RESUMO
Regarding the structural analysis of variable effective CDK-9 suppressors, we record the design and synthesis of two new sets of sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles with expected anticancer and CDK-9 inhibiting activity. In the designed molecules, the pyrazole ring and sulphaguanidine fragment were linked together for the first time through diazo linkers as they are expected to enhance the anticancer activity and CDK degrading interaction. All derivatives have been estimated regarding their cytotoxic activity toward three tumor cells where CDK overexpression has been reported (HePG2, HCT-116, and MCF-7). Among these, four derivatives VII, VIII, X, and XIII exerted potent cytotoxicity against the chosen tumor cells presenting IC50 range equal to 2.86-25.89 µM. As well cytotoxicity on non-cancer cells and CDK-9 inhibition assay have been also assessed for these candidates to evaluate their selectivity indices and enzyme inhibition. The 3,5-diaminopyrazole-1-carboxamide derivative XIII showed a superior combined profile as cytotoxic with high selectivity toward cancer cells (HePG2: IC50 = 6.57 µM, SI = 13.31; HCT-116: IC50 = 9.54 µM, SI = 9.16; MCF-7: IC50 = 7.97 µM, SI = 10.97). Accordingly, it has been chosen to evaluate its probable mechanistic effect both in vitro (via enzyme assay, apoptosis induction, and cell cycle study) as well as in silico (through molecular docking). Overall, this work introduces the 3,5-diaminopyrazole-1-carboxamide derivative XIII as a potent CDK-9 inhibitor candidate (IC50 = 0.16 µM) that merits further investigations for the management of breast, colorectal, and hepatic malignancies.
Assuntos
Antineoplásicos , Quinase 9 Dependente de Ciclina , Pirazóis , Sulfaguanidina , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfaguanidina/análogos & derivados , Sulfaguanidina/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidoresRESUMO
Nanoparticles are inevitable byproducts of modern industry. However, the environmental impacts arising from industrial applications of nanoparticles are largely under-reported. This study evaluated the ecotoxicological effects of aluminum oxide nanoparticles (Al2O3NP) and its influence on sulfacetamide (SA) biodegradation by a freshwater microalga, Scenedesmus obliquus. Although Al2O3NP showed limited toxicity effect on S. obliquus, we observed the toxicity attenuation aspect of Al2O3NP in a mixture of sulfacetamide on microalgae. The addition of 100 mg L-1 of Al2O3NP and 1 mg L-1 of SA reduced total chlorophyll by 23.3% and carotenoids by 21.6% in microalgal compared to control. The gene expression study demonstrated that ATPF0C, Lhcb1, HydA, and psbA genes responsible for ATP synthesis and the photosynthetic system were significantly downregulated, while the Tas gene, which plays a major role in biodegradation of organic xenobiotic chemicals, was significantly upregulated at 1 and 100 mg L-1 of Al2O3NP. The S. obliquus removed 16.8% of SA at 15 mg L-1 in 14 days. However, the removal was slightly enhanced (18.8%) at same concentration of SA in the presence of 50 mg L-1 Al2O3NP. This result proves the stability of sulfacetamide biodegradation capacity of S. obliquus in the presence of Al2O3NP co-contamination. The metabolic analysis showed that SA was degraded into simpler byproducts such as sulfacarbamide, sulfaguanidine, sulfanilamide, 4-(methyl sulfonyl)aniline, and N-hydroxy-benzenamine which have lower ecotoxicity than SA, demonstrating that the ecotoxicity of sulfacetamide has significantly decreased after the microalgal degradation, suggesting the environmental feasibility of microalgae-mediated wastewater technology. This study provides a deeper understanding of the impact of nanoparticles such as Al2O3NP on aquatic ecosystems.
Assuntos
Microalgas , Nanopartículas , Scenedesmus , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Óxido de Alumínio/toxicidade , Carotenoides/metabolismo , Carotenoides/farmacologia , Clorofila/metabolismo , Clorofila/farmacologia , Ecossistema , Água Doce , Nanopartículas/toxicidade , Scenedesmus/metabolismo , Sulfacetamida/metabolismo , Sulfacetamida/farmacologia , Sulfaguanidina/metabolismo , Sulfaguanidina/farmacologia , Águas Residuárias , Xenobióticos/metabolismoRESUMO
A series of six N-carbamimidoyl-4-(3-substituted phenylureido)benzenesulfonamide derivatives were synthesized by reaction of sulfaguanidine with aromatic isocyanates. In vitro and in silico inhibitory effects of the novel ureido-substituted sulfaguanidine derivatives were investigated by spectrophotometric methods for α-glycosidase (α-GLY), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes associated with diabetes mellitus (DM) and Alzheimer's disease (AD). N-Carbamimidoyl-4-{[(3,4-dichlorophenyl)carbamoyl]amino}benzene-1-sulfonamide (2f) showed AChE and BChE inhibitory effects, with KI values of 515.98±45.03â nM and 598.47±59.18â nM, respectively, while N-carbamimidoyl-4-{[(3-chlorophenyl)carbamoyl]amino}benzene-1-sulfonamide (2e) showed strong α-GLY inhibitory effect, with KI values of 103.94±13.06â nM. The antidiabetic effects of the novel synthesized compounds are higher than their anti-Alzheimer's effects, because the inhibition effect of the compounds on the α-GLY with diabetic enzyme is greater than the effect on esterase enzymes. Indeed, inhibition of the metabolic enzymes is important for the treatment of DM and AD.
Assuntos
Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Sulfaguanidina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Sulfaguanidina/síntese química , Sulfaguanidina/química , alfa-Glucosidases/metabolismoRESUMO
The high acquisition rate of drug resistance by Mycobacterium tuberculosis necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high-throughput screening of compounds against thiol-deficient Mycobacterium smegmatis strains and subsequent validation with thiol-deficient M. tuberculosis strains revealed that ΔegtA and ΔmshA mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su); ΔegtB and ΔegtE mutants had increased susceptibility to bacitracin (Ba); and ΔegtA, ΔmshA, and ΔegtB mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the levels of thiols and oxidative stress in M. tuberculosis This study reports the activities of Aza, Su, Fu, and Ba against M. tuberculosis and provides a rationale for further investigations.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Azaguanina/farmacologia , Mutação/genética , Mycobacterium tuberculosis/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Sulfaguanidina/farmacologia , Compostos de Sulfidrila/metabolismoRESUMO
Sulfaguanidine (SG), belongs to the class of sulfonamide drug used as an effective antibiotic. In the present work, using crystal engineering approach two novel cocrystals of SG were synthesized (SG-TBA and SG-PT) with thiobarbutaric acid (TBA) and 1,10-phenanthroline (PT), characterized by solid state techniques viz., powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and the crystal structures were determined by single crystal X-ray diffraction studies. A comparative antibacterial activity and hemolytic potential was done on SG drug, coformers and their cocrystals. The tested cocrystals formulations showed almost two fold higher antibacterial activity against the tested strains of bacteria Gram-positive bacteria (S. mutans and E. faecalis) and Gram-negative bacteria (E. coli, K. pneumonia and E. clocae) over SG alone and their coformers. Cocrystal SG-TBA showed better antibacterial activity and reduced hemolysis, thereby, reduced cytotoxicity than SG-PT.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Composição de Medicamentos/métodos , Hemólise/efeitos dos fármacos , Sulfaguanidina/farmacologia , Antibacterianos/química , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Cristalização/métodos , Cristalografia por Raios X/métodos , Voluntários Saudáveis , Humanos , Testes de Sensibilidade Microbiana/métodos , Conformação Molecular , Fenantrolinas/química , Fenantrolinas/farmacologia , Difração de Pó , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Sulfaguanidina/química , Tiobarbitúricos/química , Tiobarbitúricos/farmacologiaRESUMO
Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, is the causative agent of Kaposi sarcoma; this malignant angiosarcoma is usually treated with conventional antitumor agents that can control disease evolution, but do not clear the latent KSHV episome that binds to cellular DNA. Some commercial antibacterial sulfonamides were tested for the ability to suppress latent KSHV. Quantitative PCR (qPCR) and cytofluorometry assays were used for detecting both viral DNA and the latency factor LANA (latency-associated nuclear antigen) in BC3 cells, respectively. The capacity of sulfonamides to impair MDM2-p53 complex formation was detected by an enzyme-linked immunosorbent assay method. The analysis of variance was performed according to one-way analysis of variance with Fisher as a post hoc test. Here we show that sulfonamide antibiotics are able to suppress the KSHV latent state in permanently infected BC3 lymphoma cells and interfere with the formation of the MDM2-p53 complex that KSHV seemingly needs to support latency and to trigger tumor cell transformation. These findings detected a new molecular target for the activity of sulfonamides and offer a new potential perspective for treating KSHV-induced lymphoproliferative diseases.
Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Herpesvirus Humano 8/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sulfonamidas/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Antibacterianos/efeitos adversos , Antígenos Virais/metabolismo , Antivirais/efeitos adversos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Viral/efeitos dos fármacos , Células Cultivadas , DNA Viral/metabolismo , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/virologia , Humanos , Concentração Inibidora 50 , Proteínas Nucleares/metabolismo , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Sulfaguanidina/efeitos adversos , Sulfaguanidina/farmacologia , Sulfametoxazol/efeitos adversos , Sulfametoxazol/farmacologia , Sulfanilamida , Sulfanilamidas/efeitos adversos , Sulfanilamidas/farmacologia , Sulfatiazol , Sulfatiazóis/efeitos adversos , Sulfatiazóis/farmacologia , Sulfonamidas/efeitos adversos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Novel sulfaguanidines incorporating acridine moiety were synthesized by the reaction of cyclohexane-1,3-dione, sulfaguanidine, and aromatic aldehydes. Synthesis of these compounds was performed in water at room temperature, and their structures were confirmed by using spectral analysis (IR, 1H-NMR, 13C-NMR, and HRMS). Human carbonic anhydrase isoenzymes (hCA I and II) were purified from erythrocyte cells with affinity chromatography. hCA I was purified 83.40-fold with a specific activity, 1060.9 EU mg protein-1, and hCA II was purified 262.32-fold with a specific activity, 3336.8 EU mg protein-1. The inhibitory effects of newly synthesized sulfaguanidines and acetazolamide, (AAZ) as a control compound, on hydratase and esterase activities of these isoenzymes have been studied in vitro. Synthesized compounds have moderate inhibition potentials on hCA I and hCA II isoenzymes. IC50 values of compounds for esterase activity are in the range of 118.4 ± 7.0 µM-257.5 ± 5.2 µM for hCA I and 86.7 ± 3.0 µM-249.4 ± 10.2 µM for hCA II, respectively.
Assuntos
Acridinas/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Sulfaguanidina/farmacologia , Acridinas/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cromatografia de Afinidade , Relação Dose-Resposta a Droga , Eritrócitos/enzimologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Sulfaguanidina/químicaRESUMO
Eight selected sulfonamide drugs were investigated as inhibitors of heat shock protein 90 (Hsp90). The investigation included simulated docking experiments to fit the selected compounds within the binding pocket of Hsp90. The selected molecules were found to readily fit within the ATP-binding pocket of Hsp90 in low-energy poses. The sulfonamides torsemide, sulfathiazole, and sulfadiazine were found to inhibit the ATPase activity of Hsp90 with IC(50) values of 1.0, 2.6, and 1.5 µM, respectively. Our results suggest that these well-established sulfonamides can be good leads for subsequent optimization into potent Hsp90 inhibitors.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Sulfonamidas/farmacologia , Bioensaio , Corantes/química , Simulação por Computador , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/genética , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Reprodutibilidade dos Testes , Corantes de Rosanilina/química , Sulfaguanidina/química , Sulfaguanidina/farmacologia , Sulfonamidas/químicaRESUMO
A series of compounds has been prepared by reaction of dicyandiamide with alkyl/arylsulfonyl halides as well as arylsulfonylisocyanates to locate a lead for obtaining weakly basic thrombin inhibitors with sulfonyldicyandiamide moieties as the S1 anchoring group. The detected lead was sulfanilyl-dicyandiamide (K1 of 3 microM against thrombin, and 15 microM against trypsin), which has been further derivatized at the 4-amino group by incorporating arylsulfonylureido as well as amino acyl/dipeptidyl groups protected at the amino terminal moiety with benzyloxycarbonyl or tosylureido moieties. The best compound obtained (ts-D-Phe-Pro-sulfanilyl-dicyandiamide) showed inhibition constants of 9 nM against thrombin and 1400 nM against trypsin. pKa measurements showed that the new derivatives reported here do indeed possess a reduced basicity, with the pKa of the modified guanidine moieties in the range 7.9-8.3 pKa units. Molecular mechanics calculations showed that the preferred tautomeric form of these compounds is of the type ArSO2N=C(NH2) NH-CN, probably allowing for the formation of favorable interaction between this new anchoring group and the active site amino acid residue Asp 189, critical for substrate/inhibitor binding to this type of serine protease. Thus, the main finding of the present paper is that the sulfonyldicyandiamide group may constitute an interesting alternative for obtaining weakly basic, potent thrombin inhibitors, which bind with less affinity to trypsin.
Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Trombina/antagonistas & inibidores , Química Orgânica/métodos , Dipeptídeos/síntese química , Fibrinolíticos/síntese química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Relação Estrutura-Atividade , Sulfaguanidina/farmacologia , Sulfonamidas/síntese química , Tripsina/efeitos dos fármacosRESUMO
Guanidinobenzoatase (GB) is a cell surface proteolytic enzyme capable of degrading fibronectin, and is associated with tumour cells and cells capable of migration. The location of active GB in sections has been demonstrated with 9-aminoacridine (9-AA), a competitive inhibitor of GB. 3,4-Dichloroisocoumarin (3,4-DCI) and pentamidine isethionate (PI) are inhibitors of trypsin-like enzymes. It has now been demonstrated that 3,4-DCI, PI, and guanidino derivative compounds are significant inhibitors of GB, on the surfaces of lung squamous cell carcinoma cells in frozen sections and free GB in solution. Dexamethasone acetate (DMA) and medroxy-progesterone (MP) did not show any significant inhibition of GB activity. These molecules lack a reactive chloride or guanidino groups and are thought to react at the nuclear level, rather than directly on this cell surface protease. Kinetic studies have shown that 3,4-DCI, PI and guanidino derivatives are reversible competitive inhibitors of GB, as determined in vitro on the purified enzyme. The inhibition resulting with 3,4-DCI was a time-dependent process. It is suggested that these inhibitors interact with GB by binding to its active site, resulting in the formation of enzyme-inhibiter complexes (GB-I). The GB-I complexes can be dissociated with SDS treatment, resulting in the regain of GB activity.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Cumarínicos/farmacologia , Endopeptidases/metabolismo , Guanidinas/farmacologia , Neoplasias Pulmonares/enzimologia , Pentamidina/farmacologia , Inibidores de Proteases/farmacologia , Benzoatos/farmacologia , Ligação Competitiva , Carcinoma de Células Escamosas/enzimologia , Membrana Celular/enzimologia , Dexametasona/farmacologia , Humanos , Isocumarinas , Cinética , Medroxiprogesterona/farmacologia , Microscopia de Fluorescência , Dodecilsulfato de Sódio/farmacologia , Sulfaguanidina/farmacologiaRESUMO
Effects of sulfaguanidine, leucine, or leucine plus isoleucine in a niacin free diet on body weight changes, liver weight, pyridine nucleotide concentrations, and activities of enzymes in mature female or immature Japanese quail were measured. The inclusion of .5% of sulfaguanidine or a high level of leucine in a niacin free diet had no influence during an 8-week period on liver pyridine nucleotide levels and the development of niacin deficiency symptoms in mature female quail. This would suggest that the mature female quail has a low requirement for dietary niacin. Immature quail were also tested to study the effects of amino acid imbalance on the induction of niacin deficiency. Although there was a marked reduction in body weight gains by the administration of leucine or leucine plus isoleucine, these treatments did not appear to accentuate niacin deficiency symptoms in these animals. Also pyridine nucleotide levels and malic enzyme, glyceraldehyde-3-phosphate dehydrogenase, and aldolase activities in liver tissues were not affected by these treatments.
Assuntos
Coturnix/metabolismo , Niacina/deficiência , Codorniz/metabolismo , Animais , Dieta , Feminino , Isoleucina/farmacologia , Leucina/farmacologia , Sulfaguanidina/farmacologiaAssuntos
Infecções por Enterobacteriaceae/epidemiologia , Adolescente , Adulto , Idoso , Antibacterianos/farmacologia , Criança , Pré-Escolar , Infecção Hospitalar/epidemiologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Humanos , Lactente , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sulfaguanidina/farmacologia , TunísiaRESUMO
Several methods for measuring cholesterol absorption in the rat have been compared. After administration of an oral dose of labeled cholesterol ((14)C or (3)H) and an intravenous dose of colloidal labeled cholesterol ((3)H or (14)C) the ratio of the two labels in plasma or whole blood 48 hr or more after dosing compared closely to the ratio of areas under the respective specific activity-time curves. The area ratio method is independent of a time lag between the appearance of oral and intravenous label in the bloodstream. Both measures of cholesterol absorption agree fairly well with a method based on measuring the unabsorbed dietary cholesterol in a pooled fecal sample. The plasma isotope ratio method gave more reproducible results than the fecal collection method when the measurement was repeated in the same animals 5 days after the first measurement. Cholesterol absorption was overestimated by the use of Tween 20-solubilized labeled cholesterol for the intravenous dose. The plasma disappearance curves of injected labeled colloidal cholesterol and cholesterol-labeled chylomicrons infused intravenously over a 3.5-hr period in the same animal coincided within experimental error from the first day until 75 days after injection. The plasma isotope ratio method for cholesterol absorption gave the same results in rats practicing coprophagy as in those in which this practice was prevented. The addition of sulfaguanidine to the diet lowered cholesterol absorption as measured by the plasma isotope ratio to the same degree as that measured by the fecal collection method.