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1.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360555

RESUMO

Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds 3b and 3c showing EC50 values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling 3b into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Bioensaio/métodos , Simulação por Computador , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirazinamida/química , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/isolamento & purificação , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica
2.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34451864

RESUMO

Despite the established treatment regimens, tuberculosis remains an alarming threat to public health according to WHO. Novel agents are needed to overcome the increasing rate of resistance and perhaps achieve eradication. As part of our long-term research on pyrazine derived compounds, we prepared a series of their ortho fused derivatives, N-phenyl- and N-benzyl quinoxaline-2-carboxamides, and evaluated their in vitro antimycobacterial activity. In vitro activity against Mycobacterium tuberculosis H37Ra (represented by minimum inhibitory concentration, MIC) ranged between 3.91-500 µg/mL, with most compounds having moderate to good activities (MIC < 15.625 µg/mL). The majority of the active compounds belonged to the N-benzyl group. In addition to antimycobacterial activity assessment, final compounds were screened for their in vitro cytotoxicity. N-(naphthalen-1-ylmethyl)quinoxaline-2-carboxamide (compound 29) was identified as a potential antineoplastic agent with selective cytotoxicity against hepatic (HepG2), ovarian (SK-OV-3), and prostate (PC-3) cancer cells lines. Molecular docking showed that human DNA topoisomerase and vascular endothelial growth factor receptor could be potential targets for 29.

3.
Bioorg Chem ; 110: 104806, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33799176

RESUMO

Aminoacyl-tRNA synthetases (aaRSs) are crucial for the correct assembly of amino acids to cognate tRNA to maintain the fidelity of proteosynthesis. AaRSs have become a hot target in antimicrobial research. Three aaRS inhibitors are already in clinical practice; antibacterial mupirocin inhibits the synthetic site of isoleucyl-tRNA synthetase, antifungal tavaborole inhibits the editing site of leucyl-tRNA synthetase, and antiprotozoal halofuginone inhibits proline-tRNA synthetase. According to the World Health Organization, tuberculosis globally remains the leading cause of death from a single infectious agent. The rising incidence of multidrug-resistant tuberculosis is alarming and urges the search for new antimycobacterial compounds, preferably with yet unexploited mechanism of action. In this literature review, we have covered the up-to-date state in the field of inhibitors of mycobacterial aaRSs. The most studied aaRS in mycobacteria is LeuRS with at least four structural types of inhibitors, followed by TyrRS and AspRS. Inhibitors of MetRS, LysRS, and PheRS were addressed in a single significant study each. In many cases, the enzyme inhibition activity translated into micromolar or submicromolar inhibition of growth of mycobacteria. The most promising aaRS inhibitor as an antimycobacterial compound is GSK656 (compound 8), the only aaRS inhibitor in clinical trials (Phase IIa) for systemic use against tuberculosis. GSK656 is orally available and shares the oxaborole tRNA-trapping mechanism of action with antifungal tavaborole.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Aminoacil-tRNA Sintetases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
4.
Chem Biol Drug Des ; 97(3): 686-700, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33068457

RESUMO

A series of N-pyridinylbenzamides was designed and prepared to investigate the influence of isosterism and positional isomerism on antimycobacterial activity. Comparison to previously published isosteric N-pyrazinylbenzamides was made as an attempt to draw structure-activity relationships in such type of compounds. In total, we prepared 44 different compounds, out of which fourteen had minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis H37Ra below 31.25 µg/ml, most promising being N-(5-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (23) and N-(6-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (24) with MIC = 7.81 µg/ml (26 µm). Five compounds showed broad-spectrum antimycobacterial activity against M. tuberculosis H37Ra, M. smegmatis and M. aurum. N-(pyridin-2-yl)benzamides were generally more active than N-(pyridin-3-yl)benzamides, indicating that N-1 in the parental structure of N-pyrazinylbenzamides might be more important for antimycobacterial activity than N-4. Marginal antibacterial and antifungal activity was observed for title compounds. The hepatotoxicity of title compounds was assessed in vitro on hepatocellular carcinoma cell line HepG2, and they may be considered non-toxic (22 compounds with IC50 over 200 µm).

5.
Molecules ; 25(7)2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32231166

RESUMO

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Pirazinamida/química , Pirazinas/química , Antituberculosos/síntese química , Antituberculosos/isolamento & purificação , Desenho de Fármacos , Desenvolvimento de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Molecules ; 25(7)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32230728

RESUMO

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing ʟ-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-ᴅ/ʟ-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the ᴅ- and ʟ-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/farmacologia , Tuberculose/tratamento farmacológico , Aminoácidos/química , Aspergillus flavus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Cromatografia Gasosa-Espectrometria de Massas , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Rotação Ocular , Pseudomonas aeruginosa/efeitos dos fármacos , Pirazinamida/química , Staphylococcus aureus/efeitos dos fármacos
7.
J Med Chem ; 63(17): 8901-8916, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32275822

RESUMO

Pyrazine-based compounds are of great importance in medicinal chemistry. Due to their heteroaromatic nature, they uniquely combine properties of heteroatoms (polar interactions) with the properties of aromatic moieties (nonpolar interactions). This review summarizes results of a systematic analysis of RCSB PDB database focused on important binding interactions of pyrazine-based ligands cocrystallized in protein targets. The most frequent interaction of pyrazine was hydrogen bond to pyrazine nitrogen atom as an acceptor, followed by weak hydrogen bond with pyrazine hydrogen as donor. We also identified intramolecular hydrogen bonds within pyrazine ligands, π-interactions, coordination to metal ions, and few halogen bonds in chloropyrazines. In many cases the binding mode of the pyrazine fragment was complex, involving a combination of several interactions. We conclude that pyrazine as a molecular fragment should not be perceived as a simple aromatic isostere but rather as a readily interacting moiety of drug-like molecules with high potential for interactions to proteins.


Assuntos
Proteínas/química , Pirazinas/química , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/metabolismo , Sítios de Ligação , Bases de Dados de Proteínas , Humanos , Ligação de Hidrogênio , Ligantes , Metais/química , Simulação de Dinâmica Molecular , Proteínas/metabolismo , Pirazinas/metabolismo
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117414, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376725

RESUMO

This article represents the spectroscopic and computational studies of two new pyrazine compounds. In order to establish the structure and functional nature of the compounds, we have employed Fourier transformed infrared (FT-IR) and Raman spectra, nuclear magnetic resonance (NMR) spectra, and ultraviolet (UV) absorptions and have compared them with the simulated computational spectra and found that they are in the agreeable range. Simulated hyperpolarisability values are used to obtain the nonlinear optic (NLO) activity of the compound, to be used in organic electronic materials. The charge transfer and related properties was investigated by the simulation of electronic spectrum with time dependent density functional theory (TD-DFT). Natural transition orbitals (NTO) provides information about which region of the molecules are more involved in the electronic transitions and the charge transfer properties for the lowest energy excitation have been analyzed on the basis of electron density variation. Molecular dynamics simulations provide information about the behavior of the molecule in solutions. Frontier orbital analysis and study of various reactivity descriptors like ALIE and Fukui provided deep knowledge on the reactivity side. Molecular docking has been also performed to investigate the interaction between title molecules and exhibits inhibitory activity against Pseudomonas aeruginosa Enoyl-Acyl carrier protein reductase (Fabl).


Assuntos
Pirazinas , Antibacterianos/análise , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Descoberta de Drogas , Simulação de Acoplamento Molecular , Pirazinas/análise , Pirazinas/química , Pirazinas/metabolismo , Análise Espectral , Eletricidade Estática
9.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925695

RESUMO

We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Antibacterianos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirazinas/química
10.
Molecules ; 25(1)2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31905775

RESUMO

We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino-N-(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 µg/mL, 25 µM) and 4-amino-N-(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 µg/mL, 22 µM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Anti-Infecciosos/química , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Fenômenos Químicos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/química
11.
Molecules ; 23(9)2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30231544

RESUMO

Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R² = Me; 2i: R² = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-ylbenzamides with hydroxy substitution (2b: R² = 2-OH; 2d: R² = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Antibacterianos/síntese química , Benzamidas/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Medchemcomm ; 9(4): 685-696, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108959

RESUMO

Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for in vitro growth inhibition activity against M. tuberculosis H37Rv, M. kansasii, M. avium and M. smegmatis by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for in vitro cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-N-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited M. tuberculosis, M. kansasii, and M. avium with MIC = 0.78 µg mL-1 (2.3 µM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.

13.
Curr Med Chem ; 25(38): 5142-5167, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28933298

RESUMO

BACKGROUND: Despite of the globally positive trends in the epidemiology of tuberculosis, the increasing rates of drug-resistant strains are urging to introduce new antituberculars into clinical practice. Development of a new chemical entity from hit to marketed drug is an extremely time and resources consuming process with uncertain outcome. Repurposing of clinically used drugs can be a cheaper alternative to develop new drugs effective in the treatment of tuberculosis. OBJECTIVE: To extract the latest information on new mechanisms of action described or proposed for clinically used antitubercular drugs. To identify drugs from various pharmacodynamic groups as candidates for repurposing to become effective in combatting tuberculosis. Attention will be paid to elucidate the connection between repurposed drugs and new antituberculars in clinical practice or in clinical trials. METHODS: Scientific databases were searched for the keywords. RESULTS: We reviewed the latest aspects of usage and new mechanisms of action for both first-line and second-line antitubercular drugs in clinical practice. Further, we found that surprisingly large number of clinically used drugs from various pharmacodynamic groups have potential to be used in the treatment of tuberculosis, including antimicrobial drugs not typically used against tuberculosis, statins, CNS drugs (tricyclic phenothiazines, antidepressants, anticonvulsants), non-steroidal anti-inflammatory drugs, kinase inhibitors, and others (metformin, disulfiram, verapamil, lansoprazole). Repurposed drugs may become effective antituberculars, acting either by direct effects on mycobacteria or as adjunct, host-directed therapy. CONCLUSION: In this review, we showed that proper research of old drugs is a very efficient tool to develop new antituberculars.


Assuntos
Antituberculosos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Tuberculose/tratamento farmacológico , Animais , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos
14.
Molecules ; 22(11)2017 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-29143778

RESUMO

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.


Assuntos
Composição de Medicamentos , Química Farmacêutica , Humanos , Colaboração Intersetorial , Farmacêuticos , Relação Quantitativa Estrutura-Atividade , Pesquisadores , Eslováquia
15.
Molecules ; 22(10)2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29065539

RESUMO

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 µg/mL, 5.19 µM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 µg/mL, 18.91 µM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proliferação de Células/efeitos dos fármacos , Fagopyrum/química , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Pirazinamida/química , Pirazinamida/farmacologia , Pirazinas/síntese química , Pirazinas/química , Estresse Fisiológico/efeitos dos fármacos
16.
Molecules ; 22(9)2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28880230

RESUMO

Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 µg·mL-1 (5 µM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 µg·mL-1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-ß-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/química , Antifúngicos/química , Antifúngicos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Simulação por Computador , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular/métodos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Molecules ; 22(3)2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28335571

RESUMO

A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 µg·mL-1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 µM, and Staphylococcus epidermidis with MIC = 15.62 µM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Antibacterianos/química , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Molecules ; 22(2)2017 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-28157178

RESUMO

Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 µM. The best MIC (6 µM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 µM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhAinhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Pirazinamida/síntese química , Pirazinamida/farmacologia , Amidas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazinas/química , Relação Estrutura-Atividade
19.
Expert Opin Ther Pat ; 26(9): 1079-94, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27399249

RESUMO

INTRODUCTION: Enoyl-(acyl-carrier-protein) reductase (ENR) is a limiting step enzyme in the Fatty Acid Synthase II system. In mammals, there is no homologue to ENR, which makes it an optimal candidate target for selective anti-infective drugs. Up-to-date, only two ENR inhibitors are used in clinical practice. AREA COVERED: This review is a survey on important patents on low molecular weight compounds with ENR inhibiting activity published in 2011-2015. Common patent databases (SciFinder, esp@cenet, WIPO) were used to locate patent applications on the proposed topic and in the timespan of 2011-2015. EXPERT OPINION: In 2011-2015, we have observed patents in previously known structural groups of diphenyl ethers and acrylamides as well as new structural classes, often identified by high-throughput screening campaigns. The spectrum of activity of applied derivatives covers significant bacteria, mycobacteria, and apicomplexan parasites (Plasmodia and Toxoplasma). Good news from research of ENR inhibitors: a) four selective anti-staphylococcal compounds applied in 2011-2015 or earlier were pushed to Phase I or Phase II clinical trials and some of them proved safety and tolerability after peroral and/or intravenous administration; b) big pharma companies have renewed their interest in the development of new anti-infective compounds against resistant strains of clinical relevance.


Assuntos
Anti-Infecciosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Ensaios de Triagem em Larga Escala , Humanos , Patentes como Assunto
20.
Expert Opin Ther Pat ; 25(12): 1487-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26536813

RESUMO

INTRODUCTION: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson`s and Alzheimer`s Disease to various brain injuries. AREAS COVERED: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature. EXPERT OPINION: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously.


Assuntos
Indóis/farmacologia , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Adulto , Animais , Disponibilidade Biológica , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Humanos , Indóis/química , Indóis/farmacocinética , Transtornos Mentais/fisiopatologia , Transtornos Mentais/prevenção & controle , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/prevenção & controle , Neurogênese/efeitos dos fármacos , Patentes como Assunto
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