND THEIR NON-CYCLIC PRECURSORS AGAINST STAPHILOCOCCYS AUREUS. Astrakhan medical journal. 2017;12(2):56–63. RussianGajdács M. The continuing threat of methicillin-resistant Staphylococcus aureus // Antibiotics. – 2019. – Vol. 8. – Р. 52. DOI: 10.3390/antibiotics8020052.Gajdács M. The Continuing Threat of Methicillin-Resistant Staphylococcus aureus. Antibiotics (Basel). 2019 May 2;8(2):52. DOI: 10.3390/antibiotics8020052.Nandwana N.K., Singh R.P., Patel O.P.S., Dhiman S., Saini H.K., Jha P.N., Kumar A. Design and synthesis of Imidazo/Benzimidazo[1,2-c]quinazolinederivatives and evaluation of their antimicrobial activity// ACS Omega. – 2018. – Vol.3, No. 11. – Р. 16338−16346. DOI: 10.1021/acsomega.8b01592.Nandwana NK, Singh RP, Patel OPS, Dhiman S, Saini HK, Jha PN, Kumar A. Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity. ACS Omega. 2018 Nov 30;3(11):16338–46. DOI: 10.1021/acsomega.8b01592.Maruthamuthu D., Rajam S., Christina Ruby Stella P., BharathiDileepan A.G., Ranjith R. The chemistry and biological significance of imidazole, benzimidazole, benzoxazole, tetrazole and quinazolinone nucleus // J. Chem. Pharm. Res. – 2016. – Vol. 8, No. 5. – Р. 505–526.Maruthamuthu D, Rajam S, Christina Ruby Stella P, BharathiDileepan AG, Ranjith R. The chemistry and biological significance of imidazole, benzimidazole, benzoxazole, tetrazole and quinazolinone nucleus. J. Chem. Pharm. Res. 2016;8(5):505–26.Mahato A., Shrivastava B., Shanthi N. Synthesis, Molecular Docking and Biological Evaluation of Substituted Quinazolinones as Antibacterial Agents // Chemical Science Transactions. – 2015. – Vol. 4, No. 2. – Р. 595–603. DOI: 10.7598/cst2015.995.Mahato A, Shrivastava B, Shanthi N. Synthesis, Molecular Docking and Biological Evaluation of Substituted Quinazolinones as Antibacterial Agents. Chemical Science Transactions. 2015;4(2):595–603. DOI: 10.7598/cst2015.995.Fisher J.F., Mobashery S. Constructing and deconstructing the bacterial cell wall // Protein Science. – 2020. – Vol. 29. – Р. 629–646. DOI: 10.1002/pro.3737.Fisher JF, Mobashery S. Constructing and deconstructing the bacterial cell wall. Protein Sci. 2020 Mar;29(3):629–46. DOI: 10.1002/pro.3737.Ibrahim M.A.A., Abdeljawaad K.A.A., Abdelrahman A.H.M., Alzahrani O.R., Alshabrmi F.M., Khalaf E., Moustafa M.F., Alrumaihi F., Allemailem K.S., Soliman M.E.S., Paré P.W., Hegazy M.E.F., Atia M.A.M. Non-b-Lactam allosteric inhibitors target methicillin-resistant Staphylococcus aureus: an in silico drug discovery study // Antibiotics. – 2021. – Vol. 10, No. 8. – Art. No. 934. DOI:10.3390/antibiotics10080934.Ibrahim MAA, Abdeljawaad KAA, Abdelrahman AHM, Alzahrani OR, Alshabrmi FM, Khalaf E, Moustafa MF, Alrumaihi F, Allemailem KS, Soliman MES, Paré PW, Hegazy MF, Atia MAM. Non-β-Lactam Allosteric Inhibitors Target Methicillin-Resistant Staphylococcus aureus: An In Silico Drug Discovery Study. Antibiotics (Basel). 2021 Aug 1;10(8):934. DOI: 10.3390/antibiotics10080934.Mahasenan K.V., Molina R., Bouley R., Batuecas M.T., Fisher J.F., Hermoso J.A., Chang M., Mobashery S. Conformational dynamics in penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus, allosteric communication network and enablement of catalysis // J Am Chem Soc. – 2017. – Vol. 139, No. 5. – Р. 2102–2110. DOI: 10.1021/jacs.6b12565.Mahasenan KV, Molina R, Bouley R, Batuecas MT, Fisher JF, Hermoso JA, Chang M, Mobashery S. Conformational Dynamics in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus, Allosteric Communication Network and Enablement of Catalysis. J Am Chem Soc. 2017 Feb 8;139(5):2102–2110. DOI: 10.1021/jacs.6b12565.Higgins D.L., Chang R., Debabov D.V., Leung J., Wu T., Krause K.M., Sandvik E., Hubbard J.M., Kaniga K., Schmidt D.E. Jr, Gao Q., Cass R.T., Karr D.E., Benton B.M., Humphrey P.P. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus // Antimicrobial agents and chemotherapy. – 2005. – Vol. 49, No. 3. – P. 1127–1134. DOI: 10.1128/AAC.49.3.1127-1134.2005.Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM, Kaniga K, Schmidt DE Jr, Gao Q, Cass RT, Karr DE, Benton BM, Humphrey PP. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2005 Mar;49(3):1127–34. DOI: 10.1128/AAC.49.3.1127-1134.2005.Bayer A.S., Schneider T., Sahl H.G. Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall // Ann N Y Acad Sci. – 2013. – Vol. 1277, No. 1. – Р. 139-158. DOI: 10.1111/j.1749-6632.2012.06819.x.Bayer AS, Schneider T, Sahl HG. Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall. Ann N Y Acad Sci. 2013 Jan;1277(1):139–58. DOI: 10.1111/j.1749-6632.2012.06819.x.Зубарева И.В., Беренштейн Т.Ф., Федянин С.Д. Об адгезии грамположительных кокков // Вестник ВГМУ. – 2010. – Т. 9, №1. – C. 1–15.Zubareva IV, Berenshtein TF, Fedyanin SD. Ob adgezii grampolozhitel’nyh kokkov [On the adhesion of gram-positive cocci]. Journal “Vestnik of Vitebsk State Medical University”. 2010;9(1):6–15. Russian

The authors declare that there are no conflicts of interest present.