RESUMO
Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC = 6.25 µg/mL) better than other acylhydrazones described in the literature (MIC = 12.5 µg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.
Assuntos
Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Aldeídos/química , Aldeídos/isolamento & purificação , Aldeídos/farmacologia , Antituberculosos/química , Hidrazonas/química , Hidrazonas/isolamento & purificação , Hidrazonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolonas/química , Quinolonas/isolamento & purificação , Quinolonas/farmacologiaRESUMO
In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 1-[(5â³-methyl-1â³-(4â´-fluorophenylamino)-1H-1,2,3-triazol-4â³-yl)carbonyl]-2-(4'-methylphenylsulfonyl)hydrazine and 1-[(5'-methyl-1'-(2â³,5â³-dichlorophenylamino)-1H-1,2,3-triazol-4'-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC(50) values of 1.30 and 1.26 µM, respectively, displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity indices are high. Under the assay conditions, they have better performance than does the reference compound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional NMR techniques ((1)H, (13)C-APT, COSY-(1)H×(1)H and HETCOR (1)J(CH)) and by elemental analysis.
Assuntos
Antivirais/síntese química , Herpesvirus Humano 1/efeitos dos fármacos , Triazóis/síntese química , Animais , Antivirais/química , Antivirais/toxicidade , Chlorocebus aethiops , Replicação do DNA/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Triazóis/química , Triazóis/toxicidade , Células VeroRESUMO
Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a-b, 8e-f, 8i-j and 8n-o) and new analogues (8c-d, 8g-h, 8l-m and 8p-q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5 µg/mL) similar to or better than the current drugs on the market. The theoretical structure-activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO(2)) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Hidrazinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Triazóis/química , Antituberculosos/química , Relação Dose-Resposta a Droga , Hidrazinas/síntese química , Hidrazinas/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis.
Assuntos
Antivirais/química , Antivirais/farmacologia , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Animais , Antivirais/síntese química , Linhagem Celular , Chlorocebus aethiops , Herpes Simples/tratamento farmacológico , Humanos , Quinolonas/síntese química , Relação Estrutura-Atividade , Células VeroRESUMO
This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a-j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a-j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.
Assuntos
Hidrazinas/síntese química , Inibidores da Agregação Plaquetária/síntese química , Triazóis/síntese química , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
The current treatment used against envenomation by Lachesis muta venom still presents several side effects. This paper describes the synthesis, pharmacological and theoretical evaluations of new 1-arylsulfonylamino-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters (8a-f) tested against the hemolytic profile of the L. muta snake venom. Their structures were elucidated by one- and two-dimensional NMR techniques ((1)H, APT, HETCOR (1)J(CH) and (n)J(CH), n=2, 3) and high-resolution electrospray ionization mass spectrometry. The series of triazole derivatives significantly neutralized the hemolysis induced by L. muta crude venom presenting a dose-dependent inhibitory profile (IC(50)=30-83 microM) with 1-(4'-chlorophenylsulfonylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl ester (8e) being the most potent compound. The theoretical evaluation revealed the correlation of the antiophidian profile with the coefficient distribution and density map of the Highest Occupied Molecular Orbitals (HOMO) of these molecules. The elucidation of this new series may help on designing new and more efficient antiophidian molecules.
Assuntos
Venenos de Crotalídeos/toxicidade , Triazóis/síntese química , Viperidae/metabolismo , Animais , Ésteres/química , Hemólise , Humanos , Espectroscopia de Ressonância Magnética , Coelhos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Termodinâmica , Triazóis/química , Triazóis/farmacologiaRESUMO
In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure-activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R(2) and R(3) for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its: (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski 'rule of five', (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Infecções por HIV/tratamento farmacológico , HIV-1/crescimento & desenvolvimento , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Modelos Moleculares , Estrutura Molecular , Quinolonas/química , Quinolonas/farmacocinética , Relação Estrutura-Atividade , Células VeroRESUMO
In this work an efficient one-pot synthesis of substituted pyrroles 7a-n is described, which involves the in situ formation of dihydrofurans ethyl 5-butoxy-2-methyl-4,5-dihydrofuran-3-carboxylate (4), 1-(5-butoxy-2-methyl-4,5-dihydrofuran-3-yl)ethanone (5) and 5-butoxy-4,5-dihydrofuran-3-carbaldehyde (6) followed by reaction with primary amines.
RESUMO
BACKGROUND: Breast cancer is a major cause of death among women worldwide. Treatment for breast cancer involves the surgical removal of cancer tissue, followed by chemotherapy. Although the treatment is efficient, especially when the cancer is detected early, recurrence is common and is often resistant to the previous treatment. Therefore, a constant search for efficient and novel drugs for the treatment of breast cancer is mandatory. Recently, triazole derivatives have shown promising effects against different types of cancer, revealing these molecules as putative anticancer drugs. EXPERIMENTAL: We have synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity against a human breast cancer cell line. Among the compounds tested, we identified a molecule that killed the human breast cancer cell line MCF-7 with minimal effects on its noncancer counterpart, MCF10A. This effect was seen after 24 hours of treatment and persisted for additional 24 hours after treatment withdrawal. After 1 hour of treatment, the compound, here named 12c, promoted a decrease in cell glucose consumption and lactate production. Moreover, the cells treated with 12c for 1 hour showed diminished intracellular ATP levels with unaltered mitochondrial potential and increased reactive oxygen species production. Additionally, apoptosis was triggered after treatment with the drug for 1 hour. All of these effects are only observed with MCF-7 cells, and not MCF10A. These data show that 12c has selective activity against breast cancer cells and is a potential candidate for a novel anticancer drug. RESULTS AND CONCLUSION: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields, and one of them, 12c, exhibited strong and selective antitumor properties. The antitumor mechanism involves inhibition of glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all selective for cancer cells, since noncancer cells are unaffected, and these effects can only be attributed to the whole molecule, as different pharmacophoric groups did not reproduce these effects.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MICâ¯=â¯4-32⯵g/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08-256⯵g/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Amino Açúcares/síntese química , Amino Açúcares/química , Amino Açúcares/farmacologia , Amino Açúcares/toxicidade , Antibacterianos/síntese química , Antibacterianos/toxicidade , Infecções Bacterianas/tratamento farmacológico , Halogenação , Hemólise/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/toxicidade , Naftoquinonas/síntese química , Naftoquinonas/toxicidadeRESUMO
This paper describes the antiviral evaluation of new N-amino-1,2,3-triazole derivatives, 1-(substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters, 3 and 1-(4-substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazides, 4, on Cantagalo virus replication. 1-(4-Fluoro-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazide, 4e, exhibited a significant antiviral effect. Characterization of all compounds was confirmed by IR, (1)H and (13)C spectroscopies and elemental analysis. In addition, molecular structure of 4e was also reported.
Assuntos
Amitrol (Herbicida)/análogos & derivados , Amitrol (Herbicida)/farmacologia , Antivirais/química , Antivirais/farmacologia , Vaccinia virus/efeitos dos fármacos , Amitrol (Herbicida)/toxicidade , Animais , Antivirais/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas Virais/análise , Proteínas Virais/metabolismoRESUMO
The investigation of trypanocidal effects against Trypanosoma cruzi and cytotoxicity in VERO cell line of several oxyranes structurally related to beta-lapachone, nor-beta-lapachone, alpha-lapachone, and 4-methoxy-1,2-naphthoquinone is described. It was found that the oxyranes 10 derived from alpha-lapachone showed an approximately the same trypanocidal activity of beta-lapachone. In addition, all the oxyranes showed less cytotoxicity than the corresponding naphthoquinones.
Assuntos
Antiprotozoários/farmacologia , Inibidores do Crescimento/farmacologia , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Naftoquinonas/química , Células VeroRESUMO
Starting from alpha- and beta-lapachones, in this work we compared the biological and theoretical profile of several oxyran derivatives of lapachone as potential trypanocidal agents. Our biological results showed that the oxyrans tested act as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. The oxyran derivative of alpha-lapachone (7a) showed to be one of the most potent compounds. In our molecular modeling study, we analyzed the C-ring moiety and the redox center of beta-lapachone molecule as the moieties responsible for the trypanocidal and cytotoxic effects on mammalian cell line. The computational methods used to delineate the structural requirements for the trypanocidal profile pointed out that the transposition of the C-ring moiety of beta-lapachone, combined with its oxyran ring, introduced important molecular requirements for trypanocidal activity in the HOMO energy, HOMO orbital coefficient, LUMO density, electrostatic potential map, dipole moment vector, and calculated logP (clogP) parameter. This study could lead to the development of new antichagasic medicines based on alpha-lapachone analogs.
Assuntos
Naftoquinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Naftoquinonas/química , Oxirredução , Eletricidade EstáticaRESUMO
The central six-membered ring in the title compound, C(16)H(16)O(3), is almost planar (and almost coplanar with the aromatic ring), despite one of its C atoms being formally sp(3) hybridized. The planarity is a consequence of the C atom at the centre of the spirocyclic system also being part of the three-membered epoxide ring. The molecules are linked by pi-pi and C-H.pi interactions.