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1.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474298

RESUMO

The rapid increase in the antibiotic resistance of microorganisms, capable of causing diseases in humans as destroying cultural heritage sites, is a great challenge for modern science. In this regard, it is necessary to develop fundamentally novel and highly active compounds. In this study, a series of N4-alkylcytidines, including 5- and 6-methylcytidine derivatives, with extended alkyl substituents, were obtained in order to develop a new generation of antibacterial and antifungal biocides based on nucleoside derivatives. It has been shown that N4-alkyl 5- or 6-methylcytidines effectively inhibit the growth of molds, isolated from the paintings in the halls of the Ancient Russian Paintings of the State Tretyakov Gallery, Russia, Moscow. The novel compounds showed activity similar to antiseptics commonly used to protect works of art, such as benzalkonium chloride, to which a number of microorganisms have acquired resistance. It was also shown that the activity of N4-alkylcytidines is comparable to that of some antibiotics used in medicine to fight Gram-positive bacteria, including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis. N4-dodecyl-5- and 6-methylcytidines turned out to be the best. This compound seems promising for expanding the palette of antiseptics used in painting, since quite often the destruction of painting materials is caused by joint fungi and bacteria infection.


Assuntos
Anti-Infecciosos Locais , Desinfetantes , Pinturas , Humanos , Desinfetantes/farmacologia , Bactérias , Fungos , Antibacterianos
2.
ChemMedChem ; 18(21): e202300366, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37707314

RESUMO

The emergence of drug-resistant strains of pathogenic microorganisms necessitates the creation of new drugs. A series of uridine derivatives containing an extended substituent at the C-5 position as well as C-5 alkyloxymethyl, alkylthiomethyl, alkyltriazolylmethyl, alkylsulfinylmethyl and alkylsulfonylmethyl uridines were obtained in order to explore their antimicrobial properties and solubility. It has been shown that new ribonucleoside derivatives have an order of magnitude better solubility in water compared to their 2'-deoxy analogues and effectively inhibit the growth of a number of Gram-positive bacteria, including resistant strains of Mycobacterium smegmatis (MIC=15-200 µg/mL) and Staphylococcus aureus (MIC=25-100 µg/mL). Their activity is comparable to that of some antibiotics used in medicine.


Assuntos
Antibacterianos , Anti-Infecciosos , Uridina/farmacologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias Gram-Positivas , Bactérias Gram-Negativas
3.
Microorganisms ; 10(7)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35889017

RESUMO

Tuberculosis (TB) is the oldest human infection disease. Mortality from TB significantly decreased in the 20th century, because of vaccination and the widespread use of antibiotics. However, about a third of the world's population is currently infected with Mycobacterium tuberculosis (Mtb) and the death rate from TB is about 1.4-2 million people per year. In the second half of the 20th century, new extensively multidrug-resistant strains of Mtb were identified, which are steadily increasing among TB patients. Therefore, there is an urgent need to develop new anti-TB drugs, which remains one of the priorities of pharmacology and medicinal chemistry. The antimycobacterial activity of nucleoside derivatives and analogues was revealed not so long ago, and a lot of studies on their antibacterial properties have been published. Despite the fact that there are no clinically used drugs based on nucleoside analogues, some progress has been made in this area. This review summarizes current research in the field of the design and study of inhibitors of mycobacteria, primarily Mtb.

4.
Eur J Med Chem ; 215: 113212, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33582576

RESUMO

The emergence of drug-resistant strains of pathogenic microorganisms necessitates the creation of new drugs. In order to find new compounds that effectively inhibit the growth of pathogenic bacteria and fungi, we synthesized a set of N4-derivatives of cytidine, 2'-deoxycytidine and 5-metyl-2'-deoxycytidine bearing extended N4-alkyl and N4-phenylalkyl groups. The derivatives demonstrate activity against a number of Gram-positive bacteria, including Mycobacterium smegmatis (MIC = 24-200 µM) and Staphylococcus aureus (MIC = 50-200 µM), comparable with the activities of some antibiotics in medical use. The most promising compound appeared to be N4-dodecyl-5-metyl-2'-deoxycytidine 4h with activities of 24 and 48 µM against M. smegmatis and S. aureus, respectively, and high inhibitory activity of 0.5 mM against filamentous fungi that can, among other things, damage works of art, such as tempera painting. Noteworthy, some of other synthesized compounds are active against fungal growth with the inhibitory concentration in the range of 0.5-3 mM.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Citidina/análogos & derivados , Citidina/farmacologia , Células A549 , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Antifúngicos/síntese química , Antifúngicos/toxicidade , Bactérias/efeitos dos fármacos , Citidina/toxicidade , Descoberta de Drogas , Fungos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana
5.
Biochimie ; 171-172: 170-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147512

RESUMO

The data of transmission electron microscopy (TEM) on morphology of M. tuberculosis H37Rv bacterial cells treated with four analogues of pyrimidine nucleosides with different substituents at 5 position of base are presented. We showed that the growth of M. tuberculosis H37Rv cells effectively inhibited by each of these compounds. This process is accompanied with the accumulation of lipid intracellular vacuole-like inclusions in the cells, appearance of deep protrusions and indentations on the surface, partial and/or complete destruction of the three-layered cell envelope. The exact molecular mechanism of action of 5-substituted pyrimidine nucleosides on M. tuberculosis cells remains to be proved. However, one can suggest that mechanism of action for these compounds is related either to their direct interactions with bacteria cell walls or to interactions with enzymes participating in the process of cell wall formation.


Assuntos
Mycobacterium tuberculosis , Nucleosídeos de Pirimidina/farmacologia , Microscopia Eletrônica de Transmissão , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/ultraestrutura
6.
J Antibiot (Tokyo) ; 73(4): 236-246, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31932744

RESUMO

Recently we have synthesized a set of pyrimidine nucleoside derivatives bearing extended alkyltriazolylmethyl substituents at position 5 of the nucleic base, and showed their significant activity against Mycobacterium tuberculosis virulent laboratory strain H37Rv as well as drug-resistant MS-115 strain. The presence of a lengthy hydrophobic substituent leads to the reduction of nucleoside water solubility making their antibacterial activity troublesome to study. A series of water-soluble forms of 5-modified 2'-deoxyuridines 4a-c and 8a-c were synthesized. They appeared at least two orders more soluble compared with the parent compounds 1a and 1b. Their half-hydrolysis time was 5-12 h, which can be considered optimal for prodrugs used in clinics. Obtained compounds showed moderate activity (MIC 48-95 µg·ml-1) against some Gram-positive bacteria including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis and were low cytotoxic for human cell lines (CD50 >> 100 µg·ml-1).


Assuntos
Antibacterianos/farmacologia , Desoxiuridina/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Desoxiuridina/síntese química , Desoxiuridina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Pró-Fármacos , Solubilidade , Relação Estrutura-Atividade , Água/química
7.
J Antibiot (Tokyo) ; 72(7): 535-544, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30792519

RESUMO

The emergence of new drug-resistant strains of bacteria necessitates the development of principally new antibacterial agents. One of the novel classes of antibacterial agents is nucleoside analogs. We have developed a fast and simple one-pot method for preparation of α- and ß-anomers of 5-modified 6-aza- and 2-thio-6-aza-2'-deoxyuridine derivatives in high yields. 2-Thio derivatives demonstrated moderate activity against Mycobacterium smegmatis (MIC = 0.2-0.8 mM), Staphylococcus aureus (MIC = 0.03-0.9 mM) and some other Gram-positive bacteria. 2'-Deoxy-2-thio-5-phenyl-6-azauridine (2b) effectively suppressed the growth of Gram-negative bacteria Pseudomonas aeruginosa ATCC 27853 (MIC = 0.03 mM)-the one that causes diseases difficult to treat due to high resistance to antibiotics. 5'-Monophosphates of compounds 2a, b and 3a, b were docked into a binding site of Mycobacterium tuberculosis flavin-dependent thymidylate synthase (ThyX) enzyme. The molecular modeling demonstrates the possibility of binding of the 5-modified 2-thio-6-aza-2'-deoxyuridine 5'-monophosphates within the active site of the enzyme and thereby inhibiting the growth of the bacteria.


Assuntos
Antibacterianos/síntese química , Azauridina/análogos & derivados , Azauridina/síntese química , Animais , Antibacterianos/farmacologia , Azauridina/farmacologia , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Timidilato Sintase/efeitos dos fármacos
8.
Molecules ; 23(12)2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477147

RESUMO

A series of novel 5'-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC99 of 67 µg/mL (mc²155) and a MIC99 of 6.7⁻67 µg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC99 28⁻61 µg/mL) and Mycobacterium bovis ATCC 35737 (MIC99 50⁻60 µg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC99 20⁻50 µg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC99 20⁻50 µg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/ultraestrutura , Relação Estrutura-Atividade , Uracila/análogos & derivados , Uracila/química , Uracila/farmacologia
9.
ChemistrySelect ; 3(8): 2321-2325, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32328513

RESUMO

The rational design of broad-spectrum antivirals requires data on antiviral activity of compounds against multiple viruses, which are often not available. We have developed a panel of (+)ssRNA viruses composed of Enterovirus and Flavivirus genera members allowing to study these activity spectra. Antiviral activity profiling of a set of nucleoside analogues revealed N 4-hydroxycytidine as an efficient inhibitor of replication of coxsackieviruses and other enteroviruses, but ineffective against tick-borne encephalitis virus. Furano[2, 3-d]pyrimidine nucleosides with n-pentyl or n-hexyl tails showed selective inhibition of Enterovirus A representatives. 5-(Tetradec-1-yn-1-yl)-uridine showed selective inhibition of tick-borne encephalitis virus at the micromolar level.

10.
Bioorg Med Chem ; 23(22): 7131-7, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26482569

RESUMO

A series of 5'-monophosphates of 5-substituted 2'-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2'-deoxyuridine 5'-monophosphate 3b, displaying an IC50 value against ThyX of 8.32 µM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Desoxiuridina/análogos & derivados , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Timidilato Sintase/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Desoxiuridina/síntese química , Desoxiuridina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Timidilato Sintase/metabolismo
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